RARE DISEASE
MiT family translocation renal cell carcinoma
MiT family translocation renal cell carcinoma
MiT family translocation renal cell carcinoma
Synonyms: Carcinoma associated with MITF/TFE translocation, Translocation renal cell carcinoma
Synonyms: Carcinoma associated with MITF/TFE translocation, Translocation renal cell carcinoma
Synonyms: Carcinoma associated with MITF/TFE translocation, Translocation renal cell carcinoma
Drug discovery
0
drugs
With orphan designations
Overview
MiT family translocation renal cell carcinoma (MiT RCC) encompasses rare, aggressive renal tumors driven by TFE3 or TFEB gene rearrangements, classified as Xp11.2 or t(6;11) RCC. These neoplasms account for ~40% of pediatric RCCs and 1.6–4% of adult cases, often presenting with advanced disease [1][4][16]. Diagnosis relies on immunohistochemistry (TFE3/TFEB) and fluorescence in situ hybridization. While localized tumors are managed surgically, metastatic disease lacks standardized therapies, with VEGF inhibitors, mTOR inhibitors, and immunotherapy combinations showing variable efficacy [3][7][11]. Prognosis is poorer in adults, with hematogenous metastases common [1][17].
Burden
Aggressive behavior: 20–40% of pediatric cases and 17–40% of adult cases develop metastases [1][13][17].
Diagnostic challenges: Morphologic overlap with clear cell/papillary RCC delays accurate diagnosis [4][9].
Poor prognosis: Median OS of 10–18 months with TKI monotherapy vs. 62 months with ICI-based regimens [7][11].
Therapies
Localized disease: Radical nephrectomy ± lymph node dissection [1][4].
Metastatic disease: VEGF-TKIs (e.g., cabozantinib), mTOR inhibitors, and immune checkpoint inhibitors (ICI); ICI + TKI combinations show improved response rates (ORR: 36–67%) [7][11][12].
No predictive biomarkers; clinical trials (e.g., NCT04704219) explore precision therapies [3][7].
Categories: rare neoplastic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
331 drug discovery papers about MiT family translocation renal cell carcinoma, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
331 drug discovery papers about MiT family translocation renal cell carcinoma, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-15 | YAP delactylation enhances therapy resistance in renal cell carcinoma
Abstract Lactylation is a novel lysine acylation modification, and its function and exact mechanisms remain unclear. The responsiveness to combined targeted and immunotherapy continues to be a major challenge in cancer treatment. Here, we discovered that lysine lactylation (Kla) is specifically downregulated in targeted therapy-resistant renal cancer cells and tissues. The lactylation status of YAP at lysine 90 (K90) regulates its nuclear translocation, which is critical for the expression of epithelial-mesenchymal transition (EMT)-related genes and the PD-L1 gene. Furthermore, we identified HDAC1 as the “eraser” of YAP-K90 lactylation. By transfecting YAP-K90T (a lactylation mimic), we enhanced antitumor immune activity. In xenograft models established in huCD34 + HSC NCG mice, we consistently found that HDAC1 inhibition enhances the response to combination therapy by increasing YAP lactylation and promoting CD8⁺ T cell tumor infiltration. These findings reveal lactylation as a key mechanism in targeted drug response and identify inhibiting YAP delactylation as a promising strategy for renal cell carcinoma treatment.
2026-07-18 | Abstract PR006: Target discovery in rare cancers enabled by transcriptome-based virtual CRISPR screening
Abstract Identifying cancer gene dependencies is essential for nominating new therapeutic targets. However, because most experimental models do not sufficiently represent the full diversity of tumors—especially for rare cancers—it remains challenging to use functional screening on experimental models to infer the dependency landscape of individual tumors. We used machine learning to infer gene dependencies from tumor transcriptional profiles, applying our model to the TCGA (>11000 tumors across 28 lineages), rare cancers (>1,000 samples, including multiple rare kidney cancer subtypes), and >500 previously unscreened cancer cell lines. In addition to validating our approach via recovery of known dependencies previously identified in functional genetic screens, we were able to directly infer drug response and synthetic essential relationships from tumor data, highlighting associations with RB1 inactivation, KRAS mutations, and microsatellite instability. Via dependency prediction, we discovered and validated a shared reliance on oxidative phosphorylation in two previously unscreened rare cancers both driven by TFE3 gene fusions: translocation renal cell carcinoma (tRCC) and alveolar soft part sarcoma (ASPS). We also nominate potentially actionable vulnerabilities across other rare cancers, most of which lack in experimental models, but for which RNA-Seq data from tumors are available. These findings demonstrate that machine learning applied to transcriptomic data can uncover novel cancer vulnerabilities and actionable targets in individual tumors, even in the absence of functional screening. This may represent a scalable approach to advance precision oncology in rare and/or under-characterized cancer types. Citation Format: Ananthan Sadagopan, Bingchen Li, Jiao Li, Yantong Cui, Riva Deodhar, Di Yang, Yuqianxun Wu, Prathyusha Konda, Christy Biji, Dharma Thapa, Meha Thakur, Cary Weiss, Toni Choueiri, Jaime Cheah, John Doench, Benjamin Drapkin, Srinivas Viswanathan. Target discovery in rare cancers enabled by transcriptome-based virtual CRISPR screening [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr PR006.
2026-07-02 | Potential Anticancer Effects of Limonene Associated with Reactive Oxygen Species Generation, Apoptosis Induction, and NF-κB Modulation in Papillary Renal Cell Carcinoma: A Preliminary Study.
Tumor recurrence and progression occur in many patients with renal cell carcinoma, highlighting a clinical demand for safe and effective treatment options, particularly by employing plant-derived bioactive compounds. Limonene, an aromatic monoterpene commonly found in citrus peels, has been shown to possess anticancer effects in malignancies such as prostate and bladder cancers. This study aimed to explore the potential anticancer effects of limonene on ACHN papillary renal cancer cells (pRCC). The viability of ACHN, human embryonic kidney (HEK293), and human dermal fibroblast (HDF) cells treated with limonene was assessed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Cellular migration, colony formation, 3D spheroid development, morphological alterations, and caspase 3/7 activity were evaluated in vitro. Reactive oxygen species (ROS) levels, apoptosis, and cell cycle alterations were analyzed by flow cytometry. The mRNA levels of BAX, BCL2, E-cadherin, N-cadherin, Caspase-3, Caspase-9, NF-κB, Akt1, MMP-2, MMP-9, mTOR, TNF-α, COX-2, and IL-6 were quantified using quantitative polymerase chain reaction. NF-κB protein levels and IκB phosphorylation were assessed by Western blot. Nuclear NF-κB levels were measured by ELISA. The viability of ACHN cells was reduced by limonene in a dose- and time-dependent manner, with comparatively limited effects on HEK293 and HDF cells. Limonene significantly reduced migration, colony formation, and spheroid growth in ACHN cells. Furthermore, limonene elevated ROS levels and increased apoptosis in ACHN cells without affecting cell cycle progression. After limonene exposure, mRNA expression of Akt1, mTOR, NF-κB, MMP-2, N-cadherin, BCL2, TNF-α, COX-2, and IL-6 decreased, whereas BAX and E-cadherin expression increased. Caspase-3 and Caspase-9 mRNA levels were not significantly altered, whereas caspase 3/7 activity increased. Limonene also reduced NF-κB protein levels, IκB phosphorylation, and NF-κB nuclear translocation. These preliminary in vitro findings support further investigation of limonene as a therapeutic candidate in additional pRCC models.
2026-06-29 | Targeting the ATX-LPA Axis Overcomes TKI Resistance and Immunosuppression in Renal Cell Carcinoma via Dual Inhibition of AKT/mTOR and TBK1/IRF3 Pathways.
Therapeutic resistance limits durable survival in advanced/metastatic renal cell carcinoma (RCC) treated with first-line tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI). We sought to define key resistance drivers and actionable targets. Integrated RNA sequencing of cabozantinib-resistant RCC cells, lipid metabolomics, and PD-L1 correlation analyses identified ENPP2 as a candidate driver. Its role in TKI resistance and survival signaling was validated by apoptosis, CCK-8, and colony formation assays in vitro and by nude-mouse xenograft models in vivo. ELISA, flow cytometry and tumor cell-T-cell co-culture assays were used to dissect ENPP2-dependent CD8+ T-cell dysfunction. The therapeutic benefit of pharmacologic ATX inhibition combined with standard TKI-ICI regimens was tested in RCC patient-derived xenograft models. The ATX-LPA axis conferred TKI resistance via constitutive AKT/mTOR activation and promoted immune evasion by upregulating PD-L1 through TBK1/IRF3 signaling, thereby impairing intratumoral CD8+ T-cell function. ENPP2 enhanced PD-L1 transcription by facilitating IRF3 nuclear translocation and its direct recruitment to the CD274 promoter. ATX inhibition improved the antitumor efficacy of TKI-ICI therapy in preclinical models. Targeting the ATX-LPA axis represents a promising strategy to overcome resistance to current TKI-ICI combinations.
2026-06-12 | A rare subtype of renal cell carcinoma
Introduction Kidney cancer accounts for approximately 175000 deaths worldwide each year and represents 3–5% of all cancers [ 1 ] [ 2 ]. The global age-standardized mortality rate is 1.8 deaths per 100000 population annually [ 2 ]. Microphthalmia transcription factor family (MiTF/TFE) translocation renal cell carcinoma (tRCC) is a rare and distinct subtype of renal cell carcinoma (RCC), characterised by chromosomal translocations involving the MiTF/TFE [ 1 ]. MiTF/TFE tRCC accounts for 1–4% of adult and up to 40% of paediatric RCCs [ 1 ]. Paediatric cases remain rare, with available evidence largely limited to small case series [ 1 ]. This report describes the imaging characteristics of a paediatric case with histopathological confirmation. It highlights the need to expand understanding of the radiological features to increase awareness of this rare, but clinically significant RCC. Publication History Received: 10 November 2025 Accepted after revision: 04 May 2026 Article published online: 12 June 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
proteins
2025-04-13 | TFE3 fusion oncoprotein condensates drive transcriptional reprogramming and cancer progression in translocation renal cell carcinoma.
Translocation renal cell carcinoma (tRCC) presents a significant clinical challenge due to its aggressiveness and limited treatment options. It is primarily driven by fusion oncoproteins (FOs), yet their role in oncogenesis is not fully understood. Here, we investigate TFE3 fusions in tRCC, focusing on NONO::TFE3 and SFPQ::TFE3. We demonstrate that TFE3 FOs form liquid-like condensates with increased transcriptional activity, localizing to TFE3 target genes and promoting cell proliferation and migration. The coiled-coil domains (CCDs) of NONO and SFPQ are essential for condensate formation, prolonging TFE3 FOs' chromatin binding time and enhancing transcription. Compared with wild-type TFE3, TFE3 FOs bind to new chromatin regions, alter chromatin accessibility, and form new enhancers and super-enhancers at pro-growth gene loci. Disruption of condensate formation via CCD modification abolishes these genome-wide changes. Altogether, our integrated analyses underscore the critical functions of TFE3 FO condensates in driving tumor cell growth, providing key insights for future therapeutic strategies.
2024-07-24 | Azurocidin is loaded into small extracellular vesicles via its N-linked glycosylation and promotes intravasation of renal cell carcinoma cells.
Azurocidin (AZU1) is an antimicrobial protein secreted by neutrophils that acts as a chemoattractant for monocytes and macrophages and a permeabilizer of vascular endothelial cells. We previously identified AZU1 to be specifically present in extracellular vesicles (EVs) obtained from renal cell carcinoma (RCC) tissues. Here, we examined the relationship between N-linked glycosylation and AZU1 loading into small EVs (SEVs). Inhibition of N-linked glycosylation by introducing mutations in three glycosylation sites inhibited AZU1 loading into SEVs. Furthermore, SEVs released from AZU1-wild-type cells increased the Ca2+ concentration in endothelial cells and the endothelial permeability, whereas SEVs released from AZU1-mutant cells had no significant effect. Anti-AZU1 antibodies diminished the effect of SEVs on endothelial cell sheets. Collectively, we found that N-linked glycosylation of AZU1 directs its loading into SEVs, thereby enabling AZU1-positive SEVs to function as potent permeabilizers of endothelial cells and leading to enhanced transendothelial migration of RCC cells.
2023-04-11 | PKM2 allosteric converter: A self-assembly peptide for suppressing renal cell carcinoma and sensitizing chemotherapy.
Stronger intrinsic Warburg effect and resistance to chemotherapy are the responses to high mortality of renal cell carcinoma (RCC). Pyruvate kinase M2 (PKM2) plays an important role in this process. Promoting PKM2 conversion from dimer to tetramer is a critical strategy to inhibit Warburg effect and reverse chemotherapy resistance. Herein, a PKM2 allosteric converter (PAC) is constructed based on the "in vivo self-assembly" strategy, which is able to continuously stimulate PKM2 tetramerization. The PAC contains three motifs, a serine site that is protected by enzyme cleavable β-N-acetylglucosamine, a self-assembly peptide and a AIE motif. Once PAC nanoparticles reach tumor site via the EPR effect, the protective and hydrophilic β-N-acetylglucosamine will be removed by over-expressed O-GlcNAcase (OGA), causing self-assembled peptides to transform into nanofibers with large serine (PKM2 tetramer activator) exposure and long-term retention, which promotes PKM2 tetramerization continuously. Our results show that PAC-induced PKM2 tetramerization inhibits aberrant metabolism mediated by Warburg effect in cytoplasm. In this way, tumor proliferation and metastasis behavior could be effectively inhibited. Meanwhile, PAC induced PKM2 tetramerization impedes the nuclear translocation of PKM2 dimer, which restores the sensitivity of cancer cells to first-line anticancer drugs. Collectively, the innovative PAC effectively promotes PKM2 conversion from dimer to tetramer, and it might provide a novel approach for suppressing RCC and enhancing chemotherapy sensitivity.
2022-06-14 | Precision Medicine: An Optimal Approach to Patient Care in Renal Cell Carcinoma
Renal cell cancer (RCC) is a heterogeneous tumor that shows both intra- and inter-heterogeneity. Heterogeneity is displayed not only in different patients but also among RCC cells in the same tumor, which makes treatment difficult because of varying degrees of responses generated in RCC heterogeneous tumor cells even with targeted treatment. In that context, precision medicine (PM), in terms of individualized treatment catered for a specific patient or groups of patients, can shift the paradigm of treatment in the clinical management of RCC. Recent progress in the biochemical, molecular, and histological characteristics of RCC has thrown light on many deregulated pathways involved in the pathogenesis of RCC. As PM-based therapies are rapidly evolving and few are already in current clinical practice in oncology, one can expect that PM will expand its way toward the robust treatment of patients with RCC. This article provides a comprehensive background on recent strategies and breakthroughs of PM in oncology and provides an overview of the potential applicability of PM in RCC. The article also highlights the drawbacks of PM and provides a holistic approach that goes beyond the involvement of clinicians and encompasses appropriate legislative and administrative care imparted by the healthcare system and insurance providers. It is anticipated that combined efforts from all sectors involved will make PM accessible to RCC and other patients with cancer, making a tremendous positive leap on individualized treatment strategies. This will subsequently enhance the quality of life of patients.
2022-01-04 | Loss of RANBP3L leads to transformation of renal epithelial cells towards a renal clear cell carcinoma like phenotype.
Renal cell carcinomas (RCC) are characterized by the deregulation of several hundred hyperosmolality-responsive genes. High expression of a subset of these genes including the Ran binding protein 3 like (RANBP3L) is linked to a favorable prognostic outcome in RCC. However, the cellular function of RANBP3L remains largely unknown. We used CRISPR/Cas9-mediated gene editing to generate functional deletions of the Ranbp3l and nuclear factor of activated T cells 5 (Nfat5) gene loci in a murine renal cell line. The NFAT5-KO cells were used to assess the regulation of Ranbp3l by NFAT5 using immunofluorescence, RNA-Seq and promoter assays. RANBP3L-deficient cells were analyzed for changes in cell morphology, proliferation, migration and colony-forming capacity using immunofluorescence and live cell imaging. RANPB3L-dependent changes in gene expression were identified by RNA-Seq. We show that NFAT5 directly regulates Ranpb3l under hyperosmotic conditions by binding its promoter. Functional analysis of RANBP3L-deficient cells revealed a loss of epithelial structure, an increased cell migration behavior and colony forming capacity, accompanied by massive alterations in gene expression, all of which are hallmarks for tumor cells. Strikingly, a RANBP3L dependent signature of 60 genes separated samples with clear cell carcinoma (KIRC) from papillary (KIRP), chromophobe renal carcinoma (KICH) and healthy tissue. Loss of RANBP3L induces a tumor like phenotype resembles RCC, especially KIRC, on the morphological and gene expression level and might promote tumor development and progression. Therapeutic reconstitution or elevation of osmoregulated RANBP3L expression might represent a novel treatment strategy for RCC or KIRC.
oligonucleotides
2025-08-28 | TRIM63 Overexpression in FISH-Negative MiTF Family Altered Renal Cell Carcinoma (MiTF RCC).
TFE3 and TFEB break-apart fluorescent in situ hybridization (FISH) assays are the gold standard for diagnostic confirmation of MiTF family altered renal cell carcinoma (MiTF RCC), which includes TFE3 rearranged RCC, and TFEB altered RCC. However, FISH assays for multiple reasons may lead to equivocal or false-negative results, especially in cryptic fusions resulting from intrachromosomal inversions involving 5' partner genes such as NONO, GRIPAP1, RBMX, and RBM10. When FISH results are negative in cases with strong morphologic suspicion of the listed tumor entities, pathologists may recommend targeted RT-PCR or panel-based RNA fusion sequencing for diagnostic confirmation. Our recent RNA in situ hybridization (RNA ISH) based study demonstrated RNA expression of the tripartite motif containing 63 (TRIM63) to be highly enriched in TFE3 rearranged RCC and TFEB altered RCC, including two FISH false-negative RCC cases harboring RBM10::TFE3 fusion. Based on these observations, we hypothesized that TRIM63 positivity could aid in diagnosing cases that are negative by conventional FISH assay but remain morphologically suspicious, representing an unmet clinical need in this area. We collected 20 RCC cases with morphological suspicion (equivocal/indeterminate immunohistochemistry panel) of MiTF RCC, which were TRIM63 positive, negative/equivocal for TFE3/TFEB gene rearrangement by FISH and underwent next generation sequencing (NGS). On NGS correlation, 14 of 20 (70%) FISH negative TRIM63 positive tumors harbored a MiTF gene rearrangement. In the remaining 6 cases, we were unable to fully ascertain the MITF rearrangement status due to the inherent limitation of the NGS panel utilized. The cases with MiTF gene rearrangement include TFE3 rearrangement in 60% (12/20), and TFEB low-level copy gains (with an additional missense mutation in one case) in 10% (2/20) of samples. RBM10:TFE3 fusion was seen in 67% (8/12) of TFE3 rearranged RCC in this cohort. TRIM63 RNA ISH assay could aid in identifying cases that harbor TFE3 or TFEB rearrangement associated with false-negative or equivocal TFE3/TFEB FISH results, especially those involving gene fusions with a paracentric Xp11 inversion. Overall, employment of TRIM63 RNA ISH coupled with TFE3/TFEB FISH assays and follow-up genomic interrogation enhanced diagnostic accuracy for patients with MiTF RCC.
2023-09-28 | LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner
NONO-TFE3 rearranged renal cell carcinoma (NONO-TFE3 rRCC) is one of a subtype of TFE3 rRCCs with high malignancy and poor prognosis. Compared with clear cell RCC, NONO-TFE3 rRCC shows a preference for mitochondrial respiration. We recently identified that the upregulation of nicotinamide ribokinase 2 (NMRK2) was associated with enhanced mitochondrial respiration and tumor progression in TFE3 rRCC.A tumor-bearing mouse model was established to verify the pro-oncogenic effect of NMRK2 on NONO-TFE3 rRCC. Then the expression of NMRK2 RNA and protein was detected in cell lines and patient specimens. The NMRK2 transcripts were Sanger-sequenced and blasted at NCBI website. We constructed dCas13b-HA system to investigate the factors binding with NMRK2 RNA. We also used molecular experiments like RIP-seq, IP-MS, FISH and fluorescence techniques to explore the mechanisms that long non-coding RNA (lncRNA) like NMRK2 mRNA promoted the mitochondrial respiration of NONO-TFE3 rRCC. The efficacy of the combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was assessed by CCK-8 assay.In this study, we confirmed that NMRK2 showed transcriptional-translational conflict and functioned as lncRNA like mRNA in the NONO-TFE3 rRCC. Furthermore, we revealed the molecular mechanism that NONO-TFE3 fusion suppressed the translation of NMRK2 mRNA. Most importantly, three major pathways were shown to explain the facilitation effects of lncRNA like NMRK2 mRNA on the mitochondrial respiration of NONO-TFE3 rRCC in an NAD+ kinase-independent manner. Finally, the efficacy of combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was demonstrated to be superior than either agent alone.Overall, our data comprehensively demonstrated the mechanisms for the enhanced mitochondrial respiration in NONO-TFE3 rRCC and proposed lncRNA like NMRK2 mRNA as a therapy target for NONO-TFE3 rRCC.
2023-05-01 | CircZBTB44 promotes renal carcinoma progression by stabilizing HK3 mRNA structure.
CircZBTB44 (hsa_circ_0002484) has been identified to be upregulated in renal cell carcinoma (RCC) tissues, while its role and contribution in RCC remain elusive. We confirmed the overexpression of circZBTB44 in RCC cells compared to normal kidney cell HK-2. CircZBTB44 knockdown suppressed the viability, proliferation, and migration of RCC cells and inhibited tumorigenesis in xenograft mouse models. Heterogeneous Nuclear Ribonucleoprotein C (HNRNPC) and Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) are two RNA binding proteins of circZBTB44. HNRNPC facilitated the translocation of circZBTB44 from nuclei to cytoplasm via m6A modification, facilitating the interaction of IGF2BP3 and circZBTB44 in the cytoplasm of RCC cells. Furthermore, circZBTB44 upregulated Hexokinase 3 (HK3) expression by binding to IGF2BP3 in RCC cells. HK3 exerted oncogenic effects on RCC cell malignant behaviors and tumor growth. In the co-culture of RCC cells with macrophages, circZBTB44 promoted M2 polarization of macrophages by up-regulating HK3. In summary, HNRNPC mediated circZBTB44 interaction with IGF2BP3 to up-regulate HK3, promoting the proliferation and migration of RCC cells in vitro and tumorigenesis in vivo. The results of the study shed new light on the targeted therapy of RCC.
2023-03-30 | Identification of Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs for Xp11 Translocation Renal Cell Carcinoma (RCC) Based on Whole-Transcriptome Sequencing.
We carried out whole transcriptome sequencing (WTS) on the tumor and the matching adjacent normal tissues from five patients having Xp11 translocation renal cell carcinoma (RCC). This was performed in terms of obtaining more understanding of the genomic panorama and molecular basis of this cancer. To examine gene-regulatory networks in XP11 translocation RCC, variance expression analysis was carried out, followed by functional enrichment analysis. Gene Expression Omnibus (GEO) of Xp11 translocation RCC data was used to validate the results. As per inclusion criteria, a total of 1886 differentially expressed mRNAs (DEmRNAs), 56 differentially expressed miRNAs (DEmiRNAs), 223 differentially expressed lncRNAs (DElncRNAs), and 1764 differentially expressed circRNAs (DEcircRNAs) were found. KEGG enrichment study of DEmiRNA, DElncRNA, and DEcircRNA target genes identified the function of protein processing in the endoplasmic reticulum, lysosome, and neutrophil-mediated immunity. Three subnetwork modules integrated from the PPI network also revealed the genes involved in protein processing in the endoplasmic reticulum, lysosome, and protein degradation processes, which may regulate the Xp11 translocation RCC process. The ceRNA complex network was created by Cytoscape, which included three upregulated circRNAs, five upregulated lncRNAs, 24 upregulated mRNAs, and two downregulated miRNAs (hsa-let-7d-5p and hsa-miR-433-3p). The genes as a prominent component of the complex ceRNA network may be key factors in the pathogenesis of Xp11 translocation RCC. Our findings clarified the genomic and transcriptional complexity of Xp11 translocation RCC while also pointing to possible new targets for Xp11 translocation RCC characterization.
2022-09-07 | Circ_000829 Plays an Anticancer Role in Renal Cell Carcinoma by Suppressing SRSF1-Mediated Alternative Splicing of SLC39A14.
Covalently closed circular RNAs (circRNAs) play critical oncogenic or anticancer roles in various cancers including renal cell carcinoma (RCC), pointing to their regulation as a promising strategy against development of RCC. We, thus, studied the tumor-suppressive role of circ_000829 in RCC through in vitro and in vivo experiments. The expression of circ_000829 was validated in clinical RCC tissues and RCC cell lines. Based on ectopic expression and knockdown experiments, we examined the interactions among circ_000829, serine and arginine rich splicing factor 1 (SRSF1), and solute carrier family 39 member 14 (SLC39A14, zinc transporter). Then, the effects of circ_000829, SRSF1, and SLC39A14 on cell cycle distribution and proliferation in vitro and on tumor growth in vivo were evaluated in RCC cells. Circ_000829 was poorly expressed in RCC tissues and cells, while SRSF1 was highly expressed. Restoration of circ_000829 reduced the levels of SRSF1 and SLC39A14B, thereby repressing the RCC cell proliferation in vitro and tumor growth in vivo. Meanwhile, overexpression of SRSF1 and SLC39A14B promoted the proliferation and cell cycle entry of RCC cells. Mechanistically, circ_000829 directly bound to SRSF1, and SRSF1 enhanced the expression of SLC39A14B by mediating the alternative splicing of SLC39A14. SLC39A14B upregulation negated the effect of SLC39A14 knockdown on RCC cell proliferation. Hence, this study suggests the antiproliferative role of circ_000829 in RCC growth and further elucidates the underlying mechanism involving the inhibited SRSF1-mediated alternative splicing of SLC39A14 mRNA.
antibodies
2026-08-12 | Immunotherapy in urological cancers: new paradigms and a systematic review of clinical trials and real-world evidence
Introduction The therapeutic landscape of urological cancers has undergone a paradigm shift with the advent of immunotherapy. This systematic review synthesizes clinical trials that have established new standards of care, complemented by evidence on immunotherapy-radiotherapy combinations and real-world data. Methods A comprehensive search of PubMed/MEDLINE and Embase (2010–2026) identified phase II/III trials evaluating ICIs, ADCs, vaccines, or cellular therapies, as well as immunoradiotehrapy, observational studies, and registries reporting real-world outcomes. Results Fifty-three clinical trials met the inclusion criteria: bladder cancer (n=14), kidney cancer (n=21), and prostate cancer (n=18), complemented by immunoradiotherapy trials (n=20), and real-world evidence (n=19). In bladder cancer, perioperative durvalumab and Enfortumab Vedotin (EV) plus pembrolizumab improved outcomes in MIBC, and the EV+pembrolizumab combination became a frontline standard for metastatic disease. Disitamab vedotin plus toripalimab improved outcomes in HER2-expressing tumours, and ctDNA-guided adjuvant atezolizumab introduces precision therapy for molecular residual disease. Emerging immunoradiotherapy combinations showed promising bladder-sparing potential (CR rates 64-88%). In kidney cancer, dual ICI and ICI+TKI combinations demonstrated long-term survival benefits. The RAMPART trial introduced adjuvant durvalumab ± tremelimumab, while transcriptomic-guided therapy and treatment of rare translocation RCC emerged from 2025–2026 trials. In prostate cancer, sipuleucel-T remains the first approved cancer vaccine, while newer trials explored ICIs (durvalumab+tremelimumab) and personalized peptide vaccines. Biomarker-driven approaches emerged across all tumor types, including ctDNA-guided therapy in bladder cancer, KIM 1 in kidney cancer, and PD-L1/DDR status in prostate cancer. Immunoradiotherapy combinations demonstrated activity in mCRPC (CA184-043, 5-year OS 7.9% vs 2.7%) and oligometastatic RCC (RAPPORT, ORR 63%). Real-world evidence confirmed trial findings while revealing critical gaps in access, the prognostic dominance of performance status, and the potential for radiotherapy-immunotherapy synergy. Conclusion Immunotherapy has become a cornerstone of urological oncology. Current paradigms include early ICI/ADC intensification in bladder cancer, ICI-based combinations in renal cell carcinoma, and the gradual integration of vaccines and checkpoint inhibitors in prostate cancer. Real-world evidence and immunoradiotherapy represents an emerging frontier, though optimal fractionation and sequencing require further investigation. Despite major advances, challenges remain in overcoming resistance, optimizing sequencing, and ensuring equitable access.
2026-03-13 | Abstract B023: RNA-mediated condensation of TFE3 oncofusions facilitates transcriptional hub formation to promote translocation renal cell carcinoma
Abstract Transcription factor E3 (TFE3) oncofusions are frequently detected in the Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC), a rare pediatric renal cancer with limited treatment options. The mechanisms by which TFE3 oncofusions promote tRCC malignancy remain inadequately defined. Here, we demonstrate that the RNA-binding capability conferred by TFE3 fusion partners drives the formation of TFE3 condensates. This further enables TFE3 oncofusions to co-condensate with RNA polymerase II (RNAPII) and other RNA-binding proteins, such as paraspeckle component 1 (PSPC1), ultimately driving the formation of transcriptional hubs to promote pro-oncogenic transcription. Dissolution of oncofusion condensates through nanobody-based chemogenetic manipulation effectively curtails tRCC cell growth both in vitro and in vivo, suggesting the therapeutic potential for targeting oncofusion condensation in tRCC. Collectively, our study establishes the causal role of RNA and RNA-binding proteins in facilitating oncofusion condensation to promote renal cancer progression. Citation Format: Lei Guo, Yun Huang. RNA-mediated condensation of TFE3 oncofusions facilitates transcriptional hub formation to promote translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B023.
2026-03-13 | Abstract B014: GPNMB:CD44 signaling drives tumor progression in translocation renal cell carcinoma
Abstract GPNMB (Glycoprotein non-metastatic melanoma protein B) is a canonical transcriptional target of MiT/TFE proteins (TFEB/TFE3/MITF), expressed at low levels in normal tissues but upregulated in numerous MiT/TFE-driven tumors such as translocation RCC, alveolar soft part sarcoma and MITF-driven melanoma, where it is associated with poor prognosis. CDX-011 (CR011-MMAE) is an anti-GPNMB ADC, with demonstrated efficacy in pre-clinical models of TFE3-fusion RCC. To further characterize GPNMB functionality and value as a cell-surface therapeutic target in tRCC, we engineered cell lines with genomic deletion of GPNMB via CRSIPR-Cas9 editing. Deletion of GPNMB in PRCC-TFE3 cell lines [UOK120/UOK124] significantly decreased clonogenic growth in 2D, spheroid size and viability and tumor xenograft growth in NSG mice and was associated with a decrease in phosphorylation of mTORC1 substrates [p-P70S6K, p-4EBP1]. We then examined expression of CD44, the primary receptor for GPNMB, and a tumor-associated antigen associated with poor prognosis in many cancers. Expression of CD44 and its ligand SPP1/OPN, was significantly increased in bulk RNA-Seq data from multiple transgenic models of SFPQ-TFE3, PRCC-TFE3 and ASPSCR1-TFE3, in human tRCC cases compared to normal kidney, and in SFPQ-TFE3/ PRCC-TFE3 transgenic kidney tumors and an ASPSCR-TFE3 PDX model, by immunoblotting and IHC, with increased membrane localization. shRNA-mediated depletion of CD44 profoundly and specifically decreased clonogenicity of multiple TFE3-fusion lines, with no effect seen in ccRCC lines. In conclusion, GPNMB regulates the growth of tRCC cells, potentially via an autocrine mechanism involving its receptor CD44, and targeting GPNMB-CD44 signaling may be of therapeutic benefit in tRCC. Citation Format: Kaushal Asrani, Juhyung Woo, Kewen Feng, Thiago Vidotto, Adrianna Amaral, Vikrant Palande, Jayaprakash Mandal, Eddie Imada, Christopher Thoburn, Sangeeta Ray, Huili Li, Yasser Ged, Nirmish Singla, John A. Copland, Laura Schmidt, W. Marston Linehan, Pedram Argani, Tamara Lotan. GPNMB:CD44 signaling drives tumor progression in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B014.
2025-11-03 | mTOR-mediated upregulation of B7-H3 in MiT/TFE translocation renal cell carcinoma.
Clinical trials targeting B7-H3 (CD276), a membranous immunomodulatory molecule in the B7 superfamily, have shown promise in prostate cancer and may be expanded to additional tumor types with high expression, such as those with mTOR signaling activation. MiT/TFE-rearranged translocation renal cell carcinoma (tRCC) is a rare, aggressive subtype that is relatively immune-depleted, with high levels of mTOR activity. Thus, we assessed B7-H3 expression in preclinical tRCC models and human tRCC samples. As hypothesized, we found that induction of TFE3 fusion proteins, including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3, is associated with upregulation of B7-H3 in multiple human preclinical tRCC cell line systems and transgenic mouse models. Pharmacologic or genetic inhibition of mTOR signaling is sufficient to downregulate B7-H3 expression in inducible and patient-derived, human cell line models of tRCC. In keeping with these preclinical results, human tRCC demonstrated significantly higher gene expression of CD276 than normal kidney, across five of the six fusions studied. At the protein level, tRCC had higher tumor cell B7-H3 intensity and proportion scores than normal kidney or clear cell RCC (ccRCC). B7-H3 expression in tumor vasculature was similar in tRCC and ccRCC, both of which showed significantly higher expression than normal kidney. Within tRCC cases, higher CD276 expression was observed in metastatic compared to localized tumors and was associated with lower tumoral CD4+ T-cell content by bulk RNAseq deconvolution. Taken together, tRCC fusion proteins upregulate B7-H3 expression via increased mTOR signaling, resulting in a higher tumoral B7-H3 expression compared to normal kidney or conventional RCC, suggesting that B7-H3 may be a promising therapeutic target in tRCC. © 2025 The Pathological Society of Great Britain and Ireland.
2025-10-01 | RNA-mediated condensation of TFE3 oncofusions facilitates transcriptional hub formation to promote translocation renal cell carcinoma.
Transcription factor E3 (TFE3) oncofusions are frequently detected in the Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC), a rare pediatric renal cancer with limited treatment options. The mechanisms by which TFE3 oncofusions promote tRCC malignancy remain inadequately defined. Here, we demonstrate that the RNA-binding capability conferred by TFE3 fusion partners drives the formation of TFE3 condensates. This further enables TFE3 oncofusions to co-condensate with RNA polymerase II (RNAPII) and other RNA-binding proteins, such as paraspeckle component 1 (PSPC1), ultimately driving the formation of transcriptional hubs to promote pro-oncogenic transcription. Dissolution of oncofusion condensates through nanobody-based chemogenetic manipulation effectively curtails tRCC cell growth both in vitro and in vivo, suggesting the therapeutic potential for targeting oncofusion condensation in tRCC. Collectively, our study establishes the causal role of RNA and RNA-binding proteins in facilitating oncofusion condensation to promote renal cancer progression.
other
2026-07-02 | GPNMB-directed CAR T cell therapy against MiT/TFE-family fusion-driven solid tumors.
Chimeric antigen receptor (CAR) T cell therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify glycoprotein NMB (GPNMB)-an MiT/TFE-family fusion-driven protein-as being highly, homogeneously and stably expressed in primary and relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma. We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. Post hoc interim analysis of a first-in-human open-label, individual-participant trial ( NCT07104682 ) for a participant with relapsed/refractory, metastatic ASPS showed that GCAR1 induces stable disease for up to 3 months, accompanied by resolution of many nontarget lesions (primary endpoint), and is well tolerated. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for 1 month. Spatial transcriptomics identified immunosuppressive niches in a treatment-resistant lesion and immune checkpoint blockade synergized with GCAR1 in a xenograft model. Altogether, our data provide a proof of concept for treating GPNMB-expressing solid tumors with GCAR1 and more broadly targeting surface antigens driven by oncogenic gene fusions with CAR T cell therapies.
2026-05-13 | Rethinking Advanced Renal Cell Carcinoma: Integrative Genomics, Immunotherapy, and Molecular-Orthomolecular Strategies.
Renal cell carcinoma (RCC) is acknowledged as a heterogeneous malignancy underlined by complex genetic, metabolic, and immune dysregulation. In particular, molecular studies have revealed distinct oncogenic mechanisms that have been exploited and studied as therapeutic intervention targets. These include hypoxia-driven signaling, chromosomal translocations, and gene fusion events that affect tumor progression. This review provides a comprehensive overview of these targets and rethinks RCC management. Therapeutic concepts include the targeting of genomic fusion biology with emerging cell-based immunotherapies or targeted molecular inhibition, and orthomolecular therapeutic strategies are presented. Two clinical and pathological features are highlighted-namely, the TFE3 fusion proteins in translocation RCC and the growing role of hypoxia-inducible factor-2α (HIF-2α) inhibitors in clear-cell RCC. We also present recent data on novel immunotherapeutic approaches, including autologous hematopoietic stem and progenitor cell-based interferon-α gene therapy, as well as chimeric antigen receptor T-cell therapy. These therapies are discussed in light of their mechanistic rationale, translational potential, and existing clinical challenges due to unwanted side effects. At last, orthomolecular and natural product-based therapies are reviewed for their potential as adjunctive therapies that might be used for oxidative stress management, the targeting of tumor metabolism and immune effects, and to increase standard treatment tolerance. This review points to a multidimensional framework that might support further research and studies in precision-guided RCC management, as integrative approaches may enhance therapeutic efficacy, reduce toxicity, and support the development of personalized interventions for advanced or treatment-resistant RCC.
2026-04-03 | Abstract 6180: Gene editing in the mouse reveals functional mechanisms of ASPS-TFE3 induced translocation renal cell carcinoma
Abstract Translocation renal cell carcinoma (tRCC) is an aggressive form of kidney cancer that predominantly affects children and young adults. With no specific FDA-approved therapies, it remains an unmet clinical need. Patients often present with metastatic disease and median overall survival is less than two years. tRCC is driven by oncogenic fusion proteins involving transcription factors of the MiTF family, most commonly TFE3, yet the mechanisms by which these fusion proteins promote tumorigenesis remain poorly understood. To investigate tRCC tumorigenesis, we expressed human ASPS-TFE3, the most prevalent oncogenic fusion, in postnatal renal proximal tubule cells generating the first tRCC mouse model faithfully reproducing the human disease. These mice developed aggressive tRCC with complete penetrance and short latency. In addition, they also developed ASPS and PEComas, illustrating a shared pathogenesis that goes beyond MiTF fusion oncoproteins. Through integrated histologic, ultrastructural, transcriptomic, proteomic and functional analyses, we found that ASPS-TFE3 simultaneously activates mTORC1 signaling and lysosomal pathways. To dissect the role of ASPS-TFE3 in tumor initiation, we employed CRISPR-mediated gene editing. Structural modeling, mutagenesis, and localization studies identified a bHLH domain mutant [ASPS-TFE3(2RA)] that retains nuclear localization but fails to bind DNA and lacks transactivation activity. Unlike wild-type fusions, ASPS-TFE3(2RA) failed to induce tRCC, demonstrating that DNA binding is essential for tumorigenesis. Furthermore, its broader expression in renal epithelial cells compared to ASPS-TFE3 (despite the same driver) illustrates oncogene-induced protective mechanisms expanding our ex vivo studies. Interbreeding experiments coupled with phenotypic and functional studies revealed a context-dependent lineage-specific dominant-negative effect modulating tumor spectrum and latency. Together, these findings provide insight into ASPS-TFE3 tRCC pathogenesis and establish a genetically tractable platform to dissect fusion-driven oncogenesis and evaluate therapeutic strategies. Citation Format: Gopinath Prakasam, Alana Christie, Lisa Kinch, Jeffrey Miyata, Quyen Do, Mylinh Nguyen, Robert Hammer, Payal Kapur, James Brugarolas, . Gene editing in the mouse reveals functional mechanisms of ASPS-TFE3 induced translocation renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6180.
2026-03-13 | Abstract PR020: Targeting cadherin-17 in translocation renal cell carcinoma
Abstract Background Translocation renal cell carcinoma (tRCC) is a rare and aggressive variant of kidney cancer (RCC) defined by an oncogenic gene fusion of a transcription factor in the MiT/TFE gene family, most commonly TFE3. tRCC lacks a biologically-directed treatment strategy and patients have poor clinical outcomes, representing an unmet need amongst kidney cancers. Cadherin-17 (CDH17) has been previously shown to be a promising cell surface target in neuroendocrine and gastrointestinal cancers. Methods We analyzed differentially expressed genes between tRCCs (n=17) vs ccRCCs (n=526) or normal kidneys (n=129) from the TCGA bulk RNA-seq cohort to identify tRCC-enriched genes. Upregulated genes from both comparisons were intersected and filtered for those encoding proteins localized to the plasma membrane or cell junctions to identify potential cell surface targets. Cadherin-17 (CDH17) emerged from these analyses as a tRCC-specific transcript. We validated CDH17 transcriptomic expression in tRCC in bulk RNA-seq from the PCAWG, Wang1, and IMMotion2 cohorts. We generated a tissue microarray (TMA) of 23 tRCC tumors (primary and metastatic) from 21 patients and performed immunohistochemistry staining for CDH17. Staining was independently reviewed by two pathologists. Thereafter, we generated a panel of fully human heavy-chain only (VH) antibodies against extracellular domains of CDH17 using a humanized mouse platform and expressed them in a second-generation chimeric antigen receptor (CAR) – T cell format. We tested the anti-CDH17 CAR-T panel against tRCC cell lines in in vitro functional assays and validated the top performers in murine models. Results CDH17 is highly expressed in tRCC (regardless of TFE fusion partner) compared to normal kidney and other RCC subtypes in bulk RNA-seq data from TCGA, PCAWG, Wang1 and IMMotion2 cohorts and has limited expression in normal tissues. TMA of tRCC tumors showed high membranous CDH17 staining (Median H-score 268, n = 23). A panel of 17 anti-CDH17 VH antibody binders was subjected to epitope mapping and identified binders were shown to target various extracellular domains of CDH17. Anti-CDH17 CAR-T cells demonstrated high cytotoxicity against tRCC in co-culture assays. Top performing CAR-T candidates were tested in two tRCC cell derived xenograft and one tRCC patient derived xenograft murine models and showed complete and durable tumor responses. Conclusions CDH17 is a novel cell surface target in tRCC. CAR-T therapy targeting CDH17 is a promising treatment strategy in tRCC. References: 1. Wang et al. Malignant melanotic Xp11 neoplasms exhibit a clinicopathologic spectrum and gene expression profiling akin to alveolar soft part sarcoma: a proposal for reclassification. J Pathol. 2020. Aug;251(4):365-377. PMID: 32418203. 2. Motzer et al. Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade. Cancer Cell. 2020 Dec 14;38(6):803-817.e4. PMID: 33157048. Citation Format: Prateek Khanna, Jiao Li, Shahryar Khoshtinat. Nikkhoi, Prathyusha Konda, Cary N. Weiss, Shanivi Srikonda, Yasmin Nabil. Laimon, Berkay Simsek, Sayed Matar, Martina De. Vizio, Sabina Signoretti, Anusuya M. Ramasubramanian, Eric L. Smith, Srinivas R. Viswanathan. Targeting cadherin-17 in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr PR020.
2025-10-01 | 19A phase 0 pilot study of memory-like natural killer (NK) cell immune therapy in patients with renal cell carcinoma or urothelial carcinoma (NCT06318871)
Abstract Background PD-1 based combination therapies improve survival in advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC), but most patients still experience subsequent disease progression and death. Natural killer (NK) cells are immune effector lymphocytes specialized in the elimination of malignant cells and play an important role in the immune response against RCC and UC. However, prior efforts to develop NK cell-based therapies have been limited by the short half-life of NK cells (10-14 days). Cytokine induced memory-like (CIML) NK cells have prolonged survival, enhanced proliferation, and improved cytotoxicity and prior trials have demonstrated clinical activity in myeloid malignancies and head/neck cancer. Methods We are performing the first study of CIML NK cell therapy among patients with RCC and UC. Patients are eligible who have advanced RCC (including clear cell, chromophobe and translocation RCC) or UC and progression after ≥1 prior treatment regimens, including prior therapy with PD-1/PD-L1 inhibitors. Participants undergo apheresis for autologous NK cell collection followed by fludarabine and cyclophosphamide lymphodepleting chemotherapy. On day 0, patients receive CIML NK cells (which have undergone a 6-day maintenance culture) followed by subcutaneous IL-2 for up to 5 doses to promote CIML NK cell growth and expansion. We plan to enroll 5-10 patients for this pilot study. The primary outcome is feasibility defined as the ability to collect cells, generate product, and administer CIML NK plus 6-day maintenance culture cells to patients. The feasibility endpoint will be met if 60% or more patients are successful per the feasibility criteria. Exploratory objectives will evaluate the safety and efficacy of this regimen. Significance & Vision In this study, we are evaluating the feasibility of treating patients with autologous CIML NK cells. This is the first use of CIML NK cell-based therapy for RCC and UC. Correlative studies will evaluate the phenotype and function of CIML NK cells and determinants of treatment response. This data will inform the development of novel NK cell based therapies in RCC and UC, including NK chimeric antigen receptor strategies. Trial Schema
small molecules
2026-08-15 | YAP delactylation enhances therapy resistance in renal cell carcinoma
Abstract Lactylation is a novel lysine acylation modification, and its function and exact mechanisms remain unclear. The responsiveness to combined targeted and immunotherapy continues to be a major challenge in cancer treatment. Here, we discovered that lysine lactylation (Kla) is specifically downregulated in targeted therapy-resistant renal cancer cells and tissues. The lactylation status of YAP at lysine 90 (K90) regulates its nuclear translocation, which is critical for the expression of epithelial-mesenchymal transition (EMT)-related genes and the PD-L1 gene. Furthermore, we identified HDAC1 as the “eraser” of YAP-K90 lactylation. By transfecting YAP-K90T (a lactylation mimic), we enhanced antitumor immune activity. In xenograft models established in huCD34 + HSC NCG mice, we consistently found that HDAC1 inhibition enhances the response to combination therapy by increasing YAP lactylation and promoting CD8⁺ T cell tumor infiltration. These findings reveal lactylation as a key mechanism in targeted drug response and identify inhibiting YAP delactylation as a promising strategy for renal cell carcinoma treatment.
2026-07-18 | Abstract PR006: Target discovery in rare cancers enabled by transcriptome-based virtual CRISPR screening
Abstract Identifying cancer gene dependencies is essential for nominating new therapeutic targets. However, because most experimental models do not sufficiently represent the full diversity of tumors—especially for rare cancers—it remains challenging to use functional screening on experimental models to infer the dependency landscape of individual tumors. We used machine learning to infer gene dependencies from tumor transcriptional profiles, applying our model to the TCGA (>11000 tumors across 28 lineages), rare cancers (>1,000 samples, including multiple rare kidney cancer subtypes), and >500 previously unscreened cancer cell lines. In addition to validating our approach via recovery of known dependencies previously identified in functional genetic screens, we were able to directly infer drug response and synthetic essential relationships from tumor data, highlighting associations with RB1 inactivation, KRAS mutations, and microsatellite instability. Via dependency prediction, we discovered and validated a shared reliance on oxidative phosphorylation in two previously unscreened rare cancers both driven by TFE3 gene fusions: translocation renal cell carcinoma (tRCC) and alveolar soft part sarcoma (ASPS). We also nominate potentially actionable vulnerabilities across other rare cancers, most of which lack in experimental models, but for which RNA-Seq data from tumors are available. These findings demonstrate that machine learning applied to transcriptomic data can uncover novel cancer vulnerabilities and actionable targets in individual tumors, even in the absence of functional screening. This may represent a scalable approach to advance precision oncology in rare and/or under-characterized cancer types. Citation Format: Ananthan Sadagopan, Bingchen Li, Jiao Li, Yantong Cui, Riva Deodhar, Di Yang, Yuqianxun Wu, Prathyusha Konda, Christy Biji, Dharma Thapa, Meha Thakur, Cary Weiss, Toni Choueiri, Jaime Cheah, John Doench, Benjamin Drapkin, Srinivas Viswanathan. Target discovery in rare cancers enabled by transcriptome-based virtual CRISPR screening [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr PR006.
2026-07-02 | Potential Anticancer Effects of Limonene Associated with Reactive Oxygen Species Generation, Apoptosis Induction, and NF-κB Modulation in Papillary Renal Cell Carcinoma: A Preliminary Study.
Tumor recurrence and progression occur in many patients with renal cell carcinoma, highlighting a clinical demand for safe and effective treatment options, particularly by employing plant-derived bioactive compounds. Limonene, an aromatic monoterpene commonly found in citrus peels, has been shown to possess anticancer effects in malignancies such as prostate and bladder cancers. This study aimed to explore the potential anticancer effects of limonene on ACHN papillary renal cancer cells (pRCC). The viability of ACHN, human embryonic kidney (HEK293), and human dermal fibroblast (HDF) cells treated with limonene was assessed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Cellular migration, colony formation, 3D spheroid development, morphological alterations, and caspase 3/7 activity were evaluated in vitro. Reactive oxygen species (ROS) levels, apoptosis, and cell cycle alterations were analyzed by flow cytometry. The mRNA levels of BAX, BCL2, E-cadherin, N-cadherin, Caspase-3, Caspase-9, NF-κB, Akt1, MMP-2, MMP-9, mTOR, TNF-α, COX-2, and IL-6 were quantified using quantitative polymerase chain reaction. NF-κB protein levels and IκB phosphorylation were assessed by Western blot. Nuclear NF-κB levels were measured by ELISA. The viability of ACHN cells was reduced by limonene in a dose- and time-dependent manner, with comparatively limited effects on HEK293 and HDF cells. Limonene significantly reduced migration, colony formation, and spheroid growth in ACHN cells. Furthermore, limonene elevated ROS levels and increased apoptosis in ACHN cells without affecting cell cycle progression. After limonene exposure, mRNA expression of Akt1, mTOR, NF-κB, MMP-2, N-cadherin, BCL2, TNF-α, COX-2, and IL-6 decreased, whereas BAX and E-cadherin expression increased. Caspase-3 and Caspase-9 mRNA levels were not significantly altered, whereas caspase 3/7 activity increased. Limonene also reduced NF-κB protein levels, IκB phosphorylation, and NF-κB nuclear translocation. These preliminary in vitro findings support further investigation of limonene as a therapeutic candidate in additional pRCC models.
2026-06-29 | Targeting the ATX-LPA Axis Overcomes TKI Resistance and Immunosuppression in Renal Cell Carcinoma via Dual Inhibition of AKT/mTOR and TBK1/IRF3 Pathways.
Therapeutic resistance limits durable survival in advanced/metastatic renal cell carcinoma (RCC) treated with first-line tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI). We sought to define key resistance drivers and actionable targets. Integrated RNA sequencing of cabozantinib-resistant RCC cells, lipid metabolomics, and PD-L1 correlation analyses identified ENPP2 as a candidate driver. Its role in TKI resistance and survival signaling was validated by apoptosis, CCK-8, and colony formation assays in vitro and by nude-mouse xenograft models in vivo. ELISA, flow cytometry and tumor cell-T-cell co-culture assays were used to dissect ENPP2-dependent CD8+ T-cell dysfunction. The therapeutic benefit of pharmacologic ATX inhibition combined with standard TKI-ICI regimens was tested in RCC patient-derived xenograft models. The ATX-LPA axis conferred TKI resistance via constitutive AKT/mTOR activation and promoted immune evasion by upregulating PD-L1 through TBK1/IRF3 signaling, thereby impairing intratumoral CD8+ T-cell function. ENPP2 enhanced PD-L1 transcription by facilitating IRF3 nuclear translocation and its direct recruitment to the CD274 promoter. ATX inhibition improved the antitumor efficacy of TKI-ICI therapy in preclinical models. Targeting the ATX-LPA axis represents a promising strategy to overcome resistance to current TKI-ICI combinations.
2026-06-12 | A rare subtype of renal cell carcinoma
Introduction Kidney cancer accounts for approximately 175000 deaths worldwide each year and represents 3–5% of all cancers [ 1 ] [ 2 ]. The global age-standardized mortality rate is 1.8 deaths per 100000 population annually [ 2 ]. Microphthalmia transcription factor family (MiTF/TFE) translocation renal cell carcinoma (tRCC) is a rare and distinct subtype of renal cell carcinoma (RCC), characterised by chromosomal translocations involving the MiTF/TFE [ 1 ]. MiTF/TFE tRCC accounts for 1–4% of adult and up to 40% of paediatric RCCs [ 1 ]. Paediatric cases remain rare, with available evidence largely limited to small case series [ 1 ]. This report describes the imaging characteristics of a paediatric case with histopathological confirmation. It highlights the need to expand understanding of the radiological features to increase awareness of this rare, but clinically significant RCC. Publication History Received: 10 November 2025 Accepted after revision: 04 May 2026 Article published online: 12 June 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
proteins
2025-04-13 | TFE3 fusion oncoprotein condensates drive transcriptional reprogramming and cancer progression in translocation renal cell carcinoma.
Translocation renal cell carcinoma (tRCC) presents a significant clinical challenge due to its aggressiveness and limited treatment options. It is primarily driven by fusion oncoproteins (FOs), yet their role in oncogenesis is not fully understood. Here, we investigate TFE3 fusions in tRCC, focusing on NONO::TFE3 and SFPQ::TFE3. We demonstrate that TFE3 FOs form liquid-like condensates with increased transcriptional activity, localizing to TFE3 target genes and promoting cell proliferation and migration. The coiled-coil domains (CCDs) of NONO and SFPQ are essential for condensate formation, prolonging TFE3 FOs' chromatin binding time and enhancing transcription. Compared with wild-type TFE3, TFE3 FOs bind to new chromatin regions, alter chromatin accessibility, and form new enhancers and super-enhancers at pro-growth gene loci. Disruption of condensate formation via CCD modification abolishes these genome-wide changes. Altogether, our integrated analyses underscore the critical functions of TFE3 FO condensates in driving tumor cell growth, providing key insights for future therapeutic strategies.
2024-07-24 | Azurocidin is loaded into small extracellular vesicles via its N-linked glycosylation and promotes intravasation of renal cell carcinoma cells.
Azurocidin (AZU1) is an antimicrobial protein secreted by neutrophils that acts as a chemoattractant for monocytes and macrophages and a permeabilizer of vascular endothelial cells. We previously identified AZU1 to be specifically present in extracellular vesicles (EVs) obtained from renal cell carcinoma (RCC) tissues. Here, we examined the relationship between N-linked glycosylation and AZU1 loading into small EVs (SEVs). Inhibition of N-linked glycosylation by introducing mutations in three glycosylation sites inhibited AZU1 loading into SEVs. Furthermore, SEVs released from AZU1-wild-type cells increased the Ca2+ concentration in endothelial cells and the endothelial permeability, whereas SEVs released from AZU1-mutant cells had no significant effect. Anti-AZU1 antibodies diminished the effect of SEVs on endothelial cell sheets. Collectively, we found that N-linked glycosylation of AZU1 directs its loading into SEVs, thereby enabling AZU1-positive SEVs to function as potent permeabilizers of endothelial cells and leading to enhanced transendothelial migration of RCC cells.
2023-04-11 | PKM2 allosteric converter: A self-assembly peptide for suppressing renal cell carcinoma and sensitizing chemotherapy.
Stronger intrinsic Warburg effect and resistance to chemotherapy are the responses to high mortality of renal cell carcinoma (RCC). Pyruvate kinase M2 (PKM2) plays an important role in this process. Promoting PKM2 conversion from dimer to tetramer is a critical strategy to inhibit Warburg effect and reverse chemotherapy resistance. Herein, a PKM2 allosteric converter (PAC) is constructed based on the "in vivo self-assembly" strategy, which is able to continuously stimulate PKM2 tetramerization. The PAC contains three motifs, a serine site that is protected by enzyme cleavable β-N-acetylglucosamine, a self-assembly peptide and a AIE motif. Once PAC nanoparticles reach tumor site via the EPR effect, the protective and hydrophilic β-N-acetylglucosamine will be removed by over-expressed O-GlcNAcase (OGA), causing self-assembled peptides to transform into nanofibers with large serine (PKM2 tetramer activator) exposure and long-term retention, which promotes PKM2 tetramerization continuously. Our results show that PAC-induced PKM2 tetramerization inhibits aberrant metabolism mediated by Warburg effect in cytoplasm. In this way, tumor proliferation and metastasis behavior could be effectively inhibited. Meanwhile, PAC induced PKM2 tetramerization impedes the nuclear translocation of PKM2 dimer, which restores the sensitivity of cancer cells to first-line anticancer drugs. Collectively, the innovative PAC effectively promotes PKM2 conversion from dimer to tetramer, and it might provide a novel approach for suppressing RCC and enhancing chemotherapy sensitivity.
2022-06-14 | Precision Medicine: An Optimal Approach to Patient Care in Renal Cell Carcinoma
Renal cell cancer (RCC) is a heterogeneous tumor that shows both intra- and inter-heterogeneity. Heterogeneity is displayed not only in different patients but also among RCC cells in the same tumor, which makes treatment difficult because of varying degrees of responses generated in RCC heterogeneous tumor cells even with targeted treatment. In that context, precision medicine (PM), in terms of individualized treatment catered for a specific patient or groups of patients, can shift the paradigm of treatment in the clinical management of RCC. Recent progress in the biochemical, molecular, and histological characteristics of RCC has thrown light on many deregulated pathways involved in the pathogenesis of RCC. As PM-based therapies are rapidly evolving and few are already in current clinical practice in oncology, one can expect that PM will expand its way toward the robust treatment of patients with RCC. This article provides a comprehensive background on recent strategies and breakthroughs of PM in oncology and provides an overview of the potential applicability of PM in RCC. The article also highlights the drawbacks of PM and provides a holistic approach that goes beyond the involvement of clinicians and encompasses appropriate legislative and administrative care imparted by the healthcare system and insurance providers. It is anticipated that combined efforts from all sectors involved will make PM accessible to RCC and other patients with cancer, making a tremendous positive leap on individualized treatment strategies. This will subsequently enhance the quality of life of patients.
2022-01-04 | Loss of RANBP3L leads to transformation of renal epithelial cells towards a renal clear cell carcinoma like phenotype.
Renal cell carcinomas (RCC) are characterized by the deregulation of several hundred hyperosmolality-responsive genes. High expression of a subset of these genes including the Ran binding protein 3 like (RANBP3L) is linked to a favorable prognostic outcome in RCC. However, the cellular function of RANBP3L remains largely unknown. We used CRISPR/Cas9-mediated gene editing to generate functional deletions of the Ranbp3l and nuclear factor of activated T cells 5 (Nfat5) gene loci in a murine renal cell line. The NFAT5-KO cells were used to assess the regulation of Ranbp3l by NFAT5 using immunofluorescence, RNA-Seq and promoter assays. RANBP3L-deficient cells were analyzed for changes in cell morphology, proliferation, migration and colony-forming capacity using immunofluorescence and live cell imaging. RANPB3L-dependent changes in gene expression were identified by RNA-Seq. We show that NFAT5 directly regulates Ranpb3l under hyperosmotic conditions by binding its promoter. Functional analysis of RANBP3L-deficient cells revealed a loss of epithelial structure, an increased cell migration behavior and colony forming capacity, accompanied by massive alterations in gene expression, all of which are hallmarks for tumor cells. Strikingly, a RANBP3L dependent signature of 60 genes separated samples with clear cell carcinoma (KIRC) from papillary (KIRP), chromophobe renal carcinoma (KICH) and healthy tissue. Loss of RANBP3L induces a tumor like phenotype resembles RCC, especially KIRC, on the morphological and gene expression level and might promote tumor development and progression. Therapeutic reconstitution or elevation of osmoregulated RANBP3L expression might represent a novel treatment strategy for RCC or KIRC.
oligonucleotides
2025-08-28 | TRIM63 Overexpression in FISH-Negative MiTF Family Altered Renal Cell Carcinoma (MiTF RCC).
TFE3 and TFEB break-apart fluorescent in situ hybridization (FISH) assays are the gold standard for diagnostic confirmation of MiTF family altered renal cell carcinoma (MiTF RCC), which includes TFE3 rearranged RCC, and TFEB altered RCC. However, FISH assays for multiple reasons may lead to equivocal or false-negative results, especially in cryptic fusions resulting from intrachromosomal inversions involving 5' partner genes such as NONO, GRIPAP1, RBMX, and RBM10. When FISH results are negative in cases with strong morphologic suspicion of the listed tumor entities, pathologists may recommend targeted RT-PCR or panel-based RNA fusion sequencing for diagnostic confirmation. Our recent RNA in situ hybridization (RNA ISH) based study demonstrated RNA expression of the tripartite motif containing 63 (TRIM63) to be highly enriched in TFE3 rearranged RCC and TFEB altered RCC, including two FISH false-negative RCC cases harboring RBM10::TFE3 fusion. Based on these observations, we hypothesized that TRIM63 positivity could aid in diagnosing cases that are negative by conventional FISH assay but remain morphologically suspicious, representing an unmet clinical need in this area. We collected 20 RCC cases with morphological suspicion (equivocal/indeterminate immunohistochemistry panel) of MiTF RCC, which were TRIM63 positive, negative/equivocal for TFE3/TFEB gene rearrangement by FISH and underwent next generation sequencing (NGS). On NGS correlation, 14 of 20 (70%) FISH negative TRIM63 positive tumors harbored a MiTF gene rearrangement. In the remaining 6 cases, we were unable to fully ascertain the MITF rearrangement status due to the inherent limitation of the NGS panel utilized. The cases with MiTF gene rearrangement include TFE3 rearrangement in 60% (12/20), and TFEB low-level copy gains (with an additional missense mutation in one case) in 10% (2/20) of samples. RBM10:TFE3 fusion was seen in 67% (8/12) of TFE3 rearranged RCC in this cohort. TRIM63 RNA ISH assay could aid in identifying cases that harbor TFE3 or TFEB rearrangement associated with false-negative or equivocal TFE3/TFEB FISH results, especially those involving gene fusions with a paracentric Xp11 inversion. Overall, employment of TRIM63 RNA ISH coupled with TFE3/TFEB FISH assays and follow-up genomic interrogation enhanced diagnostic accuracy for patients with MiTF RCC.
2023-09-28 | LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner
NONO-TFE3 rearranged renal cell carcinoma (NONO-TFE3 rRCC) is one of a subtype of TFE3 rRCCs with high malignancy and poor prognosis. Compared with clear cell RCC, NONO-TFE3 rRCC shows a preference for mitochondrial respiration. We recently identified that the upregulation of nicotinamide ribokinase 2 (NMRK2) was associated with enhanced mitochondrial respiration and tumor progression in TFE3 rRCC.A tumor-bearing mouse model was established to verify the pro-oncogenic effect of NMRK2 on NONO-TFE3 rRCC. Then the expression of NMRK2 RNA and protein was detected in cell lines and patient specimens. The NMRK2 transcripts were Sanger-sequenced and blasted at NCBI website. We constructed dCas13b-HA system to investigate the factors binding with NMRK2 RNA. We also used molecular experiments like RIP-seq, IP-MS, FISH and fluorescence techniques to explore the mechanisms that long non-coding RNA (lncRNA) like NMRK2 mRNA promoted the mitochondrial respiration of NONO-TFE3 rRCC. The efficacy of the combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was assessed by CCK-8 assay.In this study, we confirmed that NMRK2 showed transcriptional-translational conflict and functioned as lncRNA like mRNA in the NONO-TFE3 rRCC. Furthermore, we revealed the molecular mechanism that NONO-TFE3 fusion suppressed the translation of NMRK2 mRNA. Most importantly, three major pathways were shown to explain the facilitation effects of lncRNA like NMRK2 mRNA on the mitochondrial respiration of NONO-TFE3 rRCC in an NAD+ kinase-independent manner. Finally, the efficacy of combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was demonstrated to be superior than either agent alone.Overall, our data comprehensively demonstrated the mechanisms for the enhanced mitochondrial respiration in NONO-TFE3 rRCC and proposed lncRNA like NMRK2 mRNA as a therapy target for NONO-TFE3 rRCC.
2023-05-01 | CircZBTB44 promotes renal carcinoma progression by stabilizing HK3 mRNA structure.
CircZBTB44 (hsa_circ_0002484) has been identified to be upregulated in renal cell carcinoma (RCC) tissues, while its role and contribution in RCC remain elusive. We confirmed the overexpression of circZBTB44 in RCC cells compared to normal kidney cell HK-2. CircZBTB44 knockdown suppressed the viability, proliferation, and migration of RCC cells and inhibited tumorigenesis in xenograft mouse models. Heterogeneous Nuclear Ribonucleoprotein C (HNRNPC) and Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) are two RNA binding proteins of circZBTB44. HNRNPC facilitated the translocation of circZBTB44 from nuclei to cytoplasm via m6A modification, facilitating the interaction of IGF2BP3 and circZBTB44 in the cytoplasm of RCC cells. Furthermore, circZBTB44 upregulated Hexokinase 3 (HK3) expression by binding to IGF2BP3 in RCC cells. HK3 exerted oncogenic effects on RCC cell malignant behaviors and tumor growth. In the co-culture of RCC cells with macrophages, circZBTB44 promoted M2 polarization of macrophages by up-regulating HK3. In summary, HNRNPC mediated circZBTB44 interaction with IGF2BP3 to up-regulate HK3, promoting the proliferation and migration of RCC cells in vitro and tumorigenesis in vivo. The results of the study shed new light on the targeted therapy of RCC.
2023-03-30 | Identification of Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs for Xp11 Translocation Renal Cell Carcinoma (RCC) Based on Whole-Transcriptome Sequencing.
We carried out whole transcriptome sequencing (WTS) on the tumor and the matching adjacent normal tissues from five patients having Xp11 translocation renal cell carcinoma (RCC). This was performed in terms of obtaining more understanding of the genomic panorama and molecular basis of this cancer. To examine gene-regulatory networks in XP11 translocation RCC, variance expression analysis was carried out, followed by functional enrichment analysis. Gene Expression Omnibus (GEO) of Xp11 translocation RCC data was used to validate the results. As per inclusion criteria, a total of 1886 differentially expressed mRNAs (DEmRNAs), 56 differentially expressed miRNAs (DEmiRNAs), 223 differentially expressed lncRNAs (DElncRNAs), and 1764 differentially expressed circRNAs (DEcircRNAs) were found. KEGG enrichment study of DEmiRNA, DElncRNA, and DEcircRNA target genes identified the function of protein processing in the endoplasmic reticulum, lysosome, and neutrophil-mediated immunity. Three subnetwork modules integrated from the PPI network also revealed the genes involved in protein processing in the endoplasmic reticulum, lysosome, and protein degradation processes, which may regulate the Xp11 translocation RCC process. The ceRNA complex network was created by Cytoscape, which included three upregulated circRNAs, five upregulated lncRNAs, 24 upregulated mRNAs, and two downregulated miRNAs (hsa-let-7d-5p and hsa-miR-433-3p). The genes as a prominent component of the complex ceRNA network may be key factors in the pathogenesis of Xp11 translocation RCC. Our findings clarified the genomic and transcriptional complexity of Xp11 translocation RCC while also pointing to possible new targets for Xp11 translocation RCC characterization.
2022-09-07 | Circ_000829 Plays an Anticancer Role in Renal Cell Carcinoma by Suppressing SRSF1-Mediated Alternative Splicing of SLC39A14.
Covalently closed circular RNAs (circRNAs) play critical oncogenic or anticancer roles in various cancers including renal cell carcinoma (RCC), pointing to their regulation as a promising strategy against development of RCC. We, thus, studied the tumor-suppressive role of circ_000829 in RCC through in vitro and in vivo experiments. The expression of circ_000829 was validated in clinical RCC tissues and RCC cell lines. Based on ectopic expression and knockdown experiments, we examined the interactions among circ_000829, serine and arginine rich splicing factor 1 (SRSF1), and solute carrier family 39 member 14 (SLC39A14, zinc transporter). Then, the effects of circ_000829, SRSF1, and SLC39A14 on cell cycle distribution and proliferation in vitro and on tumor growth in vivo were evaluated in RCC cells. Circ_000829 was poorly expressed in RCC tissues and cells, while SRSF1 was highly expressed. Restoration of circ_000829 reduced the levels of SRSF1 and SLC39A14B, thereby repressing the RCC cell proliferation in vitro and tumor growth in vivo. Meanwhile, overexpression of SRSF1 and SLC39A14B promoted the proliferation and cell cycle entry of RCC cells. Mechanistically, circ_000829 directly bound to SRSF1, and SRSF1 enhanced the expression of SLC39A14B by mediating the alternative splicing of SLC39A14. SLC39A14B upregulation negated the effect of SLC39A14 knockdown on RCC cell proliferation. Hence, this study suggests the antiproliferative role of circ_000829 in RCC growth and further elucidates the underlying mechanism involving the inhibited SRSF1-mediated alternative splicing of SLC39A14 mRNA.
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2026-08-12 | Immunotherapy in urological cancers: new paradigms and a systematic review of clinical trials and real-world evidence
Introduction The therapeutic landscape of urological cancers has undergone a paradigm shift with the advent of immunotherapy. This systematic review synthesizes clinical trials that have established new standards of care, complemented by evidence on immunotherapy-radiotherapy combinations and real-world data. Methods A comprehensive search of PubMed/MEDLINE and Embase (2010–2026) identified phase II/III trials evaluating ICIs, ADCs, vaccines, or cellular therapies, as well as immunoradiotehrapy, observational studies, and registries reporting real-world outcomes. Results Fifty-three clinical trials met the inclusion criteria: bladder cancer (n=14), kidney cancer (n=21), and prostate cancer (n=18), complemented by immunoradiotherapy trials (n=20), and real-world evidence (n=19). In bladder cancer, perioperative durvalumab and Enfortumab Vedotin (EV) plus pembrolizumab improved outcomes in MIBC, and the EV+pembrolizumab combination became a frontline standard for metastatic disease. Disitamab vedotin plus toripalimab improved outcomes in HER2-expressing tumours, and ctDNA-guided adjuvant atezolizumab introduces precision therapy for molecular residual disease. Emerging immunoradiotherapy combinations showed promising bladder-sparing potential (CR rates 64-88%). In kidney cancer, dual ICI and ICI+TKI combinations demonstrated long-term survival benefits. The RAMPART trial introduced adjuvant durvalumab ± tremelimumab, while transcriptomic-guided therapy and treatment of rare translocation RCC emerged from 2025–2026 trials. In prostate cancer, sipuleucel-T remains the first approved cancer vaccine, while newer trials explored ICIs (durvalumab+tremelimumab) and personalized peptide vaccines. Biomarker-driven approaches emerged across all tumor types, including ctDNA-guided therapy in bladder cancer, KIM 1 in kidney cancer, and PD-L1/DDR status in prostate cancer. Immunoradiotherapy combinations demonstrated activity in mCRPC (CA184-043, 5-year OS 7.9% vs 2.7%) and oligometastatic RCC (RAPPORT, ORR 63%). Real-world evidence confirmed trial findings while revealing critical gaps in access, the prognostic dominance of performance status, and the potential for radiotherapy-immunotherapy synergy. Conclusion Immunotherapy has become a cornerstone of urological oncology. Current paradigms include early ICI/ADC intensification in bladder cancer, ICI-based combinations in renal cell carcinoma, and the gradual integration of vaccines and checkpoint inhibitors in prostate cancer. Real-world evidence and immunoradiotherapy represents an emerging frontier, though optimal fractionation and sequencing require further investigation. Despite major advances, challenges remain in overcoming resistance, optimizing sequencing, and ensuring equitable access.
2026-03-13 | Abstract B023: RNA-mediated condensation of TFE3 oncofusions facilitates transcriptional hub formation to promote translocation renal cell carcinoma
Abstract Transcription factor E3 (TFE3) oncofusions are frequently detected in the Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC), a rare pediatric renal cancer with limited treatment options. The mechanisms by which TFE3 oncofusions promote tRCC malignancy remain inadequately defined. Here, we demonstrate that the RNA-binding capability conferred by TFE3 fusion partners drives the formation of TFE3 condensates. This further enables TFE3 oncofusions to co-condensate with RNA polymerase II (RNAPII) and other RNA-binding proteins, such as paraspeckle component 1 (PSPC1), ultimately driving the formation of transcriptional hubs to promote pro-oncogenic transcription. Dissolution of oncofusion condensates through nanobody-based chemogenetic manipulation effectively curtails tRCC cell growth both in vitro and in vivo, suggesting the therapeutic potential for targeting oncofusion condensation in tRCC. Collectively, our study establishes the causal role of RNA and RNA-binding proteins in facilitating oncofusion condensation to promote renal cancer progression. Citation Format: Lei Guo, Yun Huang. RNA-mediated condensation of TFE3 oncofusions facilitates transcriptional hub formation to promote translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B023.
2026-03-13 | Abstract B014: GPNMB:CD44 signaling drives tumor progression in translocation renal cell carcinoma
Abstract GPNMB (Glycoprotein non-metastatic melanoma protein B) is a canonical transcriptional target of MiT/TFE proteins (TFEB/TFE3/MITF), expressed at low levels in normal tissues but upregulated in numerous MiT/TFE-driven tumors such as translocation RCC, alveolar soft part sarcoma and MITF-driven melanoma, where it is associated with poor prognosis. CDX-011 (CR011-MMAE) is an anti-GPNMB ADC, with demonstrated efficacy in pre-clinical models of TFE3-fusion RCC. To further characterize GPNMB functionality and value as a cell-surface therapeutic target in tRCC, we engineered cell lines with genomic deletion of GPNMB via CRSIPR-Cas9 editing. Deletion of GPNMB in PRCC-TFE3 cell lines [UOK120/UOK124] significantly decreased clonogenic growth in 2D, spheroid size and viability and tumor xenograft growth in NSG mice and was associated with a decrease in phosphorylation of mTORC1 substrates [p-P70S6K, p-4EBP1]. We then examined expression of CD44, the primary receptor for GPNMB, and a tumor-associated antigen associated with poor prognosis in many cancers. Expression of CD44 and its ligand SPP1/OPN, was significantly increased in bulk RNA-Seq data from multiple transgenic models of SFPQ-TFE3, PRCC-TFE3 and ASPSCR1-TFE3, in human tRCC cases compared to normal kidney, and in SFPQ-TFE3/ PRCC-TFE3 transgenic kidney tumors and an ASPSCR-TFE3 PDX model, by immunoblotting and IHC, with increased membrane localization. shRNA-mediated depletion of CD44 profoundly and specifically decreased clonogenicity of multiple TFE3-fusion lines, with no effect seen in ccRCC lines. In conclusion, GPNMB regulates the growth of tRCC cells, potentially via an autocrine mechanism involving its receptor CD44, and targeting GPNMB-CD44 signaling may be of therapeutic benefit in tRCC. Citation Format: Kaushal Asrani, Juhyung Woo, Kewen Feng, Thiago Vidotto, Adrianna Amaral, Vikrant Palande, Jayaprakash Mandal, Eddie Imada, Christopher Thoburn, Sangeeta Ray, Huili Li, Yasser Ged, Nirmish Singla, John A. Copland, Laura Schmidt, W. Marston Linehan, Pedram Argani, Tamara Lotan. GPNMB:CD44 signaling drives tumor progression in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B014.
2025-11-03 | mTOR-mediated upregulation of B7-H3 in MiT/TFE translocation renal cell carcinoma.
Clinical trials targeting B7-H3 (CD276), a membranous immunomodulatory molecule in the B7 superfamily, have shown promise in prostate cancer and may be expanded to additional tumor types with high expression, such as those with mTOR signaling activation. MiT/TFE-rearranged translocation renal cell carcinoma (tRCC) is a rare, aggressive subtype that is relatively immune-depleted, with high levels of mTOR activity. Thus, we assessed B7-H3 expression in preclinical tRCC models and human tRCC samples. As hypothesized, we found that induction of TFE3 fusion proteins, including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3, is associated with upregulation of B7-H3 in multiple human preclinical tRCC cell line systems and transgenic mouse models. Pharmacologic or genetic inhibition of mTOR signaling is sufficient to downregulate B7-H3 expression in inducible and patient-derived, human cell line models of tRCC. In keeping with these preclinical results, human tRCC demonstrated significantly higher gene expression of CD276 than normal kidney, across five of the six fusions studied. At the protein level, tRCC had higher tumor cell B7-H3 intensity and proportion scores than normal kidney or clear cell RCC (ccRCC). B7-H3 expression in tumor vasculature was similar in tRCC and ccRCC, both of which showed significantly higher expression than normal kidney. Within tRCC cases, higher CD276 expression was observed in metastatic compared to localized tumors and was associated with lower tumoral CD4+ T-cell content by bulk RNAseq deconvolution. Taken together, tRCC fusion proteins upregulate B7-H3 expression via increased mTOR signaling, resulting in a higher tumoral B7-H3 expression compared to normal kidney or conventional RCC, suggesting that B7-H3 may be a promising therapeutic target in tRCC. © 2025 The Pathological Society of Great Britain and Ireland.
2025-10-01 | RNA-mediated condensation of TFE3 oncofusions facilitates transcriptional hub formation to promote translocation renal cell carcinoma.
Transcription factor E3 (TFE3) oncofusions are frequently detected in the Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC), a rare pediatric renal cancer with limited treatment options. The mechanisms by which TFE3 oncofusions promote tRCC malignancy remain inadequately defined. Here, we demonstrate that the RNA-binding capability conferred by TFE3 fusion partners drives the formation of TFE3 condensates. This further enables TFE3 oncofusions to co-condensate with RNA polymerase II (RNAPII) and other RNA-binding proteins, such as paraspeckle component 1 (PSPC1), ultimately driving the formation of transcriptional hubs to promote pro-oncogenic transcription. Dissolution of oncofusion condensates through nanobody-based chemogenetic manipulation effectively curtails tRCC cell growth both in vitro and in vivo, suggesting the therapeutic potential for targeting oncofusion condensation in tRCC. Collectively, our study establishes the causal role of RNA and RNA-binding proteins in facilitating oncofusion condensation to promote renal cancer progression.
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2026-07-02 | GPNMB-directed CAR T cell therapy against MiT/TFE-family fusion-driven solid tumors.
Chimeric antigen receptor (CAR) T cell therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify glycoprotein NMB (GPNMB)-an MiT/TFE-family fusion-driven protein-as being highly, homogeneously and stably expressed in primary and relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma. We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. Post hoc interim analysis of a first-in-human open-label, individual-participant trial ( NCT07104682 ) for a participant with relapsed/refractory, metastatic ASPS showed that GCAR1 induces stable disease for up to 3 months, accompanied by resolution of many nontarget lesions (primary endpoint), and is well tolerated. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for 1 month. Spatial transcriptomics identified immunosuppressive niches in a treatment-resistant lesion and immune checkpoint blockade synergized with GCAR1 in a xenograft model. Altogether, our data provide a proof of concept for treating GPNMB-expressing solid tumors with GCAR1 and more broadly targeting surface antigens driven by oncogenic gene fusions with CAR T cell therapies.
2026-05-13 | Rethinking Advanced Renal Cell Carcinoma: Integrative Genomics, Immunotherapy, and Molecular-Orthomolecular Strategies.
Renal cell carcinoma (RCC) is acknowledged as a heterogeneous malignancy underlined by complex genetic, metabolic, and immune dysregulation. In particular, molecular studies have revealed distinct oncogenic mechanisms that have been exploited and studied as therapeutic intervention targets. These include hypoxia-driven signaling, chromosomal translocations, and gene fusion events that affect tumor progression. This review provides a comprehensive overview of these targets and rethinks RCC management. Therapeutic concepts include the targeting of genomic fusion biology with emerging cell-based immunotherapies or targeted molecular inhibition, and orthomolecular therapeutic strategies are presented. Two clinical and pathological features are highlighted-namely, the TFE3 fusion proteins in translocation RCC and the growing role of hypoxia-inducible factor-2α (HIF-2α) inhibitors in clear-cell RCC. We also present recent data on novel immunotherapeutic approaches, including autologous hematopoietic stem and progenitor cell-based interferon-α gene therapy, as well as chimeric antigen receptor T-cell therapy. These therapies are discussed in light of their mechanistic rationale, translational potential, and existing clinical challenges due to unwanted side effects. At last, orthomolecular and natural product-based therapies are reviewed for their potential as adjunctive therapies that might be used for oxidative stress management, the targeting of tumor metabolism and immune effects, and to increase standard treatment tolerance. This review points to a multidimensional framework that might support further research and studies in precision-guided RCC management, as integrative approaches may enhance therapeutic efficacy, reduce toxicity, and support the development of personalized interventions for advanced or treatment-resistant RCC.
2026-04-03 | Abstract 6180: Gene editing in the mouse reveals functional mechanisms of ASPS-TFE3 induced translocation renal cell carcinoma
Abstract Translocation renal cell carcinoma (tRCC) is an aggressive form of kidney cancer that predominantly affects children and young adults. With no specific FDA-approved therapies, it remains an unmet clinical need. Patients often present with metastatic disease and median overall survival is less than two years. tRCC is driven by oncogenic fusion proteins involving transcription factors of the MiTF family, most commonly TFE3, yet the mechanisms by which these fusion proteins promote tumorigenesis remain poorly understood. To investigate tRCC tumorigenesis, we expressed human ASPS-TFE3, the most prevalent oncogenic fusion, in postnatal renal proximal tubule cells generating the first tRCC mouse model faithfully reproducing the human disease. These mice developed aggressive tRCC with complete penetrance and short latency. In addition, they also developed ASPS and PEComas, illustrating a shared pathogenesis that goes beyond MiTF fusion oncoproteins. Through integrated histologic, ultrastructural, transcriptomic, proteomic and functional analyses, we found that ASPS-TFE3 simultaneously activates mTORC1 signaling and lysosomal pathways. To dissect the role of ASPS-TFE3 in tumor initiation, we employed CRISPR-mediated gene editing. Structural modeling, mutagenesis, and localization studies identified a bHLH domain mutant [ASPS-TFE3(2RA)] that retains nuclear localization but fails to bind DNA and lacks transactivation activity. Unlike wild-type fusions, ASPS-TFE3(2RA) failed to induce tRCC, demonstrating that DNA binding is essential for tumorigenesis. Furthermore, its broader expression in renal epithelial cells compared to ASPS-TFE3 (despite the same driver) illustrates oncogene-induced protective mechanisms expanding our ex vivo studies. Interbreeding experiments coupled with phenotypic and functional studies revealed a context-dependent lineage-specific dominant-negative effect modulating tumor spectrum and latency. Together, these findings provide insight into ASPS-TFE3 tRCC pathogenesis and establish a genetically tractable platform to dissect fusion-driven oncogenesis and evaluate therapeutic strategies. Citation Format: Gopinath Prakasam, Alana Christie, Lisa Kinch, Jeffrey Miyata, Quyen Do, Mylinh Nguyen, Robert Hammer, Payal Kapur, James Brugarolas, . Gene editing in the mouse reveals functional mechanisms of ASPS-TFE3 induced translocation renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6180.
2026-03-13 | Abstract PR020: Targeting cadherin-17 in translocation renal cell carcinoma
Abstract Background Translocation renal cell carcinoma (tRCC) is a rare and aggressive variant of kidney cancer (RCC) defined by an oncogenic gene fusion of a transcription factor in the MiT/TFE gene family, most commonly TFE3. tRCC lacks a biologically-directed treatment strategy and patients have poor clinical outcomes, representing an unmet need amongst kidney cancers. Cadherin-17 (CDH17) has been previously shown to be a promising cell surface target in neuroendocrine and gastrointestinal cancers. Methods We analyzed differentially expressed genes between tRCCs (n=17) vs ccRCCs (n=526) or normal kidneys (n=129) from the TCGA bulk RNA-seq cohort to identify tRCC-enriched genes. Upregulated genes from both comparisons were intersected and filtered for those encoding proteins localized to the plasma membrane or cell junctions to identify potential cell surface targets. Cadherin-17 (CDH17) emerged from these analyses as a tRCC-specific transcript. We validated CDH17 transcriptomic expression in tRCC in bulk RNA-seq from the PCAWG, Wang1, and IMMotion2 cohorts. We generated a tissue microarray (TMA) of 23 tRCC tumors (primary and metastatic) from 21 patients and performed immunohistochemistry staining for CDH17. Staining was independently reviewed by two pathologists. Thereafter, we generated a panel of fully human heavy-chain only (VH) antibodies against extracellular domains of CDH17 using a humanized mouse platform and expressed them in a second-generation chimeric antigen receptor (CAR) – T cell format. We tested the anti-CDH17 CAR-T panel against tRCC cell lines in in vitro functional assays and validated the top performers in murine models. Results CDH17 is highly expressed in tRCC (regardless of TFE fusion partner) compared to normal kidney and other RCC subtypes in bulk RNA-seq data from TCGA, PCAWG, Wang1 and IMMotion2 cohorts and has limited expression in normal tissues. TMA of tRCC tumors showed high membranous CDH17 staining (Median H-score 268, n = 23). A panel of 17 anti-CDH17 VH antibody binders was subjected to epitope mapping and identified binders were shown to target various extracellular domains of CDH17. Anti-CDH17 CAR-T cells demonstrated high cytotoxicity against tRCC in co-culture assays. Top performing CAR-T candidates were tested in two tRCC cell derived xenograft and one tRCC patient derived xenograft murine models and showed complete and durable tumor responses. Conclusions CDH17 is a novel cell surface target in tRCC. CAR-T therapy targeting CDH17 is a promising treatment strategy in tRCC. References: 1. Wang et al. Malignant melanotic Xp11 neoplasms exhibit a clinicopathologic spectrum and gene expression profiling akin to alveolar soft part sarcoma: a proposal for reclassification. J Pathol. 2020. Aug;251(4):365-377. PMID: 32418203. 2. Motzer et al. Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade. Cancer Cell. 2020 Dec 14;38(6):803-817.e4. PMID: 33157048. Citation Format: Prateek Khanna, Jiao Li, Shahryar Khoshtinat. Nikkhoi, Prathyusha Konda, Cary N. Weiss, Shanivi Srikonda, Yasmin Nabil. Laimon, Berkay Simsek, Sayed Matar, Martina De. Vizio, Sabina Signoretti, Anusuya M. Ramasubramanian, Eric L. Smith, Srinivas R. Viswanathan. Targeting cadherin-17 in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr PR020.
2025-10-01 | 19A phase 0 pilot study of memory-like natural killer (NK) cell immune therapy in patients with renal cell carcinoma or urothelial carcinoma (NCT06318871)
Abstract Background PD-1 based combination therapies improve survival in advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC), but most patients still experience subsequent disease progression and death. Natural killer (NK) cells are immune effector lymphocytes specialized in the elimination of malignant cells and play an important role in the immune response against RCC and UC. However, prior efforts to develop NK cell-based therapies have been limited by the short half-life of NK cells (10-14 days). Cytokine induced memory-like (CIML) NK cells have prolonged survival, enhanced proliferation, and improved cytotoxicity and prior trials have demonstrated clinical activity in myeloid malignancies and head/neck cancer. Methods We are performing the first study of CIML NK cell therapy among patients with RCC and UC. Patients are eligible who have advanced RCC (including clear cell, chromophobe and translocation RCC) or UC and progression after ≥1 prior treatment regimens, including prior therapy with PD-1/PD-L1 inhibitors. Participants undergo apheresis for autologous NK cell collection followed by fludarabine and cyclophosphamide lymphodepleting chemotherapy. On day 0, patients receive CIML NK cells (which have undergone a 6-day maintenance culture) followed by subcutaneous IL-2 for up to 5 doses to promote CIML NK cell growth and expansion. We plan to enroll 5-10 patients for this pilot study. The primary outcome is feasibility defined as the ability to collect cells, generate product, and administer CIML NK plus 6-day maintenance culture cells to patients. The feasibility endpoint will be met if 60% or more patients are successful per the feasibility criteria. Exploratory objectives will evaluate the safety and efficacy of this regimen. Significance & Vision In this study, we are evaluating the feasibility of treating patients with autologous CIML NK cells. This is the first use of CIML NK cell-based therapy for RCC and UC. Correlative studies will evaluate the phenotype and function of CIML NK cells and determinants of treatment response. This data will inform the development of novel NK cell based therapies in RCC and UC, including NK chimeric antigen receptor strategies. Trial Schema
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