RARE DISEASE
Chordoma
Chordoma
Chordoma
Synonyms: Notochordal sarcoma
Synonyms: Notochordal sarcoma
Synonyms: Notochordal sarcoma
Drug discovery
3
drugs
With orphan designations
Overview
Chordoma is a rare malignant tumor arising from notochord remnants, typically occurring in the skull base, spine, or sacrum. It is locally aggressive, often recurs despite treatment, and can metastasize. Diagnosis involves imaging and histopathology, with management requiring multidisciplinary care. Current research focuses on molecular targets (e.g., brachyury) and immunotherapy [1][3][9][18].
Burden
Five-year survival: 50–65% (improves to 65–70% with complete resection) [14][16].
High recurrence (~50%) and metastasis rates (30–40%), often impacting neurologic function and quality of life [4][16][19].
Requires long-term surveillance and multidisciplinary care due to chronic morbidity [4][9][19].
Therapies
Surgery: En bloc resection with negative margins is preferred, though challenging due to proximity to critical structures [8][13].
Radiation: High-dose proton beam or carbon ion therapy improves local control post-surgery [13][14].
Systemic therapy: Tyrosine kinase inhibitors (e.g., imatinib, erlotinib) for advanced/metastatic disease; clinical trials exploring brachyury-targeted vaccines [3][18].
Categories: rare bone diseases, rare endocrine diseases, rare genetic diseases, rare neoplastic diseases
Research Papers
2,045 drug discovery papers about Chordoma, with 4 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,045 drug discovery papers about Chordoma, with 4 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-23 | New Progress in Pathological Classification and Treatment of Intracranial Chordoma.
Chordoma is a rare malignant bone tumor with an annual incidence of approximately 0.08 per 100,000 individuals according to the Surveillance, Epidemiology, and End Results (SEER) database, and intracranial chordoma accounts for approximately one-third of all chordoma cases. Its rarity has limited understanding of the disease, particularly of uncommon pathological subtypes, and no universal consensus has been established regarding pathological classification and optimal treatment strategies. Intracranial chordoma is also characterized by difficulty in achieving gross total resection, resistance to conventional radiotherapy and chemotherapy, and a high recurrence rate, which complicate clinical management. This narrative review synthesizes clinical studies and translational research addressing the pathological classification and treatment of intracranial chordoma, with emphasis on surgical approaches, radiotherapy, and targeted therapies. More detailed characterization of pathological subtypes, together with developments in neuroendoscopic surgery, proton beam therapy, carbon ion radiotherapy, and molecularly targeted treatment, has expanded the available approaches to disease classification and management. Evaluation of these developments provides an updated overview of current strategies and remaining challenges in the diagnosis and treatment of intracranial chordoma.
2026-09-11 | Anti‑cancer effects of the circadian clock modulating compound SR9009 in chordoma cell lines.
Originating from notochord remains, chordoma is a rare, chronic, low-grade axial skeletal cancer that is characterized by metastasis and adjacent tissue invasion, as well as a high risk of treatment resistance. Surgical intervention is the most common method used for treatment followed by radiotherapy to avoid the relapse of the tumor. Targeting the proteins involved in tumor-associated pathways is crucial since alternative drugs are required for the cure. The nuclear receptor REV-ERBα, a member of the circadian rhythm family, has elevated expression levels, which function as a tumor suppressor. SR9009 is a pyrrole-derived specific agonist that target REV-ERBα negatively regulates autophagy in cancer and induce apoptosis in a caspase-dependent manner and shown antitumor activity in several cancer models. Chordoma cells were treated with SR9009, and functional assays including colony formation, viability, and migration were tested. In addition, molecular docking analyses were performed to predict the interaction of SR9009 with proteins involved in migration, colony formation, proliferation were targeted. SR9009 reduced viability of chordoma cells in a concentration-dependent manner while sparing HNPCs, and 30 µM was selected as an effective concentration for subsequent experiments. At this concentration, SR9009 markedly inhibited chordoma cell migration and strongly suppressed colony formation in both CH22 and MUG-Chor1 cells. Molecular docking predicted high-affinity binding of SR9009 to PI3K, Akt1, Wnt3, β-catenin, and Nanog, suggesting potential interference with signaling networks implicated in chordoma cell proliferation and survival. Our findings indicate that SR9009 exerts robust anti-cancer effects in chordoma cell lines and highlight SR9009 as a promising candidate for further preclinical evaluation in chordoma. The involvement of circadian clock-related and associated signaling pathways in these effects remains putative and warrants mechanistic validation in future studies.
2026-09-08 | Reconstitution of the Fovea Through Foveation After Ifosfamide-Induced Foveolysis.
To describe a case of acute, severe bilateral foveolysis following systemic ifosfamide therapy and the subsequent anatomical and functional recovery after discontinuation of the drug and administration of metabolic therapy targeting mitochondrial dysfunction. The patient had a comprehensive ophthalmological examination including high resolution optical coherence tomography. After cessation of ifosfamide, she was treated with nicotinamide adenine dinucleotide 850 mg, alpha lipoic acid 600 mg, and coenzyme Q10 100 mg daily. A 34-year-old woman receiving ifosfamide for an inoperable skull-base chordoma developed rapid bilateral 20/60 visual acuity. Optical coherence tomography revealed complete dissolution of the central fovea in each eye with accumulation of necrotic debris centrally. Given the known pathway of ifosfamide neurotoxicity, mitochondrial complex I inhibition with depletion of nicotinamide adenine dinucleotide (NAD), the patient received high-dose oral NAD, coenzyme Q10, and alpha-lipoic acid. Over the next several weeks, both eyes showed symmetrical reconstitution of the fovea with centripetal migration of the outer nuclear layer and eventual restoration of outer retinal architecture. By 12 weeks, foveal structure was normal and visual acuity improved to 20/25 and 20/20. Systemic ifosfamide was associated with an acute symmetrical dissolution of the central fovea, termed foveolysis. Although spontaneous improvement after drug withdrawal cannot be excluded, the rapid and near-complete recovery after metabolic therapy supports a mechanistic link between ifosfamide-induced mitochondrial dysfunction, NAD depletion, and reversible foveal injury. The foveal architecture was restored through the defined sequence of foveation, demonstrating the capacity of the adult fovea for organized structural reconstitution.
2026-09-01 | Ultrastructural pathological features and clinical significance of recurrent chordoma
Chordoma is a low-grade malignant osseous neoplasm characterized by an exceedingly high postoperative recurrence rate. Conventional histopathological assessment cannot identify early subcellular alterations that drive tumor recurrence, and the ultrastructural mechanisms mediating chordoma recurrence and malignant progression remain poorly delineated. This study was designed to characterise the distinct subcellular pathological features of recurrent chordoma and evaluate their clinical value in prognostic assessment and risk stratification. 50 surgically resected recurrent chordoma specimens were included as the recurrent cohort, with 50 contemporaneously collected primary chordoma specimens serving as the primary control cohort. Among these, 16 pairs consisted of matched TEM specimens from the same patient's primary and recurrent chordomas, while the remaining 34 pairs comprised non-matched primary and recurrent chordomas from different patients.; Transmission electron microscopy (TEM) was employed to systematically compare ultrastructural differences across cytoplasmic vacuolar patterns, organellar architecture, intercellular junctional complexes, nuclear morphology, and stromal microvascular ultrastructure, and the prevalence of each ultrastructural abnormality was analysed statistically. Compared with primary chordoma, recurrent lesions displayed extensive and progressive subcellular pathological remodelling, including atypical cytoplasmic vacuolation with giant cystic fusion, diffuse mitochondrial injury and rough endoplasmic reticulum degranulation, widespread disintegration of mitochondria-associated endoplasmic reticulum membrane (MAM) complexes, marked nuclear atypia, loss of intercellular desmosomal junctions, activation of invasive invadopodia, and stromal microvascular dysplasia. The prevalence of all these ultrastructural aberrations was significantly higher in the recurrent cohort than in the primary control cohort (all P < 0.001), and the severity of ultrastructural damage was positively correlated with the frequency of prior tumor recurrence. In this cross-sectional series, recurrent chordoma presents characteristic progressive ultrastructural lesions, in which organellar remodelling, loss of intercellular junctions, stromal microvascular abnormalities and nuclear atypia co-segregate with recurrent disease. These findings describe a subcellular morphological correlate of recurrence; because the present cohort was cross-sectional and did not correlate ultrastructural scores with survival, the value of TEM for recurrence-risk prediction, malignant grading or individualised treatment remains a hypothesis to be tested prospectively.
2026-08-28 | Spinal laser interstitial thermal therapy for treatment of chordoma: single-center experience and literature review.
Chordomas are rare, locally aggressive tumors for which effective salvage options are limited once maximal surgical and radiation therapy have been exhausted. Laser interstitial thermal therapy (LITT) is a minimally invasive, MRI-guided ablative technique established for spinal metastases, but published experience with LITT for chordoma remains limited to isolated case reports. We report the largest clinical experience with spinal LITT (sLITT) for chordoma and review the existing literature. We performed a retrospective, IRB-approved single-institution case series of patients with histologically confirmed chordoma treated with sLITT. Clinical, operative, and radiographic data were abstracted, including tumor volumes, ablation parameters, and functional and oncologic outcomes. A systematic PubMed search was performed to identify all prior published reports of LITT for chordoma. Four patients underwent sLITT across five procedures, treating metastatic foci from primary sacral, clival, and cervical chordomas, as well as one primary thoracic lesion. sLITT was used as salvage treatment in four procedures and as primary treatment in one patient to avoid the morbidity of open surgery. Median time from diagnosis to LITT was 19.1 months (range 2.5-168.3), and pre-operative KPS was 90-100 in all patients. A median of four laser fibers and 16 ablations were used per procedure (12-15 W). Median case duration was 352.5 min and length of stay was two days. Postoperative SRS was administered in all but one procedure. All patients experienced volumetric tumor reduction on the earliest post-operative MRI (median 4.2 months, range 2.8-8.8), with a mean reduction of 25.7% ± 12.7%. Median radiographic follow-up was 16.8 months (range 3.5-48.1). No procedure required additional intervention at the LITT-treated site, and no progression at the treated site was identified on available follow-up imaging. Median overall survival from LITT was 23.0 months. One procedure was complicated by transient radiculopathy that resolved with steroids. Literature review identified four previously published case reports of LITT for chordoma, three of which described complete thermal ablation with radiographic response; our series represents the largest reported clinical experience to date. This series represents the largest reported clinical experience with LITT for chordoma and provides proof-of-concept supporting prospective evaluation of this technique. sLITT was technically feasible and well tolerated in this small chordoma cohort, applied both as salvage therapy and, in one patient, as primary local treatment. Because SRS followed all but one procedure, the independent contribution of sLITT to the radiographic responses observed cannot be determined from these data.
cell therapies
2026-04-20 | Cervical Spine Reconstruction With Vascularized Osteoadipofascial Fibular Flap and Periosteum Extension After Chordoma Resection and Adjuvant Proton Therapy: A Case Report.
Cervical spine reconstruction is essential following en bloc tumor resections, particularly in defects exceeding four centimeters. Traditional mechanical solutions or non-vascularized grafts are often suboptimal, with complications such as non-union, infections, and instability. The vascularized osteoadipofascial fibular flap offers a durable alternative with structural and biological benefits. We present the case of a 55-year-old woman with an 8-month history of cervicobrachialgia and left upper limb paresis. Imaging revealed a 7-cm lesion spanning C4-T1 with foraminal infiltration, and histopathology confirmed a chordoma. A two-stage surgery was performed: posterior stabilization and partial tumor resection, followed by anterior corpectomies (C5, C6, C7) and reconstruction with a vascularized fibular flap. The flap was anastomosed to the superior thyroid vessels, and its adipofascial component isolated the esophagus from the anterior cervical plate. Postoperative proton therapy was administered. Postoperative recovery was uneventful, with a 10-day hospital stay. At 24 months, the patient showed no recurrence, complete symptom resolution, and stable osteosynthesis with evidence of bone callus formation at graft-vertebra junctions. This case suggests that vascularized fibular reconstruction may provide reliable structural support and biological integration in complex cervical oncologic defects.
2026-03-06 | Wrist Arthrodesis with Scaphoid Autograft for Treatment of Extra-Axial Chordoma
Abstract Extra-axial chordoma (EAC) is a very rare, malignant tumor with metastatic potential that arises in the extra-axial skeleton and soft tissues. We report the case of a 51-year-old right-handed male with EAC of the left capitate. He underwent capitate resection and wrist arthrodesis utilizing scaphoid autograft with the treatment goal of minimizing risk of tumor recurrence and metastasis while maximizing hand and wrist function. His radiographic outcome demonstrated union of his arthrodesis site. However, 7 months postoperatively, he started experiencing increased hand and wrist pain and was found to have early tumor reoccurrence. Few cases of EAC have been reported in the literature. EAC is typically treated with resection alone, although there is a limited role for chemotherapy and radiation in the setting of locally reoccurring or metastatic disease. Functional outcomes of the affected extremity and survival outcomes vary widely. This is the first report in the literature of EAC of a single carpal bone and describes an innovative technique for definitive surgical treatment of this rare tumor. Utilization of scaphoid autograft for wrist arthrodesis in the setting of capitate resection allows the use of autograft in a wrist arthrodesis without the additional morbidity of iliac crest bone grafting. This case also demonstrates the importance of appropriate diagnosis and oncologic technique at the index surgery.
2025-12-26 | Targeting the tumor immune microenvironment in chordoma: From mechanistic insights to therapeutic breakthroughs.
Chordoma is a rare, malignant bone tumor characterized by high local recurrence rates and resistance to conventional therapies. While immunotherapy has emerged as a promising avenue, its clinical efficacy is currently limited by a profoundly immunosuppressive tumor immune microenvironment (TIME). This review systematically elucidates the molecular and cellular mechanisms underpinning the distinct "immune-excluded" phenotype in chordoma. In this architecture, effector T cells are physically sequestered from tumor cells by dense stromal septa, which paradoxically function as hubs for myeloid-T cell interaction rather than simple physical barriers. This immune-excluded architecture is orchestrated through multiple interconnected mechanisms. Cancer-associated fibroblasts (CAFs), particularly inflammatory and stress-related subpopulations, construct physical barriers via extracellular matrix remodeling while secreting chemokines (such as CXCL12) that spatially anchor T cells within the stroma. The transforming growth factor-beta (TGF-β) pathway reinforces this exclusion by suppressing cytotoxic T cell function and impeding tumor infiltration. Intrinsically, chordoma exhibits a low tumor mutational burden and specific genomic alterations-most notably the loss of CDKN2A/B and PBRM1. Furthermore, despite high chromosomal instability (CIN), co-occurring deletions of 9p and 10q silence the cGAS-STING pathway, thereby impairing antigen presentation and immune cell recruitment. The microenvironment is further dominated by M2-polarized tumor-associated macrophages and regulatory T cells, driving effector T cell exhaustion. Clinical evidence indicates that immune checkpoint inhibitors and targeted vaccines yield limited efficacy as monotherapies, highlighting the immune-excluded phenotype and the scarcity of PD-L1 protein expression as primary obstacles. Future therapeutic breakthroughs will require rational combination strategies, including CAR-T cell therapies targeting novel antigens (e.g., B7-H3) and adoptive T-cell transfer, designed to dismantle stromal barriers and exploit systemic anti-tumor immunity.
2025-10-27 | Cervical chordoma en bloc resection and staged suprascapular nerve transfer reanimation: illustrative case.
Cervical chordomas offer unique challenges to en bloc resection given their proximity to complex anatomy. Achieving tumor-free margins often requires extensive reconstruction that can limit radiotherapy dosing and postoperative visualization due to metal artifact, compounded by the unavailability of cervical carbon fiber implants. Multidisciplinary multistage approaches focused on oncological resections and maintenance of neurological function can improve quality and quantity of life. The authors present such an approach to the resection of a cervical chordoma with nerve transfer for shoulder reanimation. A 26-year-old woman with cervical myelopathy and upper extremity and trunk weakness and numbness was found to have a cervical chordoma spanning C4-7 with severe spinal cord compression. Following balloon test occlusion, resection included (1) posterior decompression of the spinal cord and dorsal dissection of the tumor with spine stabilization, (2) an anterior approach for a vertebral artery-to-superior thyroid artery bypass and ventral dissection, and (3) anterior en bloc resection. Three months postoperatively, a spinal accessory-to-suprascapular nerve transfer was performed. After 6 months, the patient had improved arm function and ambulation. A multidisciplinary, staged en bloc resection using carbon fiber-reinforced polymer instrumentation is safe in the cervical spine, with nerve transfers offering improved quality of life. https://thejns.org/doi/10.3171/CASE25367.
2025-10-22 | Abstract C036: Comprehensive chordoma cell systems: Profiling brachyury-independent persistence and stem-like transitions in novel patient-derived sacral culture models
Abstract Chordomas, rare and malignant tumors of the spine, are notable for their highly morbid and slow-growing nature accompanied by high recurrence rates despite en bloc resection. Once maximal safe radiation dosing and surgical options are exhausted, no proven clinical treatments remain. At present, significant transcriptomic divergence persists between tumor subtypes, with molecular profiles remaining poorly studied. Given its rarity and heterogeneity, limited preclinical models comprehensively capture the genetic and phenotypic landscape of its tumorigenesis. To address the need for reliable model systems, we established two novel patient-derived chordoma cell lines from primary sacral tumor samples collected intraoperatively from patients at a single institution. Molecular characterization was performed using quantitative PCR to assess the expression of brachyury, a key chordoma marker, alongside stemness and EMT-related markers. In particular, CHI3L1, SPP1, and PTEN–genes identified as differentially expressed through ongoing NanoString and RNA-seq analyses. Both retrospective chart and systematic literature reviews were conducted to contextualize transcriptomic results. Search terms in PubMed included ("chordoma" AND ("brachyury" OR "chi3l1" OR "spp1" OR "pten")) in all literature published between 2005 and 2025, yielding 264 articles. We report successful establishment of two chordoma cell lines from pathologically confirmed sacral tumors. Genetic profiling across multiple passages bears marked resemblance to existing commercial in vitro primary models and retains chordoma-like morphology in culture. Our findings reveal that brachyury varies significantly throughout the culturing period, yet cell doubling endures, suggesting an enrichment of stem cell populations over time. Such variability is crucial for informing optimal passage selection for future characterization studies and implies influence between brachyury expression and stem cell populations, potentially underlying tumor recurrence dynamics. Initial findings indicate that these novel patient-derived cell lines represent a valuable tool for exploring chordoma biology and stem-like transition. While brachyury expression is often absent at tumor margins in histologic sections, recurrence still occurs, suggesting that chordoma cells may persist through stem-like states despite losing brachyury expression. Our data support the idea that chordoma cells can undergo a stem-like transition, contributing to recurrence even in the absence of brachyury. Clinically, this variability may underscore why recurrent or dedifferentiated chordomas exhibit distinct brachyury expression. As our institutional biobanking efforts continue to expand, we are establishing additional cell lines from diverse chordoma subtypes–including recurrent and metastatic tumors–to better encapsulate the disease spectrum and further elucidate mechanisms underlying tumor recurrence. Citation Format: Beatrice Campilan, Christian Godinez, Margot Martinez-Moreno, Ziya Gokaslan, Patricia Sullivan. Comprehensive chordoma cell systems: Profiling brachyury-independent persistence and stem-like transitions in novel patient-derived sacral culture models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C036.
oligonucleotides
2026-08-29 | Restoration of m6A-Modified circPSMB1 Suppresses Chordoma Progression and Enables Local Nanotherapeutic Intervention.
Chordoma is a rare malignant bone tumor characterized by aggressive local invasion and high recurrence, yet its molecular regulatory mechanisms remain poorly understood. Circular RNAs (circRNAs) have emerged as important regulators of gene expression, but how circRNA epigenetic modifications contribute to oncogenic signaling is largely unknown. Here, we identify circPSMB1 as a significantly downregulated circRNA in chordoma tissues through high-throughput circRNA sequencing. Functionally, circPSMB1 suppresses chordoma cell proliferation, migration, and invasion in vitro and inhibits tumor growth in vivo. Mechanistically, METTL3-dependent m6A modification facilitates the association of circPSMB1 with the m6A reader HNRNPA2B1. CircPSMB1 competitively reduces the association of HNRNPA2B1 with c-MYC mRNA, thereby decreasing c-MYC protein expression without altering c-MYC transcript abundance. Beyond mechanistic insight, we develop an injectable circPSMB1-loaded HMnO2-based nanohydrogel that enables sustained circRNA delivery and tumor microenvironment-responsive therapy, effectively suppressing chordoma progression in vivo.
2024-11-04 | Current understanding of brachyury in chordoma.
Chordomas are rare malignant tumors that pose significant challenges in terms of effective treatment options. Surgical resection remains the only established approach that has proven useful in the treatment of chordoma. However, recent evidence has shed light on the role of brachyury, also known as the T-gene and TBXT, as both a diagnostic marker and a potential therapeutic target in chordoma. Considering these developments, this review aims to provide a comprehensive summary of the current knowledge and understanding of brachyury in chordomas.
2024-07-23 | Linc01116 Silencing Inhibits the Proliferation and Invasion, Promotes Apoptosis of Chordoma Cells via Regulating the Expression of Mir-9-5p/PKG1.
Long intergenic non-protein coding RNA 1116 (LINC01116) plays a carcinogenic role in a variety of cancers. The study aims to investigate the roles of LINC01116 and hsa-miR-9-5p (miR-9-5p) and fathom their interaction in chordoma. The predicted binding sites between miR-9-5p with LINC01116 and phosphoglycerate kinase 1 (PGK1) by starBase were confirmed through dual-luciferase reporter assay. The behaviors of chordoma cells undergoing transfection with siLINC01116 or miR-9-5p inhibitor were determined by Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and flow cytometry assays. The glucose consumption, lactate production, and adenosine triphosphate (ATP) production of chordoma cells were examined with specific kits. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to determine relevant gene expressions in chordoma cells. Silencing of LINC01116 facilitated the apoptosis and expressions of Bcl-2- associated X (Bax), cleaved caspase-3 (C caspase-3) and miR-9-5p while repressing the cell cycle, viability, proliferation, invasion, glucose consumption, lactate production, ATP production, and expressions of PGK1 and Bcl-2. Meanwhile, LINC01116 sponged miR-9-5p, which could target PGK1. Moreover, the miR-9-5p inhibitor acted contrarily and reversed the role of siLINC01116 in chordoma cells. Besides, LINC01116 downregulation facilitated apoptosis and attenuated the proliferation and invasion of chordoma cells as well as PGK1 expression by upregulating miR-9-5p expression. LINC01116/miR-9-5p plays a regulatory role in the progression of chordoma cells and is a potential biomarker for chordoma.
2024-05-01 | Unraveling molecular advancements in chordoma tumorigenesis and treatment response: a review of scientific discoveries and clinical implications.
Chordomas are tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. In adults, the most common location is the sacrum, followed by the clivus and then mobile spine, while in children a clival origin is most common. Most chordomas are slow growing. Clinical presentation of chordomas tend to occur late, with local invasion and large size often complicating surgical intervention. Radiation therapy with protons has been proven to be an effective adjuvant therapy. Unfortunately, few adjuvant systemic treatments have demonstrated significant effectiveness, and chordomas tend to recur despite intensive multimodal care. However, insight into the molecular underpinnings of chordomas may guide novel therapeutic approaches including selection for immune and molecular therapies, individualized prognostication of outcomes, and real-time noninvasive assessment of disease burden and evolution. At the genomic level, elevated levels of brachyury stemming from duplications and mutations resulting in altered transcriptional regulation may introduce druggable targets for new surgical adjuncts. Transcriptome and epigenome profiling have revealed promoter- and enhancer-dependent mechanisms of protein regulation, which may influence therapeutic response and long-term disease history. Continued scientific and clinical advancements may offer further opportunities for treatment of chordomas. Single-cell transcriptome profiling has further provided insight into the heterogeneous molecular pathways contributing to chordoma propagation. New technologies such as spatial transcriptomics and emerging biochemical analytes such as cell-free DNA have further augmented the surgeon-clinician's armamentarium by facilitating detailed characterization of intra- and intertumoral biology while also demonstrating promise for point-of-care tumor quantitation and assessment. Recent and ongoing clinical trials highlight accelerating interest to translate laboratory breakthroughs in chordoma biology and immunology into clinical care. In this review, the authors dissect the landmark studies exploring the molecular pathogenesis of chordoma. Incorporating this into an outline of ongoing clinical trials and discussion of emerging technologies, the authors aimed to summarize recent advancements in understanding chordoma pathogenesis and how neurosurgical care of chordomas may be augmented by improvements in adjunctive treatments.
2024-04-25 | N6-methyladenosine-modified circTEAD1 stabilizes Yap1 mRNA to promote chordoma tumorigenesis.
Chordoma, a rare bone tumour with aggressive local invasion and high recurrence rate with limited understanding of its molecular mechanisms. Circular RNAs (circRNAs) have been extensively implicated in tumorigenesis, yet their involvement in chordoma remains largely unexplored. N6-methyladenosine (m6A) modification holds a crucial function in regulating protein translation, RNA degradation and transcription. Initially, screening and validation of circTEAD1 in chordoma were conducted by high-throughput sequencing. Subsequently, sh-circTEAD1 and an overexpression plasmid were constructed. Colony formation assays, cell counting kit-8, Transwell and wound healing assays were utilized to validate the function of circTEAD1 in vitro. RNA pull-down assays identified the binding proteins of circTEAD1, which underwent verification through RNA immunoprecipitation (RIP). Methylated RIP assays were conducted to detect the m6A binding sites. Following this, luciferase assay, RT-qPCR, RIP and Western blotting analyses were conducted, revealing that Yap1 was the direct target of circTEAD1. Afterwards, the same methods were utilized for the validation of the function of Yap1 in chordoma in vitro. Finally, the regulatory relationship between circTEAD1 and Yap1 in chordoma was verified by an in vivo tumour formation assay. CircTEAD1 was identified as an upregulated circRNA in chordoma specimens, with heightened circTEAD1 expression emerging as a prognostic indicator. In vitro experiments convincingly demonstrated that circTEAD1 significantly promoted chordoma cell invasion, migration and aggressiveness. Furthermore, the analysis revealed that methyltransferase-like 3-mediated m6A modification facilitated the cytoplasmic export of circTEAD1. The circTEAD1/IGF2BP3/Yap1 mRNA RNA-protein ternary complex not only bolstered the stability of Yap1 mRNA but also exerted a pivotal role in driving chordoma tumorigenesis. In this study, the role of m6A-modified circTEAD1 in chordoma was identified. The findings offer novel insights into the potential molecular targets for chordoma therapy, shedding light on the intricate interplay between circRNAs, m6A modification and Yap1 mRNA in chordoma pathogenesis.
antibodies
2026-07-21 | What are the current treatment options for sacral chordoma?
The primary treatment options for sacral chordoma include surgical resection and postoperative proton beam therapy, which improves local control and survival rates. Emerging targeted and immunotherapeutic approaches hold promise but require further validation.
2026-07-15 | Clinical challenges and therapeutic strategies in chordoma: Translating molecular insights into patient care.
Chordoma is a rare, locally aggressive bone tumor originating from notochordal remnants. Despite advances in surgical and radiation-based approaches, effective systemic therapies remain limited, and recurrence rates are high. This chapter explores the current clinical landscape of chordoma management with an emphasis on the integration of molecular insights into therapeutic decision-making. In particular, we highlight emerging strategies targeting brachyury and receptor tyrosine kinases, as well as promising immunotherapies, including PD-1/PD-L1 immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapies. We further underscore the pivotal role of institutional and multi-center biobanking efforts in enabling biomarker discovery, enhancing diagnostic accuracy, and facilitating patient prognostication. Alongside these efforts, clinical trial development and public health considerations provide a comprehensive overview of the present scope and future potential of precision medicine in chordoma. By emphasizing the translational potential of molecular profiling together with advances in the clinical, institutional, and public health infrastructures that support its implementation, this chapter outlines a pathway toward more personalized and effective care for patients with chordoma.
2026-07-14 | Progression-free survival 3 of 22 months achieved through third-line therapy with adebrelimab in patient with recurrent chordoma: a case report.
Lower cervical spine origin chordomas are exceedingly uncommon tumors, and treatment may present difficulties in particular areas of the cervical spine owing to its specific anatomic architecture and the interrelationship with the vertebral arteries, cervical nerve roots, and spinal cord. Due to its rarity, the mechanisms underlying tumorigenesis and optimal therapeutic strategies for recurrence remain poorly understood. A 57-year-old Chinese female with large vertebral and paravertebral lesions from C6 to T1 underwent surgically resection on Aug 13, 2018. The pathological diagnosis in the post-operative report was chordoma close to the resection margin. No adjuvant treatment was administered after surgery. The first recurrence occurred three years postoperatively and was associated with a high tumor burden. At that time, paraplegia (lower limb paralysis and involuntary urinary and fecal control disorders) occurred. This patient received apatinib tablets, a vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI), as first-line treatment. Second-line administration of a VEGFR-TKI anlotinib capsules and programmed death-1 (PD-1) inhibitor toripalimab injection; third-line administration of the programmed death-ligand 1 (PD-L1) inhibitor adebrelimab injection, resulted in a progression-free survival 3 of 22 months and an overall survival of 7.5 years. To the best of our knowledge, this represents the first reported case of adebrelimab use in immunotherapy for chordoma.
2026-06-01 | Phase I/II, open-label, multicenter study of durvalumab in combination with tremelimumab in pediatric patients with advanced solid tumors.
We conducted a phase I/II study to evaluate durvalumab (D; anti-PD-L1) in combination with tremelimumab (T; anti-cytotoxic T-lymphocyte antigen 4) in pediatric patients with relapsed/refractory solid tumors. The dose-finding phase (phase I) assessed the safety and pharmacokinetics of D+T at two dose levels to determine the recommended phase II dose (RP2D). The primary endpoint for the dose-expansion phase (phase II) was antitumor activity (by Response Evaluation Criteria in Solid Tumors v1.1) at the RP2D. Assessment of circulating cells reflecting immune cell activation was a secondary endpoint. Based on safety and pharmacokinetic data in the dose-finding phase (n = 29), the adult-equivalent RP2D was determined as D (30 mg/kg) + T (1 mg/kg). In the dose-expansion phase, 21 patients (sarcoma, n = 11; solid tumors, n = 10) were treated at the RP2D. Of patients with sarcoma, none achieved an objective response and one had stable disease ≥7 weeks. Of the patients with solid tumors, one (chordoma) had a confirmed partial response (10.8 months duration) and one (renal cell carcinoma) had stable disease ≥7 weeks. Treatment-related adverse events occurred in 76% of patients (19% as grade 3 or 4). No adverse events leading to death were reported. Across both phases treatment with D+T resulted in an increase in CD4+Ki67+ T cells. D (30 mg/kg) + T (1 mg/kg) had limited antitumor activity in this pediatric population; however, the safety profile was manageable and consistent with the known safety profile in adult patients, with no new safety concerns identified. ClinicalTrials.gov, identifier NCT03837899; EudraCT, identifier 2018-003118-42.
2026-05-27 | A phase 2 trial of cetuximab for patients with locally advanced/metastatic chordoma.
11527 Background: Unresectable/metastatic chordoma is a rare notochordal malignancy with no approved systemic treatments. EGFR is widely expressed on chordomas. Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that inhibits EGFR signaling. In vivo testing of cetuximab has demonstrated growth inhibition and regression of chordoma. An investigator-initiated, single center, phase II study (NCT05041127) was developed to evaluate the efficacy of cetuximab for patients (pts) with advanced/metastatic chordoma. Methods: Eligible pts were ≥18 years of age, had adequate organ function, and had an ECOG performance status (PS) of ≤2. Any prior line of therapy was allowed except EGFR inhibitors. A minimum of 10 pts and maximum of 29 pts were to be enrolled onto the trial based on Simon's two-stage optimal design (H 0 RR 5% vs H 1 RR 20%; one-sided α=0.05; power=80%). Pts received cetuximab 500 mg/m 2 IV Q2 weeks until disease progression or unacceptable toxicity. The primary end point was response rate (RR) according to RECIST 1.1. Secondary objectives included safety/tolerability and survival metrics. Efficacy was assessed in the modified intention-to-treat (mITT) population (≥1 dose; ≥1 post-baseline scan). Exploratory objectives included analysis of the EGFR pathway at 2 time points from research-related biopsies. Pt reported outcomes (PROs) were assessed with MDASI (general and spine) questionnaires at several time points on study. Results: From May 2022 to Dec 2025, 29 pts enrolled. 4 were excluded from the efficacy analysis (2 withdrawal, 1 cetuximab allergy, 1 has not completed the 1 st imaging assessment). Median age was 58 years (range 21-76), 15 (58%) were men, and 24 (92%) had ECOG PS of 0 or 1. The most common primary site was skull base (46%). Tumor was classified as locally recurrent in 8 pts (31%) and metastatic in 18 pts (69%). One median line of prior systemic therapy was noted (range, 0-6). At a median follow up of 28.7 months, 12 pts (48%) had radiographic cytoreduction (any tumor reduction [ATR]), but only 2 pts (8%) had a partial response (PR). Neither PR was associated with an EGFR gene alteration. Stable disease (SD) was noted in 23 pts (92%). Preliminary median PFS and median OS was 9.9 months (95% CI, 6.3 to 13.4) and 38.8 months (95% CI, 18.6 to NR), respectively. Significantly longer PFS was observed in SD-ATR (log-rank p=0.038), with median of 14.2 months in SD-ATR versus 9.6 months in SD without tumor reduction. 7/26 pts (27%) experienced a grade 3 cetuximab-related adverse event (AE), the most common being rash in 4 pts (15%). No grade 5 AE related to cetuximab was reported. Dose reduction occurred in 2 pts (8%). 4 pts (15%) discontinued the study due to toxicity. 4 pts remain on study. Conclusions: Although the primary end point has not been reached, 2 PRs are noted, and pts with SD-ATR have a longer PFS. Translational and PRO analysis are ongoing to better define biological predictors of cetuximab activity in chordoma. Clinical trial information: NCT05041127 .
other
2026-09-24 | ABM/P-15-enhanced bone graft in oncologic cervical spine reconstruction: two case reports and narrative discussion.
Bone consolidation in musculoskeletal oncology is challenging after pathological fracture, radiotherapy, repeated surgery, extensive reconstruction, or compromised vascularity. Successful healing also requires segmental mechanical stability. Anorganic bone mineral/P-15 (ABM/P-15) bone grafts provide an osteoconductive mineral scaffold with a synthetic collagen-mimetic peptide surface, but their use in oncologic cervical spine reconstruction remains sparsely described. At the McGill University Health Centre, a tertiary referral center, we report two complex cervical oncologic reconstructions in which ABM/P-15 was used as one component of multicomponent fusion constructs. A young adult male with metastatic solitary fibrous tumor, prior radiotherapy, upper cervical nonunion, and pathologic fracture underwent revision occiput-to-T2 fusion with local autograft and ABM/P-15. A young adult female with recurrent cervical chordoma after prior resection and proton-beam radiotherapy underwent combined anterior and posterior tumor resection, instrumentation, and fibular graft reconstruction augmented with ABM/P-15. In both cases, rigid reconstruction plus adjunctive grafting was followed by CT and radiographic evidence of bridging bone or host-graft incorporation without implant loosening or pseudoarthrosis at approximately 12 months. Standardized Visual Analog Scale (VAS)/Numeric Rating Scale (NRS) and Neck Disability Index (NDI) scores were not collected. These two cases document radiographic fusion after complex oncologic cervical reconstructions in which ABM/P-15 was used as an adjunct. The perceived rationale was to provide an osteoconductive, collagen-mimetic surface in compromised host biology, but these cases do not establish that ABM/P-15 independently caused fusion or improved oncologic safety. The findings should be interpreted as descriptive and hypothesis-generating.
2026-05-13 | Efficacy and Safety of Camrelizumab Plus Apatinib in Patients With Refractory Chordoma: A Phase II Clinical Trial.
Limited efficacy of current treatments for chordoma calls for novel therapeutic options. Combination of immune checkpoint inhibitors and antiangiogenic drugs has altered the landscape of cancer treatment but has rarely been investigated in chordoma. An investigator-initiated, single-center, phase II trial was conducted on camrelizumab (a PD-1 inhibitor, 200 mg once every 2 weeks) plus apatinib (an antiangiogenic drug, 250 mg and 500 mg on alternate days, that is, 250 mg one day, 500 mg the next day, alternating) in patients with refractory chordoma for 4-week cycles. The primary end point was the objective response rate (ORR) per RECIST version 1.1. Secondary end points included ORR per Choi criteria, progression-free survival (PFS), overall survival, the disease control rate, median duration of response (mDoR), safety, and quality of life. The trial is registered with Chictr.org.cn (ChiCTR2100042938). Of the 38 patients initially screened between September 2021 and October 2024, 33 were enrolled. Median follow-up duration was 20.8 months (IQR, 13.35-26.55). ORR was 24.2% (8/33 [95% CI, 11.1 to 42.3]) per RECIST 1.1 and 48.5% (16/33 [95% CI, 30.8 to 66.5]) per Choi criteria. The median PFS was 28.4 months (95% CI, 13.53 to 43.28). The mDoR was not reached per RECIST 1.1 and was 22.2 months (95% CI, 12.5 to not reached) per Choi criteria. CDKN2A copy-number deletion or homozygous deletion was found to associate with worse prognosis. The most common grade 3 or 4 treatment-related adverse events included increased aspartate aminotransferase (13 [39.4%]) and increased alanine aminotransferase (11 [33.3%]). No treatment-related deaths occurred. Combination of camrelizumab and apatinib offered encouraging efficacy with manageable toxicity in chordoma treatment. CDKN2A alterations are associated with worse prognosis and may prove to be a potential biomarker for treatment selection.
2026-03-08 | Oncolytic adenoviral infection of chordoma achieves treatment efficacy associated with immunologic response and tumor microenvironmental alteration.
Chordoma is a midline neoplasm accounting for approximately 20% of primary spinal tumors. Due to chordoma's locally aggressive nature, patients experience high rates of disease progression and have limited treatment options, highlighting an unmet clinical need. This underscores the importance of exploring novel therapeutic strategies. Oncolytic viral (OV) therapy uses genetically modified viruses to selectively replicate in tumor cells, mediate tumor cell lysis, and initiate a pro-inflammatory response within the infected tumor microenvironment (TME). The aim of the study was to evaluate the anti-chordoma effect of the replicating oncolytic adenovirus Delta-24-RGD. The efficacy of Delta-24-RGD was assessed using in vitro approaches, ex vivo bone scaffolds, and in vivo murine models. Additionally, we explored the underlying mechanism of OV cytotoxicity, immunogenic cell death (ICD), brachyury modulation, and reshaping of the TME towards a pro-inflammatory state. Delta-24-RGD achieved viral infectivity, oncolysis, and ICD across multiple human chordoma cell lines and ex vivo bone scaffold models. In vivo murine xenograft models of human CH22 and U-CH1 chordoma treated with Delta-24-RGD resulted in tumor volume reduction, enhanced overall survival, and microenvironmental transcriptional modulation. Analyzing a human chordoma tissue microarray, the immunosuppressive macrophage marker CD163 was associated with shortened recurrence-free survival. Using macrophage/chordoma co-culture, OV infection achieved a reduction in macrophage CD163 expression and a concomitant pro-inflammatory macrophage polarization. The immunosuppressive chordoma TME is associated with clinical outcomes and our data suggests OV infection reverses this deleterious immunosuppressive profile. These studies provide a framework for future clinical implementation among chordoma patients.
2026-02-27 | Methylation and Proteomic Signatures of Radiosensitivity in Chordoma
Introduction: Chordomas are rare, aggressive primary bone malignancies of the skull base and spine that remain therapeutically challenging. Despite radical surgical resection and adjuvant radiotherapy representing the current standard of care, long-term outcomes remain poor, with a 10-year overall survival of ~40% and frequent disease recurrence. Although radiotherapy is a cornerstone of treatment, its clinical benefit is variable, and prior studies have yielded inconsistent evidence regarding its impact on survival. To clarify the molecular determinants of radiotherapy response, we investigated the role of DNA methylation-defined subtypes and complementary proteomic alterations in chordoma. Methodology: We analyzed a multi-institutional cohort of n = 102 patients spanning a 20-year period, comprised of a discovery cohort of our previously published cohort as well as n = 32 newly analyzed samples in our validation cohort. Genome-wide DNA methylation profiling was performed using the Illumina EPIC array Clinical outcomes were assessed in relation to molecular subtype and treatment exposures using Kaplan–Meier analysis and multivariable Cox proportional hazards modeling. In a subset of cases, mass spectrometry–based proteomic profiling was performed to interrogate subtype-associated protein-level changes and to identify pathways potentially underlying treatment sensitivity. Results: Patients classified within the cellular molecular subtype who received radiotherapy demonstrated significantly improved overall survival (median 17.3 years, p = 0.0208) compared with those harboring the immune-infiltrative subtype (median 6.0 years). Notably, the favorable prognosis of the cellular subtype was largely seen in the absence of radiotherapy, suggesting a subtype-specific enhancement of radiosensitivity. Progression-free survival did not differ significantly between irradiated cellular and immune-infiltrative tumors ( p = 0.65), indicating that improved survival was not attributable solely to delayed recurrence. Proteomic analysis reinforced these findings, identifying distinct protein expression patterns related to DNA damage repair and immune signaling that aligned with methylation-derived subtypes and provided mechanistic support for differential radiotherapy responses. Conclusion: We validate and extend the utility of a DNA methylation–based chordoma classifier, demonstrating that subtype assignment has significant prognostic and predictive implications for radiotherapy benefit. Integration of proteomic profiling further highlights candidate biological mechanisms of radiosensitivity. These results support the incorporation of molecular stratification into clinical decision-making for chordoma and underscore the promise of integrative, multi-omic approaches to guide precision therapy in this rare malignancy. Publication History Article published online: 27 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-11-13 | Comparative Outcomes of Brachyury Vaccine vs. Imatinib in Advanced Chordoma: A Mayo Clinic Experience.
Background/Objectives: Chordoma, a rare slow-growing malignant bone tumor, remains therapeutically challenging due to its invasive nature. We examined institutional outcomes comparing imatinib and brachyury-directed vaccines. Methods: We used data from three sites of our quaternary care academic institution to analyze demographics, time to progression, overall survival, and adverse events in chordoma patients treated with imatinib or enrolled in a brachyury vaccine trial. Results: We included a total of 52 patients (8 in the brachyury vaccine cohort and 44 in the imatinib cohort) in the analysis. As expected, sacrococcygeal location was the most predominant in both cohorts: 62.5% in the brachyury cohort and 45.5% in the imatinib cohort. No demographic differences were present between the cohorts. ECOG was similar in both groups (p = 0.796). The primary outcome, time to progression (TTP), was shorter in the brachyury compared to the imatinib cohort (5.6 vs. 13 months, p = 0.0589), almost reaching statistical significance. Overall survival (OS) was comparable, 211 vs. 212 months for the brachyury and imatinib cohorts, respectively (p = 0.277). Although the brachyury vaccine cohort presented a higher incidence of adverse events than the imatinib cohort (75% vs. 31.8%, p = 0.021), the severity was milder. Conclusions: Imatinib showed longer disease control than the brachyury vaccine, though overall survival was similar. Future studies and deeper molecular insights are essential to develop better therapies and improve patient quality of life.
small molecules
2026-09-23 | New Progress in Pathological Classification and Treatment of Intracranial Chordoma.
Chordoma is a rare malignant bone tumor with an annual incidence of approximately 0.08 per 100,000 individuals according to the Surveillance, Epidemiology, and End Results (SEER) database, and intracranial chordoma accounts for approximately one-third of all chordoma cases. Its rarity has limited understanding of the disease, particularly of uncommon pathological subtypes, and no universal consensus has been established regarding pathological classification and optimal treatment strategies. Intracranial chordoma is also characterized by difficulty in achieving gross total resection, resistance to conventional radiotherapy and chemotherapy, and a high recurrence rate, which complicate clinical management. This narrative review synthesizes clinical studies and translational research addressing the pathological classification and treatment of intracranial chordoma, with emphasis on surgical approaches, radiotherapy, and targeted therapies. More detailed characterization of pathological subtypes, together with developments in neuroendoscopic surgery, proton beam therapy, carbon ion radiotherapy, and molecularly targeted treatment, has expanded the available approaches to disease classification and management. Evaluation of these developments provides an updated overview of current strategies and remaining challenges in the diagnosis and treatment of intracranial chordoma.
2026-09-11 | Anti‑cancer effects of the circadian clock modulating compound SR9009 in chordoma cell lines.
Originating from notochord remains, chordoma is a rare, chronic, low-grade axial skeletal cancer that is characterized by metastasis and adjacent tissue invasion, as well as a high risk of treatment resistance. Surgical intervention is the most common method used for treatment followed by radiotherapy to avoid the relapse of the tumor. Targeting the proteins involved in tumor-associated pathways is crucial since alternative drugs are required for the cure. The nuclear receptor REV-ERBα, a member of the circadian rhythm family, has elevated expression levels, which function as a tumor suppressor. SR9009 is a pyrrole-derived specific agonist that target REV-ERBα negatively regulates autophagy in cancer and induce apoptosis in a caspase-dependent manner and shown antitumor activity in several cancer models. Chordoma cells were treated with SR9009, and functional assays including colony formation, viability, and migration were tested. In addition, molecular docking analyses were performed to predict the interaction of SR9009 with proteins involved in migration, colony formation, proliferation were targeted. SR9009 reduced viability of chordoma cells in a concentration-dependent manner while sparing HNPCs, and 30 µM was selected as an effective concentration for subsequent experiments. At this concentration, SR9009 markedly inhibited chordoma cell migration and strongly suppressed colony formation in both CH22 and MUG-Chor1 cells. Molecular docking predicted high-affinity binding of SR9009 to PI3K, Akt1, Wnt3, β-catenin, and Nanog, suggesting potential interference with signaling networks implicated in chordoma cell proliferation and survival. Our findings indicate that SR9009 exerts robust anti-cancer effects in chordoma cell lines and highlight SR9009 as a promising candidate for further preclinical evaluation in chordoma. The involvement of circadian clock-related and associated signaling pathways in these effects remains putative and warrants mechanistic validation in future studies.
2026-09-08 | Reconstitution of the Fovea Through Foveation After Ifosfamide-Induced Foveolysis.
To describe a case of acute, severe bilateral foveolysis following systemic ifosfamide therapy and the subsequent anatomical and functional recovery after discontinuation of the drug and administration of metabolic therapy targeting mitochondrial dysfunction. The patient had a comprehensive ophthalmological examination including high resolution optical coherence tomography. After cessation of ifosfamide, she was treated with nicotinamide adenine dinucleotide 850 mg, alpha lipoic acid 600 mg, and coenzyme Q10 100 mg daily. A 34-year-old woman receiving ifosfamide for an inoperable skull-base chordoma developed rapid bilateral 20/60 visual acuity. Optical coherence tomography revealed complete dissolution of the central fovea in each eye with accumulation of necrotic debris centrally. Given the known pathway of ifosfamide neurotoxicity, mitochondrial complex I inhibition with depletion of nicotinamide adenine dinucleotide (NAD), the patient received high-dose oral NAD, coenzyme Q10, and alpha-lipoic acid. Over the next several weeks, both eyes showed symmetrical reconstitution of the fovea with centripetal migration of the outer nuclear layer and eventual restoration of outer retinal architecture. By 12 weeks, foveal structure was normal and visual acuity improved to 20/25 and 20/20. Systemic ifosfamide was associated with an acute symmetrical dissolution of the central fovea, termed foveolysis. Although spontaneous improvement after drug withdrawal cannot be excluded, the rapid and near-complete recovery after metabolic therapy supports a mechanistic link between ifosfamide-induced mitochondrial dysfunction, NAD depletion, and reversible foveal injury. The foveal architecture was restored through the defined sequence of foveation, demonstrating the capacity of the adult fovea for organized structural reconstitution.
2026-09-01 | Ultrastructural pathological features and clinical significance of recurrent chordoma
Chordoma is a low-grade malignant osseous neoplasm characterized by an exceedingly high postoperative recurrence rate. Conventional histopathological assessment cannot identify early subcellular alterations that drive tumor recurrence, and the ultrastructural mechanisms mediating chordoma recurrence and malignant progression remain poorly delineated. This study was designed to characterise the distinct subcellular pathological features of recurrent chordoma and evaluate their clinical value in prognostic assessment and risk stratification. 50 surgically resected recurrent chordoma specimens were included as the recurrent cohort, with 50 contemporaneously collected primary chordoma specimens serving as the primary control cohort. Among these, 16 pairs consisted of matched TEM specimens from the same patient's primary and recurrent chordomas, while the remaining 34 pairs comprised non-matched primary and recurrent chordomas from different patients.; Transmission electron microscopy (TEM) was employed to systematically compare ultrastructural differences across cytoplasmic vacuolar patterns, organellar architecture, intercellular junctional complexes, nuclear morphology, and stromal microvascular ultrastructure, and the prevalence of each ultrastructural abnormality was analysed statistically. Compared with primary chordoma, recurrent lesions displayed extensive and progressive subcellular pathological remodelling, including atypical cytoplasmic vacuolation with giant cystic fusion, diffuse mitochondrial injury and rough endoplasmic reticulum degranulation, widespread disintegration of mitochondria-associated endoplasmic reticulum membrane (MAM) complexes, marked nuclear atypia, loss of intercellular desmosomal junctions, activation of invasive invadopodia, and stromal microvascular dysplasia. The prevalence of all these ultrastructural aberrations was significantly higher in the recurrent cohort than in the primary control cohort (all P < 0.001), and the severity of ultrastructural damage was positively correlated with the frequency of prior tumor recurrence. In this cross-sectional series, recurrent chordoma presents characteristic progressive ultrastructural lesions, in which organellar remodelling, loss of intercellular junctions, stromal microvascular abnormalities and nuclear atypia co-segregate with recurrent disease. These findings describe a subcellular morphological correlate of recurrence; because the present cohort was cross-sectional and did not correlate ultrastructural scores with survival, the value of TEM for recurrence-risk prediction, malignant grading or individualised treatment remains a hypothesis to be tested prospectively.
2026-08-28 | Spinal laser interstitial thermal therapy for treatment of chordoma: single-center experience and literature review.
Chordomas are rare, locally aggressive tumors for which effective salvage options are limited once maximal surgical and radiation therapy have been exhausted. Laser interstitial thermal therapy (LITT) is a minimally invasive, MRI-guided ablative technique established for spinal metastases, but published experience with LITT for chordoma remains limited to isolated case reports. We report the largest clinical experience with spinal LITT (sLITT) for chordoma and review the existing literature. We performed a retrospective, IRB-approved single-institution case series of patients with histologically confirmed chordoma treated with sLITT. Clinical, operative, and radiographic data were abstracted, including tumor volumes, ablation parameters, and functional and oncologic outcomes. A systematic PubMed search was performed to identify all prior published reports of LITT for chordoma. Four patients underwent sLITT across five procedures, treating metastatic foci from primary sacral, clival, and cervical chordomas, as well as one primary thoracic lesion. sLITT was used as salvage treatment in four procedures and as primary treatment in one patient to avoid the morbidity of open surgery. Median time from diagnosis to LITT was 19.1 months (range 2.5-168.3), and pre-operative KPS was 90-100 in all patients. A median of four laser fibers and 16 ablations were used per procedure (12-15 W). Median case duration was 352.5 min and length of stay was two days. Postoperative SRS was administered in all but one procedure. All patients experienced volumetric tumor reduction on the earliest post-operative MRI (median 4.2 months, range 2.8-8.8), with a mean reduction of 25.7% ± 12.7%. Median radiographic follow-up was 16.8 months (range 3.5-48.1). No procedure required additional intervention at the LITT-treated site, and no progression at the treated site was identified on available follow-up imaging. Median overall survival from LITT was 23.0 months. One procedure was complicated by transient radiculopathy that resolved with steroids. Literature review identified four previously published case reports of LITT for chordoma, three of which described complete thermal ablation with radiographic response; our series represents the largest reported clinical experience to date. This series represents the largest reported clinical experience with LITT for chordoma and provides proof-of-concept supporting prospective evaluation of this technique. sLITT was technically feasible and well tolerated in this small chordoma cohort, applied both as salvage therapy and, in one patient, as primary local treatment. Because SRS followed all but one procedure, the independent contribution of sLITT to the radiographic responses observed cannot be determined from these data.
cell therapies
2026-04-20 | Cervical Spine Reconstruction With Vascularized Osteoadipofascial Fibular Flap and Periosteum Extension After Chordoma Resection and Adjuvant Proton Therapy: A Case Report.
Cervical spine reconstruction is essential following en bloc tumor resections, particularly in defects exceeding four centimeters. Traditional mechanical solutions or non-vascularized grafts are often suboptimal, with complications such as non-union, infections, and instability. The vascularized osteoadipofascial fibular flap offers a durable alternative with structural and biological benefits. We present the case of a 55-year-old woman with an 8-month history of cervicobrachialgia and left upper limb paresis. Imaging revealed a 7-cm lesion spanning C4-T1 with foraminal infiltration, and histopathology confirmed a chordoma. A two-stage surgery was performed: posterior stabilization and partial tumor resection, followed by anterior corpectomies (C5, C6, C7) and reconstruction with a vascularized fibular flap. The flap was anastomosed to the superior thyroid vessels, and its adipofascial component isolated the esophagus from the anterior cervical plate. Postoperative proton therapy was administered. Postoperative recovery was uneventful, with a 10-day hospital stay. At 24 months, the patient showed no recurrence, complete symptom resolution, and stable osteosynthesis with evidence of bone callus formation at graft-vertebra junctions. This case suggests that vascularized fibular reconstruction may provide reliable structural support and biological integration in complex cervical oncologic defects.
2026-03-06 | Wrist Arthrodesis with Scaphoid Autograft for Treatment of Extra-Axial Chordoma
Abstract Extra-axial chordoma (EAC) is a very rare, malignant tumor with metastatic potential that arises in the extra-axial skeleton and soft tissues. We report the case of a 51-year-old right-handed male with EAC of the left capitate. He underwent capitate resection and wrist arthrodesis utilizing scaphoid autograft with the treatment goal of minimizing risk of tumor recurrence and metastasis while maximizing hand and wrist function. His radiographic outcome demonstrated union of his arthrodesis site. However, 7 months postoperatively, he started experiencing increased hand and wrist pain and was found to have early tumor reoccurrence. Few cases of EAC have been reported in the literature. EAC is typically treated with resection alone, although there is a limited role for chemotherapy and radiation in the setting of locally reoccurring or metastatic disease. Functional outcomes of the affected extremity and survival outcomes vary widely. This is the first report in the literature of EAC of a single carpal bone and describes an innovative technique for definitive surgical treatment of this rare tumor. Utilization of scaphoid autograft for wrist arthrodesis in the setting of capitate resection allows the use of autograft in a wrist arthrodesis without the additional morbidity of iliac crest bone grafting. This case also demonstrates the importance of appropriate diagnosis and oncologic technique at the index surgery.
2025-12-26 | Targeting the tumor immune microenvironment in chordoma: From mechanistic insights to therapeutic breakthroughs.
Chordoma is a rare, malignant bone tumor characterized by high local recurrence rates and resistance to conventional therapies. While immunotherapy has emerged as a promising avenue, its clinical efficacy is currently limited by a profoundly immunosuppressive tumor immune microenvironment (TIME). This review systematically elucidates the molecular and cellular mechanisms underpinning the distinct "immune-excluded" phenotype in chordoma. In this architecture, effector T cells are physically sequestered from tumor cells by dense stromal septa, which paradoxically function as hubs for myeloid-T cell interaction rather than simple physical barriers. This immune-excluded architecture is orchestrated through multiple interconnected mechanisms. Cancer-associated fibroblasts (CAFs), particularly inflammatory and stress-related subpopulations, construct physical barriers via extracellular matrix remodeling while secreting chemokines (such as CXCL12) that spatially anchor T cells within the stroma. The transforming growth factor-beta (TGF-β) pathway reinforces this exclusion by suppressing cytotoxic T cell function and impeding tumor infiltration. Intrinsically, chordoma exhibits a low tumor mutational burden and specific genomic alterations-most notably the loss of CDKN2A/B and PBRM1. Furthermore, despite high chromosomal instability (CIN), co-occurring deletions of 9p and 10q silence the cGAS-STING pathway, thereby impairing antigen presentation and immune cell recruitment. The microenvironment is further dominated by M2-polarized tumor-associated macrophages and regulatory T cells, driving effector T cell exhaustion. Clinical evidence indicates that immune checkpoint inhibitors and targeted vaccines yield limited efficacy as monotherapies, highlighting the immune-excluded phenotype and the scarcity of PD-L1 protein expression as primary obstacles. Future therapeutic breakthroughs will require rational combination strategies, including CAR-T cell therapies targeting novel antigens (e.g., B7-H3) and adoptive T-cell transfer, designed to dismantle stromal barriers and exploit systemic anti-tumor immunity.
2025-10-27 | Cervical chordoma en bloc resection and staged suprascapular nerve transfer reanimation: illustrative case.
Cervical chordomas offer unique challenges to en bloc resection given their proximity to complex anatomy. Achieving tumor-free margins often requires extensive reconstruction that can limit radiotherapy dosing and postoperative visualization due to metal artifact, compounded by the unavailability of cervical carbon fiber implants. Multidisciplinary multistage approaches focused on oncological resections and maintenance of neurological function can improve quality and quantity of life. The authors present such an approach to the resection of a cervical chordoma with nerve transfer for shoulder reanimation. A 26-year-old woman with cervical myelopathy and upper extremity and trunk weakness and numbness was found to have a cervical chordoma spanning C4-7 with severe spinal cord compression. Following balloon test occlusion, resection included (1) posterior decompression of the spinal cord and dorsal dissection of the tumor with spine stabilization, (2) an anterior approach for a vertebral artery-to-superior thyroid artery bypass and ventral dissection, and (3) anterior en bloc resection. Three months postoperatively, a spinal accessory-to-suprascapular nerve transfer was performed. After 6 months, the patient had improved arm function and ambulation. A multidisciplinary, staged en bloc resection using carbon fiber-reinforced polymer instrumentation is safe in the cervical spine, with nerve transfers offering improved quality of life. https://thejns.org/doi/10.3171/CASE25367.
2025-10-22 | Abstract C036: Comprehensive chordoma cell systems: Profiling brachyury-independent persistence and stem-like transitions in novel patient-derived sacral culture models
Abstract Chordomas, rare and malignant tumors of the spine, are notable for their highly morbid and slow-growing nature accompanied by high recurrence rates despite en bloc resection. Once maximal safe radiation dosing and surgical options are exhausted, no proven clinical treatments remain. At present, significant transcriptomic divergence persists between tumor subtypes, with molecular profiles remaining poorly studied. Given its rarity and heterogeneity, limited preclinical models comprehensively capture the genetic and phenotypic landscape of its tumorigenesis. To address the need for reliable model systems, we established two novel patient-derived chordoma cell lines from primary sacral tumor samples collected intraoperatively from patients at a single institution. Molecular characterization was performed using quantitative PCR to assess the expression of brachyury, a key chordoma marker, alongside stemness and EMT-related markers. In particular, CHI3L1, SPP1, and PTEN–genes identified as differentially expressed through ongoing NanoString and RNA-seq analyses. Both retrospective chart and systematic literature reviews were conducted to contextualize transcriptomic results. Search terms in PubMed included ("chordoma" AND ("brachyury" OR "chi3l1" OR "spp1" OR "pten")) in all literature published between 2005 and 2025, yielding 264 articles. We report successful establishment of two chordoma cell lines from pathologically confirmed sacral tumors. Genetic profiling across multiple passages bears marked resemblance to existing commercial in vitro primary models and retains chordoma-like morphology in culture. Our findings reveal that brachyury varies significantly throughout the culturing period, yet cell doubling endures, suggesting an enrichment of stem cell populations over time. Such variability is crucial for informing optimal passage selection for future characterization studies and implies influence between brachyury expression and stem cell populations, potentially underlying tumor recurrence dynamics. Initial findings indicate that these novel patient-derived cell lines represent a valuable tool for exploring chordoma biology and stem-like transition. While brachyury expression is often absent at tumor margins in histologic sections, recurrence still occurs, suggesting that chordoma cells may persist through stem-like states despite losing brachyury expression. Our data support the idea that chordoma cells can undergo a stem-like transition, contributing to recurrence even in the absence of brachyury. Clinically, this variability may underscore why recurrent or dedifferentiated chordomas exhibit distinct brachyury expression. As our institutional biobanking efforts continue to expand, we are establishing additional cell lines from diverse chordoma subtypes–including recurrent and metastatic tumors–to better encapsulate the disease spectrum and further elucidate mechanisms underlying tumor recurrence. Citation Format: Beatrice Campilan, Christian Godinez, Margot Martinez-Moreno, Ziya Gokaslan, Patricia Sullivan. Comprehensive chordoma cell systems: Profiling brachyury-independent persistence and stem-like transitions in novel patient-derived sacral culture models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C036.
oligonucleotides
2026-08-29 | Restoration of m6A-Modified circPSMB1 Suppresses Chordoma Progression and Enables Local Nanotherapeutic Intervention.
Chordoma is a rare malignant bone tumor characterized by aggressive local invasion and high recurrence, yet its molecular regulatory mechanisms remain poorly understood. Circular RNAs (circRNAs) have emerged as important regulators of gene expression, but how circRNA epigenetic modifications contribute to oncogenic signaling is largely unknown. Here, we identify circPSMB1 as a significantly downregulated circRNA in chordoma tissues through high-throughput circRNA sequencing. Functionally, circPSMB1 suppresses chordoma cell proliferation, migration, and invasion in vitro and inhibits tumor growth in vivo. Mechanistically, METTL3-dependent m6A modification facilitates the association of circPSMB1 with the m6A reader HNRNPA2B1. CircPSMB1 competitively reduces the association of HNRNPA2B1 with c-MYC mRNA, thereby decreasing c-MYC protein expression without altering c-MYC transcript abundance. Beyond mechanistic insight, we develop an injectable circPSMB1-loaded HMnO2-based nanohydrogel that enables sustained circRNA delivery and tumor microenvironment-responsive therapy, effectively suppressing chordoma progression in vivo.
2024-11-04 | Current understanding of brachyury in chordoma.
Chordomas are rare malignant tumors that pose significant challenges in terms of effective treatment options. Surgical resection remains the only established approach that has proven useful in the treatment of chordoma. However, recent evidence has shed light on the role of brachyury, also known as the T-gene and TBXT, as both a diagnostic marker and a potential therapeutic target in chordoma. Considering these developments, this review aims to provide a comprehensive summary of the current knowledge and understanding of brachyury in chordomas.
2024-07-23 | Linc01116 Silencing Inhibits the Proliferation and Invasion, Promotes Apoptosis of Chordoma Cells via Regulating the Expression of Mir-9-5p/PKG1.
Long intergenic non-protein coding RNA 1116 (LINC01116) plays a carcinogenic role in a variety of cancers. The study aims to investigate the roles of LINC01116 and hsa-miR-9-5p (miR-9-5p) and fathom their interaction in chordoma. The predicted binding sites between miR-9-5p with LINC01116 and phosphoglycerate kinase 1 (PGK1) by starBase were confirmed through dual-luciferase reporter assay. The behaviors of chordoma cells undergoing transfection with siLINC01116 or miR-9-5p inhibitor were determined by Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and flow cytometry assays. The glucose consumption, lactate production, and adenosine triphosphate (ATP) production of chordoma cells were examined with specific kits. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to determine relevant gene expressions in chordoma cells. Silencing of LINC01116 facilitated the apoptosis and expressions of Bcl-2- associated X (Bax), cleaved caspase-3 (C caspase-3) and miR-9-5p while repressing the cell cycle, viability, proliferation, invasion, glucose consumption, lactate production, ATP production, and expressions of PGK1 and Bcl-2. Meanwhile, LINC01116 sponged miR-9-5p, which could target PGK1. Moreover, the miR-9-5p inhibitor acted contrarily and reversed the role of siLINC01116 in chordoma cells. Besides, LINC01116 downregulation facilitated apoptosis and attenuated the proliferation and invasion of chordoma cells as well as PGK1 expression by upregulating miR-9-5p expression. LINC01116/miR-9-5p plays a regulatory role in the progression of chordoma cells and is a potential biomarker for chordoma.
2024-05-01 | Unraveling molecular advancements in chordoma tumorigenesis and treatment response: a review of scientific discoveries and clinical implications.
Chordomas are tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. In adults, the most common location is the sacrum, followed by the clivus and then mobile spine, while in children a clival origin is most common. Most chordomas are slow growing. Clinical presentation of chordomas tend to occur late, with local invasion and large size often complicating surgical intervention. Radiation therapy with protons has been proven to be an effective adjuvant therapy. Unfortunately, few adjuvant systemic treatments have demonstrated significant effectiveness, and chordomas tend to recur despite intensive multimodal care. However, insight into the molecular underpinnings of chordomas may guide novel therapeutic approaches including selection for immune and molecular therapies, individualized prognostication of outcomes, and real-time noninvasive assessment of disease burden and evolution. At the genomic level, elevated levels of brachyury stemming from duplications and mutations resulting in altered transcriptional regulation may introduce druggable targets for new surgical adjuncts. Transcriptome and epigenome profiling have revealed promoter- and enhancer-dependent mechanisms of protein regulation, which may influence therapeutic response and long-term disease history. Continued scientific and clinical advancements may offer further opportunities for treatment of chordomas. Single-cell transcriptome profiling has further provided insight into the heterogeneous molecular pathways contributing to chordoma propagation. New technologies such as spatial transcriptomics and emerging biochemical analytes such as cell-free DNA have further augmented the surgeon-clinician's armamentarium by facilitating detailed characterization of intra- and intertumoral biology while also demonstrating promise for point-of-care tumor quantitation and assessment. Recent and ongoing clinical trials highlight accelerating interest to translate laboratory breakthroughs in chordoma biology and immunology into clinical care. In this review, the authors dissect the landmark studies exploring the molecular pathogenesis of chordoma. Incorporating this into an outline of ongoing clinical trials and discussion of emerging technologies, the authors aimed to summarize recent advancements in understanding chordoma pathogenesis and how neurosurgical care of chordomas may be augmented by improvements in adjunctive treatments.
2024-04-25 | N6-methyladenosine-modified circTEAD1 stabilizes Yap1 mRNA to promote chordoma tumorigenesis.
Chordoma, a rare bone tumour with aggressive local invasion and high recurrence rate with limited understanding of its molecular mechanisms. Circular RNAs (circRNAs) have been extensively implicated in tumorigenesis, yet their involvement in chordoma remains largely unexplored. N6-methyladenosine (m6A) modification holds a crucial function in regulating protein translation, RNA degradation and transcription. Initially, screening and validation of circTEAD1 in chordoma were conducted by high-throughput sequencing. Subsequently, sh-circTEAD1 and an overexpression plasmid were constructed. Colony formation assays, cell counting kit-8, Transwell and wound healing assays were utilized to validate the function of circTEAD1 in vitro. RNA pull-down assays identified the binding proteins of circTEAD1, which underwent verification through RNA immunoprecipitation (RIP). Methylated RIP assays were conducted to detect the m6A binding sites. Following this, luciferase assay, RT-qPCR, RIP and Western blotting analyses were conducted, revealing that Yap1 was the direct target of circTEAD1. Afterwards, the same methods were utilized for the validation of the function of Yap1 in chordoma in vitro. Finally, the regulatory relationship between circTEAD1 and Yap1 in chordoma was verified by an in vivo tumour formation assay. CircTEAD1 was identified as an upregulated circRNA in chordoma specimens, with heightened circTEAD1 expression emerging as a prognostic indicator. In vitro experiments convincingly demonstrated that circTEAD1 significantly promoted chordoma cell invasion, migration and aggressiveness. Furthermore, the analysis revealed that methyltransferase-like 3-mediated m6A modification facilitated the cytoplasmic export of circTEAD1. The circTEAD1/IGF2BP3/Yap1 mRNA RNA-protein ternary complex not only bolstered the stability of Yap1 mRNA but also exerted a pivotal role in driving chordoma tumorigenesis. In this study, the role of m6A-modified circTEAD1 in chordoma was identified. The findings offer novel insights into the potential molecular targets for chordoma therapy, shedding light on the intricate interplay between circRNAs, m6A modification and Yap1 mRNA in chordoma pathogenesis.
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2026-07-21 | What are the current treatment options for sacral chordoma?
The primary treatment options for sacral chordoma include surgical resection and postoperative proton beam therapy, which improves local control and survival rates. Emerging targeted and immunotherapeutic approaches hold promise but require further validation.
2026-07-15 | Clinical challenges and therapeutic strategies in chordoma: Translating molecular insights into patient care.
Chordoma is a rare, locally aggressive bone tumor originating from notochordal remnants. Despite advances in surgical and radiation-based approaches, effective systemic therapies remain limited, and recurrence rates are high. This chapter explores the current clinical landscape of chordoma management with an emphasis on the integration of molecular insights into therapeutic decision-making. In particular, we highlight emerging strategies targeting brachyury and receptor tyrosine kinases, as well as promising immunotherapies, including PD-1/PD-L1 immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapies. We further underscore the pivotal role of institutional and multi-center biobanking efforts in enabling biomarker discovery, enhancing diagnostic accuracy, and facilitating patient prognostication. Alongside these efforts, clinical trial development and public health considerations provide a comprehensive overview of the present scope and future potential of precision medicine in chordoma. By emphasizing the translational potential of molecular profiling together with advances in the clinical, institutional, and public health infrastructures that support its implementation, this chapter outlines a pathway toward more personalized and effective care for patients with chordoma.
2026-07-14 | Progression-free survival 3 of 22 months achieved through third-line therapy with adebrelimab in patient with recurrent chordoma: a case report.
Lower cervical spine origin chordomas are exceedingly uncommon tumors, and treatment may present difficulties in particular areas of the cervical spine owing to its specific anatomic architecture and the interrelationship with the vertebral arteries, cervical nerve roots, and spinal cord. Due to its rarity, the mechanisms underlying tumorigenesis and optimal therapeutic strategies for recurrence remain poorly understood. A 57-year-old Chinese female with large vertebral and paravertebral lesions from C6 to T1 underwent surgically resection on Aug 13, 2018. The pathological diagnosis in the post-operative report was chordoma close to the resection margin. No adjuvant treatment was administered after surgery. The first recurrence occurred three years postoperatively and was associated with a high tumor burden. At that time, paraplegia (lower limb paralysis and involuntary urinary and fecal control disorders) occurred. This patient received apatinib tablets, a vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI), as first-line treatment. Second-line administration of a VEGFR-TKI anlotinib capsules and programmed death-1 (PD-1) inhibitor toripalimab injection; third-line administration of the programmed death-ligand 1 (PD-L1) inhibitor adebrelimab injection, resulted in a progression-free survival 3 of 22 months and an overall survival of 7.5 years. To the best of our knowledge, this represents the first reported case of adebrelimab use in immunotherapy for chordoma.
2026-06-01 | Phase I/II, open-label, multicenter study of durvalumab in combination with tremelimumab in pediatric patients with advanced solid tumors.
We conducted a phase I/II study to evaluate durvalumab (D; anti-PD-L1) in combination with tremelimumab (T; anti-cytotoxic T-lymphocyte antigen 4) in pediatric patients with relapsed/refractory solid tumors. The dose-finding phase (phase I) assessed the safety and pharmacokinetics of D+T at two dose levels to determine the recommended phase II dose (RP2D). The primary endpoint for the dose-expansion phase (phase II) was antitumor activity (by Response Evaluation Criteria in Solid Tumors v1.1) at the RP2D. Assessment of circulating cells reflecting immune cell activation was a secondary endpoint. Based on safety and pharmacokinetic data in the dose-finding phase (n = 29), the adult-equivalent RP2D was determined as D (30 mg/kg) + T (1 mg/kg). In the dose-expansion phase, 21 patients (sarcoma, n = 11; solid tumors, n = 10) were treated at the RP2D. Of patients with sarcoma, none achieved an objective response and one had stable disease ≥7 weeks. Of the patients with solid tumors, one (chordoma) had a confirmed partial response (10.8 months duration) and one (renal cell carcinoma) had stable disease ≥7 weeks. Treatment-related adverse events occurred in 76% of patients (19% as grade 3 or 4). No adverse events leading to death were reported. Across both phases treatment with D+T resulted in an increase in CD4+Ki67+ T cells. D (30 mg/kg) + T (1 mg/kg) had limited antitumor activity in this pediatric population; however, the safety profile was manageable and consistent with the known safety profile in adult patients, with no new safety concerns identified. ClinicalTrials.gov, identifier NCT03837899; EudraCT, identifier 2018-003118-42.
2026-05-27 | A phase 2 trial of cetuximab for patients with locally advanced/metastatic chordoma.
11527 Background: Unresectable/metastatic chordoma is a rare notochordal malignancy with no approved systemic treatments. EGFR is widely expressed on chordomas. Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that inhibits EGFR signaling. In vivo testing of cetuximab has demonstrated growth inhibition and regression of chordoma. An investigator-initiated, single center, phase II study (NCT05041127) was developed to evaluate the efficacy of cetuximab for patients (pts) with advanced/metastatic chordoma. Methods: Eligible pts were ≥18 years of age, had adequate organ function, and had an ECOG performance status (PS) of ≤2. Any prior line of therapy was allowed except EGFR inhibitors. A minimum of 10 pts and maximum of 29 pts were to be enrolled onto the trial based on Simon's two-stage optimal design (H 0 RR 5% vs H 1 RR 20%; one-sided α=0.05; power=80%). Pts received cetuximab 500 mg/m 2 IV Q2 weeks until disease progression or unacceptable toxicity. The primary end point was response rate (RR) according to RECIST 1.1. Secondary objectives included safety/tolerability and survival metrics. Efficacy was assessed in the modified intention-to-treat (mITT) population (≥1 dose; ≥1 post-baseline scan). Exploratory objectives included analysis of the EGFR pathway at 2 time points from research-related biopsies. Pt reported outcomes (PROs) were assessed with MDASI (general and spine) questionnaires at several time points on study. Results: From May 2022 to Dec 2025, 29 pts enrolled. 4 were excluded from the efficacy analysis (2 withdrawal, 1 cetuximab allergy, 1 has not completed the 1 st imaging assessment). Median age was 58 years (range 21-76), 15 (58%) were men, and 24 (92%) had ECOG PS of 0 or 1. The most common primary site was skull base (46%). Tumor was classified as locally recurrent in 8 pts (31%) and metastatic in 18 pts (69%). One median line of prior systemic therapy was noted (range, 0-6). At a median follow up of 28.7 months, 12 pts (48%) had radiographic cytoreduction (any tumor reduction [ATR]), but only 2 pts (8%) had a partial response (PR). Neither PR was associated with an EGFR gene alteration. Stable disease (SD) was noted in 23 pts (92%). Preliminary median PFS and median OS was 9.9 months (95% CI, 6.3 to 13.4) and 38.8 months (95% CI, 18.6 to NR), respectively. Significantly longer PFS was observed in SD-ATR (log-rank p=0.038), with median of 14.2 months in SD-ATR versus 9.6 months in SD without tumor reduction. 7/26 pts (27%) experienced a grade 3 cetuximab-related adverse event (AE), the most common being rash in 4 pts (15%). No grade 5 AE related to cetuximab was reported. Dose reduction occurred in 2 pts (8%). 4 pts (15%) discontinued the study due to toxicity. 4 pts remain on study. Conclusions: Although the primary end point has not been reached, 2 PRs are noted, and pts with SD-ATR have a longer PFS. Translational and PRO analysis are ongoing to better define biological predictors of cetuximab activity in chordoma. Clinical trial information: NCT05041127 .
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2026-09-24 | ABM/P-15-enhanced bone graft in oncologic cervical spine reconstruction: two case reports and narrative discussion.
Bone consolidation in musculoskeletal oncology is challenging after pathological fracture, radiotherapy, repeated surgery, extensive reconstruction, or compromised vascularity. Successful healing also requires segmental mechanical stability. Anorganic bone mineral/P-15 (ABM/P-15) bone grafts provide an osteoconductive mineral scaffold with a synthetic collagen-mimetic peptide surface, but their use in oncologic cervical spine reconstruction remains sparsely described. At the McGill University Health Centre, a tertiary referral center, we report two complex cervical oncologic reconstructions in which ABM/P-15 was used as one component of multicomponent fusion constructs. A young adult male with metastatic solitary fibrous tumor, prior radiotherapy, upper cervical nonunion, and pathologic fracture underwent revision occiput-to-T2 fusion with local autograft and ABM/P-15. A young adult female with recurrent cervical chordoma after prior resection and proton-beam radiotherapy underwent combined anterior and posterior tumor resection, instrumentation, and fibular graft reconstruction augmented with ABM/P-15. In both cases, rigid reconstruction plus adjunctive grafting was followed by CT and radiographic evidence of bridging bone or host-graft incorporation without implant loosening or pseudoarthrosis at approximately 12 months. Standardized Visual Analog Scale (VAS)/Numeric Rating Scale (NRS) and Neck Disability Index (NDI) scores were not collected. These two cases document radiographic fusion after complex oncologic cervical reconstructions in which ABM/P-15 was used as an adjunct. The perceived rationale was to provide an osteoconductive, collagen-mimetic surface in compromised host biology, but these cases do not establish that ABM/P-15 independently caused fusion or improved oncologic safety. The findings should be interpreted as descriptive and hypothesis-generating.
2026-05-13 | Efficacy and Safety of Camrelizumab Plus Apatinib in Patients With Refractory Chordoma: A Phase II Clinical Trial.
Limited efficacy of current treatments for chordoma calls for novel therapeutic options. Combination of immune checkpoint inhibitors and antiangiogenic drugs has altered the landscape of cancer treatment but has rarely been investigated in chordoma. An investigator-initiated, single-center, phase II trial was conducted on camrelizumab (a PD-1 inhibitor, 200 mg once every 2 weeks) plus apatinib (an antiangiogenic drug, 250 mg and 500 mg on alternate days, that is, 250 mg one day, 500 mg the next day, alternating) in patients with refractory chordoma for 4-week cycles. The primary end point was the objective response rate (ORR) per RECIST version 1.1. Secondary end points included ORR per Choi criteria, progression-free survival (PFS), overall survival, the disease control rate, median duration of response (mDoR), safety, and quality of life. The trial is registered with Chictr.org.cn (ChiCTR2100042938). Of the 38 patients initially screened between September 2021 and October 2024, 33 were enrolled. Median follow-up duration was 20.8 months (IQR, 13.35-26.55). ORR was 24.2% (8/33 [95% CI, 11.1 to 42.3]) per RECIST 1.1 and 48.5% (16/33 [95% CI, 30.8 to 66.5]) per Choi criteria. The median PFS was 28.4 months (95% CI, 13.53 to 43.28). The mDoR was not reached per RECIST 1.1 and was 22.2 months (95% CI, 12.5 to not reached) per Choi criteria. CDKN2A copy-number deletion or homozygous deletion was found to associate with worse prognosis. The most common grade 3 or 4 treatment-related adverse events included increased aspartate aminotransferase (13 [39.4%]) and increased alanine aminotransferase (11 [33.3%]). No treatment-related deaths occurred. Combination of camrelizumab and apatinib offered encouraging efficacy with manageable toxicity in chordoma treatment. CDKN2A alterations are associated with worse prognosis and may prove to be a potential biomarker for treatment selection.
2026-03-08 | Oncolytic adenoviral infection of chordoma achieves treatment efficacy associated with immunologic response and tumor microenvironmental alteration.
Chordoma is a midline neoplasm accounting for approximately 20% of primary spinal tumors. Due to chordoma's locally aggressive nature, patients experience high rates of disease progression and have limited treatment options, highlighting an unmet clinical need. This underscores the importance of exploring novel therapeutic strategies. Oncolytic viral (OV) therapy uses genetically modified viruses to selectively replicate in tumor cells, mediate tumor cell lysis, and initiate a pro-inflammatory response within the infected tumor microenvironment (TME). The aim of the study was to evaluate the anti-chordoma effect of the replicating oncolytic adenovirus Delta-24-RGD. The efficacy of Delta-24-RGD was assessed using in vitro approaches, ex vivo bone scaffolds, and in vivo murine models. Additionally, we explored the underlying mechanism of OV cytotoxicity, immunogenic cell death (ICD), brachyury modulation, and reshaping of the TME towards a pro-inflammatory state. Delta-24-RGD achieved viral infectivity, oncolysis, and ICD across multiple human chordoma cell lines and ex vivo bone scaffold models. In vivo murine xenograft models of human CH22 and U-CH1 chordoma treated with Delta-24-RGD resulted in tumor volume reduction, enhanced overall survival, and microenvironmental transcriptional modulation. Analyzing a human chordoma tissue microarray, the immunosuppressive macrophage marker CD163 was associated with shortened recurrence-free survival. Using macrophage/chordoma co-culture, OV infection achieved a reduction in macrophage CD163 expression and a concomitant pro-inflammatory macrophage polarization. The immunosuppressive chordoma TME is associated with clinical outcomes and our data suggests OV infection reverses this deleterious immunosuppressive profile. These studies provide a framework for future clinical implementation among chordoma patients.
2026-02-27 | Methylation and Proteomic Signatures of Radiosensitivity in Chordoma
Introduction: Chordomas are rare, aggressive primary bone malignancies of the skull base and spine that remain therapeutically challenging. Despite radical surgical resection and adjuvant radiotherapy representing the current standard of care, long-term outcomes remain poor, with a 10-year overall survival of ~40% and frequent disease recurrence. Although radiotherapy is a cornerstone of treatment, its clinical benefit is variable, and prior studies have yielded inconsistent evidence regarding its impact on survival. To clarify the molecular determinants of radiotherapy response, we investigated the role of DNA methylation-defined subtypes and complementary proteomic alterations in chordoma. Methodology: We analyzed a multi-institutional cohort of n = 102 patients spanning a 20-year period, comprised of a discovery cohort of our previously published cohort as well as n = 32 newly analyzed samples in our validation cohort. Genome-wide DNA methylation profiling was performed using the Illumina EPIC array Clinical outcomes were assessed in relation to molecular subtype and treatment exposures using Kaplan–Meier analysis and multivariable Cox proportional hazards modeling. In a subset of cases, mass spectrometry–based proteomic profiling was performed to interrogate subtype-associated protein-level changes and to identify pathways potentially underlying treatment sensitivity. Results: Patients classified within the cellular molecular subtype who received radiotherapy demonstrated significantly improved overall survival (median 17.3 years, p = 0.0208) compared with those harboring the immune-infiltrative subtype (median 6.0 years). Notably, the favorable prognosis of the cellular subtype was largely seen in the absence of radiotherapy, suggesting a subtype-specific enhancement of radiosensitivity. Progression-free survival did not differ significantly between irradiated cellular and immune-infiltrative tumors ( p = 0.65), indicating that improved survival was not attributable solely to delayed recurrence. Proteomic analysis reinforced these findings, identifying distinct protein expression patterns related to DNA damage repair and immune signaling that aligned with methylation-derived subtypes and provided mechanistic support for differential radiotherapy responses. Conclusion: We validate and extend the utility of a DNA methylation–based chordoma classifier, demonstrating that subtype assignment has significant prognostic and predictive implications for radiotherapy benefit. Integration of proteomic profiling further highlights candidate biological mechanisms of radiosensitivity. These results support the incorporation of molecular stratification into clinical decision-making for chordoma and underscore the promise of integrative, multi-omic approaches to guide precision therapy in this rare malignancy. Publication History Article published online: 27 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-11-13 | Comparative Outcomes of Brachyury Vaccine vs. Imatinib in Advanced Chordoma: A Mayo Clinic Experience.
Background/Objectives: Chordoma, a rare slow-growing malignant bone tumor, remains therapeutically challenging due to its invasive nature. We examined institutional outcomes comparing imatinib and brachyury-directed vaccines. Methods: We used data from three sites of our quaternary care academic institution to analyze demographics, time to progression, overall survival, and adverse events in chordoma patients treated with imatinib or enrolled in a brachyury vaccine trial. Results: We included a total of 52 patients (8 in the brachyury vaccine cohort and 44 in the imatinib cohort) in the analysis. As expected, sacrococcygeal location was the most predominant in both cohorts: 62.5% in the brachyury cohort and 45.5% in the imatinib cohort. No demographic differences were present between the cohorts. ECOG was similar in both groups (p = 0.796). The primary outcome, time to progression (TTP), was shorter in the brachyury compared to the imatinib cohort (5.6 vs. 13 months, p = 0.0589), almost reaching statistical significance. Overall survival (OS) was comparable, 211 vs. 212 months for the brachyury and imatinib cohorts, respectively (p = 0.277). Although the brachyury vaccine cohort presented a higher incidence of adverse events than the imatinib cohort (75% vs. 31.8%, p = 0.021), the severity was milder. Conclusions: Imatinib showed longer disease control than the brachyury vaccine, though overall survival was similar. Future studies and deeper molecular insights are essential to develop better therapies and improve patient quality of life.
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Drug Discovery Landscape
3 orphan drug designations for Chordoma.
3 orphan drug designations for Chordoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
afatanib and palbociclib | small molecules | FDA | — | Collaborations Pharmaceuticals, Inc |
tazemetostat | small molecules | FDA | Epizyme, Inc. | |
BN-Brachyury; a heterologous prime/boost therapeutic cancer vaccine composed of MVA-BN-Brachyury (prime) and FPV-Brachyury (boost) | vaccines | FDA | Bavarian Nordic A/S |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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