RARE DISEASE
Von Hippel-Lindau disease
Von Hippel-Lindau disease
Von Hippel-Lindau disease
Synonyms: Familial cerebelloretinal angiomatosis, Lindau disease, VHL, Von Hippel-Lindau syndrome
Synonyms: Familial cerebelloretinal angiomatosis, Lindau disease, VHL, Von Hippel-Lindau syndrome
Synonyms: Familial cerebelloretinal angiomatosis, Lindau disease, VHL, Von Hippel-Lindau syndrome
Drug discovery
4
drugs
With orphan designations
Overview
Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder caused by VHL gene mutations, leading to tumor suppressor dysfunction. It manifests with benign/malignant tumors in the CNS (hemangioblastomas), kidneys (clear cell renal carcinoma), pancreas, adrenal glands (pheochromocytomas), and retina. Clinical features depend on tumor location, with risks of blindness, neurological deficits, and metastatic renal cancer. Diagnosis combines genetic testing and imaging surveillance [1][6][9]. Management emphasizes early tumor detection and intervention to prevent complications [4][16].
Burden
Clinical: Lifelong multisystem monitoring, recurrent surgeries, and cancer risk (25–60% develop renal cell carcinoma) [1][10].
Economic: High healthcare costs from imaging, surgeries, and systemic therapies [10].
Psychological: Anxiety related to disease progression and genetic transmission risks [4][13].
Therapies
Surgical resection for symptomatic or high-risk tumors (CNS, renal, pancreatic) [4][16].
Belzutifan (HIF-2α inhibitor), FDA-approved for VHL-associated renal cell carcinoma, CNS hemangioblastomas, and pancreatic neuroendocrine tumors [7][18].
Surveillance protocols: Annual MRI (brain/spine/abdomen), ophthalmologic exams, and biochemical testing [4][9].
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare renal diseases
Research Papers
983 drug discovery papers about Von Hippel-Lindau disease, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
983 drug discovery papers about Von Hippel-Lindau disease, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).
Von Hippel-Lindau disease (VHLD) is a rare autosomal dominant disease, occuring in ~ 1 in 35,000 individuals. Overall, individuals with inherited mutations in the VHL tumor suppressor gene are predisposed to a variety of cancer, including high frequencies of clear cell renal cell carcinoma (ccRCC), pancreatic neuroendocrine tumors, and hemangioblastomas, as well as benign cystic conditions and other cancers. The degree of risk for each of these pathological conditions depends on the location and severity of the inherited germline mutation, and the specific VHL protein interactions and functions disrupted. A core VHL protein function is as the targeting subunit of an E3 ligase complex, with protein degradation activity based on interactions with elongins (ELOB, ELOC), Cullin 2 (CUL2), and RBX1. For ccRCC and some other cancers, loss of VHL-dependent degradation of key substrates-the transcription factors hypoxia-inducible factor alpha (HIF-1α and HIF-2α)-and upregulation of HIF-dependent transcripts are critical to promote tumor formation. For this reason, drugs such as the HIF signaling inhibitor belzutifan have emerged as promising clinical agents for treatment of VHLD patients prone to ccRCC. However, other biological consequences of VHL loss are independent of HIFα degradation, and in some cases independent of the VHL ubiquitin ligase activity. Non-canonical activities of VHL include regulation of microtubule stability, mitotic progression, and ciliation, as well as formation of the extracellular matrix (ECM); the degree to which disruption of these activities contributes to VHLD is currently not well understood. This review provides a concise update of the current literature on VHLD pathogenesis, the relationship of VHL structure and protein interactions to the spectrum of phenotypes associated with VHLD, and current and proposed treatment, prevention, and interception of cancer formation for VHLD patients.
2026-08-05 | Case Report: Diagnosis and treatment report and literature review of 2 cases of VHL-deficient renal cell carcinoma.
Von Hippel-Lindau (VHL) disease is a rare familial autosomal dominant disorder with an incidence rate of approximately 1 in 36,000. It primarily results from mutations or inactivation of the VHL tumor suppressor gene located on chromosome 3p25-p26. The hallmark of this disease is hereditary hemangioblastoma, which can affect multiple organs and systems, including the brain (commonly infratentorial), spinal cord, retina, and internal organs such as the kidneys, adrenal glands, and pancreas. Less commonly, lesions may include papillary cystadenomas and endolymphatic sac tumors (ELST), which can form in the epididymis or broad ligament. The leading causes of death in these patients are hemangioblastomas and renal cell carcinoma of the central nervous system. Due to the multidisciplinary nature of the disease, diagnosis and management require a multidisciplinary team (MDT) consultation and collaboration among various specialties. Clinical diagnosis, genetic implications, and prognosis must be assessed comprehensively, with genetic testing confirming the diagnosis. Cases of VHL are exceptionally rare in clinical practice, and there remains a significant unmet need for effective treatments, particularly in rare tumors. Misdiagnosis and mistreatment are common, and repeated surgical interventions can exacerbate kidney damage. Early and accurate diagnosis, followed by proactive treatment, can significantly improve prognosis. Recently, our department admitted two patients with VHL-deficient renal cell carcinoma. Through surgery, radiofrequency ablation, and subsequent targeted therapy, the therapeutic outcomes were highly favorable. This report introduces the treatment of these two cases and provides a literature review on the current progress in the diagnosis, treatment, and prognosis of VHL-deficient renal cell carcinoma. Additionally, it discusses data on the screening of VHL patients and their close relatives, while emphasizing the optimization of individualized management for renal cell carcinoma to enhance the understanding, diagnosis, and treatment of the disease.
2026-07-28 | Endovascular Embolization in Neurovascular Disease: Material Science, Multimodal Management, and Future Horizons.
Background & Objectives: Endovascular embolization has matured into a sophisticated, precision-guided discipline that is central to the management of complex neurovascular pathologies. This review synthesizes contemporary treatment strategies, evaluating the advanced material characteristics of conventional inert liquid polymers, specifically non-adhesive ethylene vinyl alcohol (EVOH) copolymers and adhesive cyanoacrylates, alongside their targeted clinical applications in brain arteriovenous malformations (bAVMs), dural arteriovenous fistulas (dAVFs), hypervascular intracranial tumors, and chronic subdural hematomas (CSDHs). Furthermore, it examines the critical material and hemodynamic constraints that limit these agents in cerebral aneurysm repair. Methods: A comprehensive literature synthesis through 3 July 2026 was integrated with peer-reviewed clinical illustrations to evaluate both procedural mechanics and the necessity of post-procedural physiological management. Review Findings: Embolization serves a critical dual role: as a definitive curative therapy and as an essential preoperative or radiosurgical adjunct. As demonstrated by recent clinical validations, technical angiographic success must be closely coupled with vigilant neurocritical oversight to manage profound, localized hemodynamic shifts. While these conventional methods represent established clinical practice, the field is evolving away from inert mechanical occlusion toward a highly integrated approach. The convergence of stimuli-responsive "smart" hydrogels and endovascular robotics is being evaluated for potential roles in transforming these interventions into dynamic, bioactive platforms capable of modulating disease-specific mechanisms, such as Rat Sarcoma-Mitogen-Activated Protein Kinase (RAS-MAPK) and Bone Morphogenetic Protein (BMP) signaling in bAVMs or the Von Hippel-Lindau/Vascular Endothelial Growth Factor (VHL/VEGF) axis in hypervascular tumors. This review further analyzes landmark data, including the Squid Trial For the Embolization of the Middle Meningeal Artery for Treatment of Chronic Subdural Hematoma (STEM) trial for CSDH, providing a synthesis for translating these advanced material sciences into standardized, multidisciplinary neurointerventional care.
2026-07-09 | Regression of retinal capillary hemangioblastoma with systemic belzutifan in von Hippel–Lindau disease: a case report
Purpose To report a case of retinal capillary hemangioblastoma (RCH) regression in a patient with von Hippel–Lindau (VHL) disease following treatment with systemic belzutifan. Case presentation A 49-year-old female with VHL disease presented with a retinal capillary hemangioblastoma in the left eye that had been previously treated with laser therapy. She subsequently developed a new retinal lesion and interval growth of a renal intraparenchymal mass, for which systemic belzutifan was initiated. Four months after treatment initiation, a reduction in the size of the retinal lesions was observed, along with decreased perfusion and vascularity. Conclusion Systemic belzutifan therapy for VHL disease may induce regression of retinal capillary hemangioblastomas and can be effective as either a primary or an adjunctive treatment modality.
2026-07-05 | Discovery of SD-2301 as a Highly Potent and Selective PROTAC STAT3 Degrader Capable of Achieving Complete Tumor Regression with Single Administration
High Resolution Image Download MS PowerPoint Slide STAT3 is a promising therapeutic target for human cancers and other diseases. Herein, we report our development of novel STAT3 proteolysis-targeting chimera degraders using high-affinity STAT3 and Von Hippel-Lindau 1 ligands, which led to the discovery of SD-2301 as a highly potent, selective, and efficacious STAT3 degrader. SD-2301 achieved DC 50 = 4 nM and D max of >95% and is >100 times more potent than SD-36 and SD-91. SD-2301 is highly selective for inducing STAT3 degradation over other Signal Transducer and Activator of Transcription members. SD-2301 inhibited cell growth with IC 50 = 5–11 nM in the SU-DHL-1 and SUP-M2 lymphoma cell lines. SD-2301 displayed an excellent pharmacokinetic profile in mice and achieved rapid and persistent depletion of STAT3 protein in native and xenograft tumor tissues in mice. SD-2301 was capable of achieving complete and long-lasting tumor regression in vivo and is a promising STAT3 degrader for the treatment of human cancers and other human diseases.
gene therapies
2026-08-03 | Diabetic ketoacidosis associated with pancreatic involvement in a patient with von Hippel-Lindau syndrome: a case report
Background Von Hippel–Lindau (VHL) disease is a rare autosomal dominant disorder predisposing individuals to multisystem neoplasms. While pheochromocytoma is a well-recognized endocrine manifestation of VHL, pancreatic involvement leading to clinically significant endocrine dysfunction is less frequently emphasized. We report a case of VHL syndrome in which diabetic ketoacidosis (DKA) occurred in the context of underlying pancreatic pathology, highlighting a potential but underexplored metabolic complication in these patients. Case summary A 31-year-old man came to the emergency department with a three-year history of polydipsia, polyuria, and hyperglycemia, and was diagnosed with diabetic ketoacidosis (DKA). His history included resection of cerebellar hemangioblastoma in 2009 and again in 2017, as well as subtotal pancreatectomy (head and body) for pancreatic lesions in 2017. At that time, his blood glucose was normal. His mother and maternal aunt both had hemangioblastoma. During this admission, we found severely impaired islet function in the residual pancreatic tail. Autoimmune diabetes was ruled out by negative anti-GAD, anti-IA-2, and anti-ZnT8 antibodies. There was no sign of infection or steroid use. Genetic testing showed a heterozygous deletion in exon 3 of the VHL gene, confirming VHL syndrome. With no other triggers identified, we attributed the DKA to acute decompensation from markedly reduced beta-cell reserve, likely due to both prior pancreatic resection and chronic VHL-related pancreatic disease. However, without serial imaging or histopathology to confirm progressive changes in the remnant tail, we could not establish a definitive causal relationship. Conclusion This case highlights that DKA can occur as an acute metabolic decompensation in patients with VHL-related pancreatic disease, particularly in those with prior pancreatic resections and progressive beta-cell loss over time. Nevertheless, the exact pathophysiological link between VHL-associated pancreatic involvement and the onset of DKA remains speculative and likely multifactorial. Clinicians should maintain vigilance for endocrine pancreatic insufficiency in VHL patients who present with unexplained hyperglycemia, even in the absence of a prior diabetes diagnosis. Further studies and accumulated case evidence are needed to clarify the mechanisms and risk factors for DKA in this specific population.
2026-02-05 | [A Family case of von Hippel-Lindau syndrome].
Von Hippel-Lindau syndrome (FHL) is a rare autosomal dominant disease that leads to the formation of multiple organ tumor syndrome. The pathology is primarily caused by the inactivation of the VHL gene, which is located on chromosome 3 (3p25/26) and encodes ubiquitin ligase, which destroys hypoxia-induced factor-1α (HIF-1α). The genetic defect leads to the accumulation of HIF-1a protein, activating key carcinogenic pathways, and activated cytokines cause abnormal proliferation of tumor cells and oncogenesis. To date, more than 500 mutations have been registered in VHL. FHL syndrome is characterized by various tumors, including hemangioblastomas of the retina and central nervous system, pheochromocytomas, clear cell renal cell carcinoma, cystic adenoma and others. In the presented clinical description, pheochromocytoma was initially diagnosed in the patient's mother, and 2 months later in the eldest son. Subsequently, the results of a molecular genetic study made it possible to verify the diagnosis, since in the gene in exon 3 of VHL, a single nucleotide was replaced in the heterozygous state of C.500 G>A, leading to the replacement of the amino acid p.R167Q. Identification of the VHL gene mutation required genetic counseling of all family members, during which a similar mutation was identified in the younger brother. Surgical treatment is the main method of treating FHL syndrome, but advances in genetic research technologies provide new opportunities for the treatment of tumors associated with this syndrome.
2026-01-21 | Hemangioblastoma of the Kidney-A Comprehensive Clinical, Pathological, and Genetic Analysis of Four Cases.
Hemangioblastoma (HB) is a benign central nervous system (CNS) tumor associated with mutations in the von Hippel-Lindau (VHL) gene. Although rare outside the CNS, the pathological and genetic features remain poorly understood. We analyzed four renal hemangioblastomas (RHB). Demographics, clinical presentation, and follow-up data were collected. After assessing hematoxylin and eosin-stained slides, immunophenotyping was conducted using CA9, α-inhibin, AE1/AE3, CD10, CD56, PAX8, S100, MelanA, HMB45, CD117, FH, SDHB, and brachyury antibodies, alongside mismatch repair (MMR) deficiency examination. Additionally, whole-exome sequencing (WES) was performed in 3 tumors. Our cohort comprised 3 male and 1 female patients, with a median age of 49 years. No data on VHL disease were available. Well-circumscribed tumors (median size: 25.5 mm) displayed clear vacuolated cytoplasm with a vascular component. Immunostaining revealed expression of PAX8, α-inhibin, AE1/AE3, S100, and cytoplasmic brachyury. WES analysis detected no pathogenic mutations. No cancer-related deaths or progressions were observed. Histologically, RHB resembles low-grade ccRCC and shares expression of PAX8, pancytokeratin, and CA9. However, RHB is uniquely positive for α-inhibin, S100, and lacks VHL alterations. Its favorable prognosis underscores the importance of distinguishing it from ccRCC to prevent unnecessary treatments. Further research is warranted to elucidate the underlying genetic mechanisms.
2025-12-27 | Phenotypic variability in von Hippel-Lindau disease, efficacy of therapy, and prognosis. A review of the literature
Von Hippel-Lindau disease is an inherited cancer predisposition that occurs due to an incorrect structure or a lack of the von Hippel-Lindau protein.Von Hippel-Lindau disease is known to have a noteworthy phenotypic variability and an elevated risk of developing tumors.A multitude of publications have demonstrated the correlation of the severity of a disease with a patient's genotype.Missense mutations in exon three are associated with one of the most severe outcomes, including the elevated risk of clear cell renal cell carcinoma and pancreatic neuroendocrine tumors.Deletions in exon one significantly raise the risk of developing pheochromocytomas.The review proved the importance of tailoring the therapeutic strategy to the genetic profile of the patient.Belzutifan shows high efficacy in treating patients with mutations in exon three.The development of gene therapy, which is currently in preclinical testing, could become a groundbreaking approach to treatment.Heterogeneity of VHL gene mutations leads to high phenotypic variability in the disease.It directly modulates the disease course, treatment efficacy, and prognosis.Early molecular diagnostics and personalized therapy based on the genetic profile are critical for improving patient care.Further studies and the improvement of modern therapeutic approaches, including gene therapy, are necessary.
2025-11-13 | Manipulation with Mutational Status of VHL Regulates Hypoxic Metabolism and Pro-Angiogenic Phenotypes in ccRCC Caki-1 Cells.
Clear cell renal cell carcinoma (ccRCC), accounting for 80-90% of renal malignancies, is frequently driven by VHL inactivation-either through mutation or promoter hypermethylation-resulting in constitutive HIF2α activation and pseudohypoxic signaling. VHL gene inactivation is a hallmark of von Hippel-Lindau syndrome, a hereditary disorder predisposing patients to ccRCC and other tumors, underscoring its central role in disease pathogenesis. While VHL dysfunction promotes aggressive tumor phenotypes, the therapeutic potential of VHL restoration remains underexplored. Here, using the Cas9 induced VHL-mutation in the Caki-1 cell line model, we demonstrate that VHL inactivation augments hypoxia-like pathways and enhances anaerobic glycolysis. Rescue of functional VHL reversed these activation patterns and modulated the expression of genes associated with angiogenesis. Using single cell transcriptomics, we show that the VHL-positive and -negative Caki-1 cells are characterized with different proportions of benign and aggressive cells as seen by analysis of specific gene expression. Furthermore, the identified angiogenesis-related genes were linked to affect clinical outcomes in ccRCC patients, suggesting that VHL restoration may mitigate high-risk molecular features.
proteins
2025-10-03 | Revealing a Heterozygous FCGR1A Variant in a Patient with Uveal Melanoma and Von Hippel-Lindau Syndrome: A Rare Case Report.
To report a rare case of uveal melanoma (UM) and Von Hippel-Lindau (VHL) syndrome in a patient who underwent whole exome sequencing (WES) to identify the possible genetic cause of the disease. A 54-year-old patient was referred to the eye clinic at the Rassoul Akram Hospital in 2016 due to complaints of blurry vision. In addition to UM, he later developed retinal capillary hemangioblastomas in his eye and a central nervous system hemangioblastoma. Proband had a family history of prostate cancer, breast cancer, skin cancer, and acute myeloid leukemia. After analyzing the Sanger sequencing and multiplex ligation-dependent probe amplification of the VHL genes, no mutations were found, leading to the decision to perform WES. WES disclosed a heterozygous known pathogenic nonsense variant: c.274C>T (p.Arg92*) in exon 3 of gene FCGR1A. Our examination indicated that FCGR1A: c.274C>T (p.Arg92*) may have contributed to the co-occurrence of UM and VHL disease. In the future, FCGR1A could be a promising therapeutic approach for retinal cancer due to its role in several cancers and retinal degeneration. To gain a better understanding of its pathogenesis mechanism, it is recommended to conduct functional analysis using appropriate animal models before using the variant in genetic counseling.
2024-09-27 | Somatostatin receptor 2A expression in von Hippel-Lindau-related hemangioblastomas.
Central nervous system hemangioblastomas are the most prevalent manifestation of von Hippel-Lindau (VHL) disease and remain the main cause of mortality. Surgical resection is the primary treatment strategy, but is not always possible, and should be used as restrictively as possible. There is an unmet need for less invasive treatment strategies, such as targeted therapy. Expression of somatostatin receptor 2A (SSTR2A) in VHL-related hemangioblastomas has been described earlier, but the extent of expression in a larger population has yet to be determined. The authors hypothesize that a substantial subset of VHL-related hemangioblastomas show SSTR2A expression, which may serve as a potential new treatment target. Patients who were surgically treated for a VHL-related hemangioblastoma from 1990 until 2021 at the UMC Utrecht were included. Clinical data was derived from a clinical database. Tissue samples were histopathologically examined with use of hematoxylin and eosin staining, and immunohistochemical analysis of SSTR2A expression was performed. Forty-three tissue samples were obtained from 26 patients. Nine showed strong positivity for SSTR2A expression, whereas 13 showed moderate and 15 sparse expression. Three samples showed no expression of SSTR2A. The distribution showed right-skewedness favoring a strong expression. SSTR2A expression colocalized with endothelial markers and not with stromal cells. Additionally, within-patient variability for SSTR2A expression was described in 14 patients. SSTR2A is expressed in varying degrees in the majority of VHL-related hemangioblastomas. Future treatment with somatostatin analogues or even peptide receptor radionuclide treatment may be considered for SSTR2A-positive cases.
2024-09-01 | A nature-inspired HIF stabilizer derived from a highland-adaptation insertion of plateau pika Epas1 protein
Hypoxia-inducible factors (HIFs) play pivotal roles in numerous diseases and high-altitude adaptation, and HIF stabilizers have emerged as valuable therapeutic tools. In our prior investigation, we identified a highland-adaptation 24-amino-acid insertion within the Epas1 protein. This insertion enhances the protein stability of Epas1, and mice engineered with this insertion display enhanced resilience to hypoxic conditions. In the current study, we delved into the biochemical mechanisms underlying the protein-stabilizing effects of this insertion. Our findings unveiled that the last 11 amino acids within this insertion adopt a helical conformation and interact with the α-domain of the von Hippel-Lindau tumor suppressor protein (pVHL), thereby disrupting the Eloc-pVHL interaction and impeding the ubiquitination of Epas1. Utilizing a synthesized peptide, E14-24, we demonstrated its favorable membrane permeability and ability to stabilize endogenous HIF-α proteins, inducing the expression of hypoxia-responsive element (HRE) genes. Furthermore, the administration of E14-24 to mice subjected to hypoxic conditions mitigated body weight loss, suggesting its potential to enhance hypoxia adaptation.
2024-06-01 | RESPONSES TO SEQUENTIAL SURGERY AND INTERFERON THERAPY OF THE NEUROENDOCRINE PANCREATIC CANCER METASTASES IN A FEMALE PATIENT WITH VON HIPPEL-LINDAU DISEASE
Abstract. Introduction. The article provides a literature review on the epidemiology, diagnosis, and treatment of neuroendocrine tumors. The morpho-functional classification by WHO 2022 is presented with the division of neuroendocrine tumors into three groups. Justifications are given for the choice of instrumental methods of topical diagnostics and the need for determining universal and specific biochemical markers in blood serum or plasma. The principles are indicated for choosing the advanced methods of treating neuroendocrine tumors. Aim. To review the scientific literature on neuroendocrine tumors, providing our own clinical observations. Materials and Methods. Russian- and English-language literature sources on this disease were searched for in the databases, such as PubMed, Medscape, Cochrane Library, and eLibrary. Clinical case of our female patient V., 36 years old, with von Hippel-Lindau disease (heterozygous mutation R167W of the VHL gene). Results and Discussion. As an example, we describe a clinical case of surgical treatment followed by long-term use of interferons in a female patient with neuroendocrine pancreatic cancer with metastases to the liver and retroperitoneal lymph nodes. Histological examination of the surgical material revealed highly differentiated neuroendocrine cancer with low malignant potential. A screening examination of the genetic syndrome components revealed a heterozygous mutation R167W of the VHL gene. Her survival under treatment exceeded 9.5 years, including more than 4.5 years from the start of interferon therapy. This pathology occurred in a young woman with one of the rare genetic multiorgan hereditary forms of neuroendocrine tumors, Von Hippel-Lindau disease that manifested itself as a combination of benign (retinal angiomatosis of both eyes and adenomas of both adrenal glands) and malignant diseases (pancreatic cancer). Conclusions. The given clinical example demonstrates that in a patient with highly differentiated metastatic pancreatic cancer, after distal subtotal resection of the pancreas, splenectomy, retroperitoneal lymphadenectomy, followed by treatment with interferons, life expectancy was more than 9.5 years, including more than 4.5 years from the start of therapy with interferons only. Despite the numerous side effects of interferons described in the literature, the patient tolerated the treatment well. At the same time, a connection between the hypothyroidism detected in the patient and treatment with interferons cannot be ruled out, since dysfunction of the thyroid gland is one of its side effects.
2022-05-11 | Immunohistochemical Expression Pattern of Theragnostic Targets SSTR2 and PSMA in Endolymphatic Sac Tumors: A Single Institution Case Series
Endolymphatic sac tumors are rare neoplasia characterized by slow growth. However, their clinical impact should not be underestimated, considering their potential for local aggressive behavior and strong association with von Hippel-Lindau syndrome. Therefore, early detection with emerging theragnostic examinations such as 68Ga-DOTATATE-PET/CT might improve patient management and reduce morbidity.We report the clinicopathological features of seven endolymphatic sac tumors. In this cohort, we performed immunohistochemical analysis of somatostatin receptor 2A (SSTR2A) and prostate specific membrane antigen (PSMA) protein expression patterns; two targets providing rationale for novel imaging modalities such as PSMA- or SSTR-targeted PET.The tumor cells of all cases were negative for prostate specific membrane antigen and somatostatin receptor 2A, however immunolabeling was consistently detected in intratumoral endothelial cells of endolymphatic sac tumors for PSMA (7/7 cases, 100%), and for SSTR2A (5/7 cases, 71%).Our results show a high rate of PSMA and SSTR2A expression in the tumor vasculature of endolymphatic sac tumors. PSMA and SSTR2A can be targeted with appropriate radioligands for diagnostic and therapeutic purposes. This finding provides a rationale for prospective clinical studies to test this approach as a sensitive screening tool for patients with suspected endolymphatic sac tumors including an improved management of von Hippel-Lindau syndrome.
antibodies
2026-06-08 | Concurrent Von Hippel-Lindau disease and enhanced S-cone syndrome leading to a distinct retinal phenotype.
Von Hippel-Lindau (VHL) disease and Enhanced S-cone syndrome (ESCS) are rare inherited disorders that independently predispose to vision-threatening retinal pathology through distinct mechanisms: VHL through hypoxia-induced activation of several angiogenic factors, which lead to the development of retinal capillary hemangioblastoma (RCH), and ESCS by disrupting photoreceptor development through NR2E3 variants. We describe the coexistence of these two conditions in a pediatric patient, confirmed by multimodal imaging, electroretinography, and genetic testing. A retrospective case report. A 13-year-old girl presented with poor vision in both eyes, mainly in dim light. Fundus examination revealed multiple small hypopigmented areas distributed nasally and temporally along the inferior arcades in both eyes, and multiple small RCHs distributed in all quadrants with superonasal exudations and macular choroidal neovascular membrane (CNVM) in the left eye. Full-field electroretinography (ff-ERG) showed nonrecordable rod responses, broadened rod-cone and cone responses, and a markedly reduced 30-Hz flicker amplitude. While the right eye was successfully managed conservatively, targeted focal laser and intravitreal anti-vascular endothelial growth factor (VEGF) therapy led to regression of neovascular lesions and visual improvement in the left eye. Whole-exome sequencing identified a heterozygous VHL c.452T > C (p.Ile151Thr) variant and a homozygous NR2E3 c.932G > A (p.Arg311Gln) variant. Both VHL disease and ESCS manifested their characteristic retinal findings of RCH, along with the typical electrophysiological features and the CNVM associated with ESCS.
2025-11-08 | Bifurcate Regulation of Hematopoietic Homeostasis and Bone Osteogenesis by VHL-HIF2α-Controlled Adipocyte Function.
Adipocytes play a pivotal role in maintaining metabolic and immunological homeostasis. Here, this work shows that VHL-HIF2α (VHL is Von Hippel-Lindau) axis in mature adipocytes regulates hematopoiesis and osteogenesis. Genetic ablation of VHL in adipocytes triggers profound systemic autoinflammation and abnormal hematopoiesis, concomitant with fat mass decrease and pathological elevation of bone mass. On one hand, VHL deficiency results in aberrantly high stem cell factor (SCF) expression in adipocytes, which exerts a negative role for hematopoietic homeostasis through disrupting hematopoietic stem cell (HSC) quiescence. In vivo anti-CD117 monoclonal antibody treatment ameliorates the hematopoietic defects in VHL-deficient mice. On the other hand, direct HIF2α binding to hypoxia-response elements in the Rarres2 locus enhances chemerin production in adipocytes, which facilitates mesenchymal stem cell (MSC) osteogenesis via Wnt/β-catenin activation. Pharmacological chemerin neutralization through CMKLR1 inhibition using α-NETA mitigates osteogenic activity both in vitro and in vivo. This work thus identifies chemerin as the pivotal molecular nexus connecting hypoxic adipocyte dysfunction to pathological osteosclerosis. The findings uncover a hypoxia-driven signaling network in adipocytes that orchestrates cross-talk with both HSCs and MSCs to regulate systemic homeostasis, thereby revealing therapeutic targets for disorders associated with adipocyte dysfunction.
2025-09-19 | Quantitative analysis of the anti-VEGF effect for retinal capillary hemangiomas and vasoproliferative tumors.
PurposeTo assess the effect of anti-VEGF intravitreal injection (IVI) on vascularity and size of retinal angiomas using quantitative analysis of color fundus images.MethodsColor fundus images of retinal angiomas underwent RGB analysis with ImageJ software. White intensity (mean RGB values) and red ratio (red value/sum of green and blue values) were calibrated to obtain the white intensity and red indices, respectively. The lesion-disc area ratio was assessed for size changes.ResultsSeventeen image sets of 10 angiomatous lesions were analyzed: 6 retinal hemangiomas from 4 eyes (4 patients) with Von Hippel-Lindau disease (VHL) and 4 retinal vasoproliferative tumors (VPT) from 4 eyes (4 patients). Overall, the white intensity index increased from 1.34 to 1.5 (P = 0.001), and the red index decreased from 1.14 to 0.85 (P < 0.001) post-IVI. In the VHL group, white intensity increased from 1.41 to 1.58 (P = 0.013), and the red index decreased from 1.04 to 0.84 (P < 0.001). In the VPT group, white intensity increased from 1.17 to 1.36 (P = 0.031) and red index decreased from 1.39 to 0.87 (P = 0.156) after IVI. Lesion-disc area ratio decreased significantly in both groups.ConclusionAnti-VEGF induces whitening and reduces the red component of angiomas, diminishing vascularity and facilitating subsequent invasive treatments.
2025-02-12 | Carbonic anhydrase-9-targeted near-infrared photoimmunotherapy as a theranostic modality for clear cell renal cell carcinoma.
Carbonic anhydrase-9 (CA9) is highly expressed in clear cell renal cell carcinoma (ccRCC) cells despite no expression in normal kidney tissues. Thus, CA9 has been proposed as a theranostic target for radioligand therapy (RLT). However, ccRCC tends to be radioresistant and may not effectively respond to RLT. Alternatively, CA9 can be targeted for near-infrared photoimmunotherapy (NIR-PIT) of ccRCC. Here, we sought to test NIR-PIT using CA9 in a preclinical model of ccRCC to determine its potential as a therapeutic strategy. Tissue microarray analysis showed that membrane CA9 was expressed in the majority of ccRCC cases. In vitro, CA9-targeted NIR-PIT induced cell membrane damage and cell killing in all CA9-expressing ccRCC cell lines specifically, UOK154, UOK220, and UOK122. In vivo, CA9-targeted NIR-PIT significantly inhibited tumor growth and prolonged survival in UOK154 and UOK220 subcutaneous xenograft models. Notably, 70%-80% of mice achieved complete remission after a single treatment of NIR-PIT. Additionally, remaining tumors after the first NIR-PIT persistently expressed CA9, suggesting that remaining tumors can be treated with repeated NIR-PIT. Furthermore, CA9-targeted NIR-PIT induced significant cytoplasmic damages on ccRCC cells in UOK154 orthotopic xenograft models. In conclusion, CA9-targeted NIR-PIT, which allow for safe and repeated application on the same lesion, is a promising treatment for ccRCC, especially in the management of multiple primary ccRCC (e.g., von Hippel-Lindau syndrome) and oligometastatic ccRCC.
2025-01-20 | Mathematical Modeling and Simulation of Tumor-Induced Angiogenesis in Retinal Hemangioblastoma
Retinal Hemangioblastoma (RH) is the most frequent manifestation of the von Hippel-Lindau syndrome (VHL), a rare disease associated with the germline mutation of the von Hippel-Lindau protein (pVHL). An emblematic feature of RH is the high vascularity, which is explained by the overexpression of angiogenic factors (AFs) arising from the pVHL impairment. The introduction of Optical Coherence Tomography Angiography (OCTA) allowed observing this feature with exceptional detail. Here, we combine OCTA images and a mechanistic model to investigate tumor growth and vascular development in a patient-specific way. We derived our model from the agreed pathology for RH and focused on the earliest stages of tumor-induced angiogenesis. Our simulations closely resemble the medical images, proving the capability of our model to recapitulate vascular patterning in actual patients. Our results also suggest that angiogenesis in RH occurs upon reaching a critical dimension (around 200 um), followed by the rapid formation of stable vascular networks. These findings open a new perspective on the crucial role of time in antiangiogenic therapy in RH, which has resulted in ineffective control. Indeed, it might be that when RH is diagnosed, angiogenesis is already too advanced to be effectively targeted with any effective means. Moreover, our simulations suggest that vascularization in RH is not a continuous process but an inconstant development with long, stable phases and rapid episodes of vascular sprouting.
other
2025-07-29 | Overexpression of BDNF and uPA Combined with the Suppression of Von Hippel-Lindau Tumor Suppressor Enhances the Neuroprotective Activity of the Secretome of Human Mesenchymal Stromal Cells in the Model of Intracerebral Hemorrhage.
Nerve tissue damage is an unsolved problem in modern neurology and neurosurgery, which prompts the need to search for approaches to stimulate neuroprotection and regeneration of neural tissue. Earlier we have shown that the secretome of human mesenchymal stromal cells (MSCs) stimulates rat survival, reduces the severity of neurological deficits, and decreases the volume of brain damage in a hemorrhagic stroke model. A significant disadvantage of using the MSC secretome is the need to concentrate it (at least 5-10 fold) to achieve appreciable pharmacological activity. This increases the cost of obtaining clinically applicable amounts of secretome and slows down the clinical translation of this technology. Here, we created a number of genetically modified human MSC cultures, including immortalized MSCs and those with hyperexpression of brain-derived neurotrophic factor (BDNF) and urokinase-type plasminogen activator (uPA) and with suppressed expression of Von Hippel-Lindau tumor suppressor (VHL), and we evaluated the pharmacological activity of their secretomes in a model of intracerebral hemorrhage (ICH) in rats. The secretome of MSCs immortalized by hyperexpression of the catalytic subunit of human telomerase (hTERT) revealed neuroprotective activity indistinguishable from that of primary MSC cultures, yet it still required 10-fold concentration to achieve neuroprotective efficacy. The secretome of MSC culture with combined hyperexpression of BDNF and uPA and suppressed expression of Von Hippel-Lindau tumor suppressor even without additional concentration reduced the severity of neurological disorders and decreased brain lesion volume in the ICH model. The secretomes of MSCs with separate overexpression of BDNF and uPA or suppression of VHL had no such effect or, on the contrary, revealed a toxic effect in the ICH model. Presumably, this may be due to an imbalance in the representation of individual growth factors in the secretome of genetically modified MSCs, which individually may lead to undesirable effects in damaged nervous tissue, such as increased permeability of the blood-brain barrier (under the influence of pro-angiogenic factors) or neural cell apoptosis (due to an excess of neurotrophic factors). The obtained data show that genetic modification of MSC cultures can enhance or alter the therapeutic activity of their secretomes, which can be used in the creation of promising sources of biopharmaceutical substances.
2023-12-16 | Outcomes of and indications for renal transplantation in patients with von Hippel Lindau disease.
Von Hippel-Lindau (VHL) is a hereditary cancer syndrome characterized by bilateral, multifocal renal masses. The cumulative impact of extirpative surgery can depreciate renal function and render patients anephric. In the larger end-stage renal disease population, renal transplant offers both excellent quality of life and functional renal replacement. This case control study aims to examine and compare oncologic and functional outcomes of patients who have undergone renal transplant as renal replacement therapy (RRT) to those who remain anephric. Patient charts were retrospectively reviewed of patients with germline testing confirmed VHL between 1980 and 2022 for transplant, all prior surgical history (within and outside the NCI), renal function and graft outcomes. Overall survival (OS) was determined from years after radical nephrectomy, and graft time was defined as years of graft function from initial transplant until failure or patient death. Graft survival was determined as time between transplant(s) to last follow up. Kaplan-Meier analysis was conducted to compare graft times of anephric VHL patients to those with transplanted kidneys. A total of 23 VHLD patients were identified as either anephric or candidates for transplant. Out of this cohort, 11 total VHLD received 12 total kidney grafts. Median wait time from nephrectomy to transplant was 22.6 months (IQR: 1.02-40.25 months). Median age at transplant was 32 years (IQR: 23-54 years). OS at 5 and 10 years of anephric patients who did not receive a transplant was 33% and 16.7%, respectively. OS rates of the transplant cohort at 10, 15, and 20 years were 91%, 78%, and 58% years, respectively. Median graft time was 161 months (IQR: 56-214 months). Graft survival at 10, 15, and 20 years was 69.8%, 69.8%, and 26.2%, respectively. We demonstrate that transplant recipients have decreased mortality with no difference in cancer recurrence compared to those who do not receive renal transplant for RRT. This data can aid in informing providers of the optimal window for early RRT planning in VHL, while also improving patient counseling.
2022-12-16 | CD70-Targeted Micelles Enhance HIF2α siRNA Delivery and Inhibit Oncogenic Functions in Patient-Derived Clear Cell Renal Carcinoma Cells.
The majority of clear cell renal cell carcinomas (ccRCCs) are characterized by mutations in the Von Hippel−Lindau (VHL) tumor suppressor gene, which leads to the stabilization and accumulation of the HIF2α transcription factor that upregulates key oncogenic pathways that promote glucose metabolism, cell cycle progression, angiogenesis, and cell migration. Although FDA-approved HIF2α inhibitors for treating VHL disease-related ccRCC are available, these therapies are associated with significant toxicities such as anemia and hypoxia. To improve ccRCC-specific drug delivery, peptide amphiphile micelles (PAMs) were synthesized incorporating peptides targeted to the CD70 marker expressed by ccRCs and anti-HIF2α siRNA, and the ability of HIF2α-CD27 PAMs to modulate HIF2α and its downstream targets was evaluated in human ccRCC patient-derived cells. Cell cultures were derived from eight human ccRCC tumors and the baseline mRNA expression of HIF2A and CD70, as well as the HIF2α target genes SLC2A1, CCND1, VEGFA, CXCR4, and CXCL12 were first determined. As expected, each gene was overexpressed by at least 63% of all samples compared to normal kidney proximal tubule cells. Upon incubation with HIF2α-CD27 PAMs, a 50% increase in ccRCC-binding was observed upon incorporation of a CD70-targeting peptide into the PAMs, and gel shift assays demonstrated the rapid release of siRNA (>80% in 1 h) under intracellular glutathione concentrations, which contributed to ~70% gene knockdown of HIF2α and its downstream genes. Further studies demonstrated that knockdown of the HIF2α target genes SLC2A1, CCND1, VEGFA, CXCR4, and CXCL12 led to inhibition of their oncogenic functions of glucose transport, cell proliferation, angiogenic factor release, and cell migration by 50−80%. Herein, the development of a nanotherapeutic strategy for ccRCC-specific siRNA delivery and its potential to interfere with key oncogenic pathways is presented.
2015-09-17 | Computational and experimental characterization of dVHL establish a Drosophila model of VHL syndrome.
The von Hippel-Lindau (VHL) cancer syndrome is associated with mutations in the VHL gene. The pVHL protein is involved in response to changes in oxygen availability as part of an E3-ligase that targets the Hypoxia-Inducible Factor for degradation. pVHL has a molten globule configuration with marginal thermodynamic stability. The cancer-associated mutations further destabilize it. The Drosophila homolog, dVHL, has relatively low sequence similarity to pVHL, and is also involved in regulating HIF1-α. Using in silico, in vitro and in vivo approaches we demonstrate high similarity between the structure and function of dVHL and pVHL. These proteins have a similar fold, secondary and tertiary structures, as well as thermodynamic stability. Key functional residues in dVHL are evolutionary conserved. This structural homology underlies functional similarity of both proteins, evident by their ability to bind their reciprocal partner proteins, and by the observation that transgenic pVHL can fully maintain normal dVHL-HIF1-α downstream pathways in flies. This novel transgenic Drosophila model is thus useful for studying the VHL syndrome, and for testing drug candidates to treat it.
2015-05-12 | Hypoxia-inducible factor as an angiogenic master switch.
Hypoxia-inducible factors (HIFs) regulate the transcription of genes that mediate the response to hypoxia. HIFs are constantly expressed and degraded under normoxia, but stabilized under hypoxia. HIFs have been widely studied in physiological and pathological conditions and have been shown to contribute to the pathogenesis of various vascular diseases. In clinical settings, the HIF pathway has been studied for its role in inhibiting carcinogenesis. HIFs might also play a protective role in the pathology of ischemic diseases. Clinical trials of therapeutic angiogenesis after the administration of a single growth factor have yielded unsatisfactory or controversial results, possibly because the coordinated activity of different HIF-induced factors is necessary to induce mature vessel formation. Thus, manipulation of HIF activity to simultaneously induce a spectrum of angiogenic factors offers a superior strategy for therapeutic angiogenesis. Because HIF-2α plays an essential role in vascular remodeling, manipulation of HIF-2α is a promising approach to the treatment of ischemic diseases caused by arterial obstruction, where insufficient development of collateral vessels impedes effective therapy. Eukaryotic initiation factor 3 subunit e (eIF3e)/INT6 interacts specifically with HIF-2α and induces the proteasome inhibitor-sensitive degradation of HIF-2α, independent of hypoxia and von Hippel-Lindau protein. Treatment with eIF3e/INT6 siRNA stabilizes HIF-2α activity even under normoxic conditions and induces the expression of several angiogenic factors, at levels sufficient to produce functional arteries and veins in vivo. We have demonstrated that administration of eIF3e/INT6 siRNA to ischemic limbs or cold-injured brains reduces ischemic damage in animal models. This review summarizes the current understanding of the relationship between HIFs and vascular diseases. We also discuss novel oxygen-independent regulatory proteins that bind HIF-α and the implications of a new method for therapeutic angiogenesis using HIF stabilizers.
small molecules
2026-08-13 | Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).
Von Hippel-Lindau disease (VHLD) is a rare autosomal dominant disease, occuring in ~ 1 in 35,000 individuals. Overall, individuals with inherited mutations in the VHL tumor suppressor gene are predisposed to a variety of cancer, including high frequencies of clear cell renal cell carcinoma (ccRCC), pancreatic neuroendocrine tumors, and hemangioblastomas, as well as benign cystic conditions and other cancers. The degree of risk for each of these pathological conditions depends on the location and severity of the inherited germline mutation, and the specific VHL protein interactions and functions disrupted. A core VHL protein function is as the targeting subunit of an E3 ligase complex, with protein degradation activity based on interactions with elongins (ELOB, ELOC), Cullin 2 (CUL2), and RBX1. For ccRCC and some other cancers, loss of VHL-dependent degradation of key substrates-the transcription factors hypoxia-inducible factor alpha (HIF-1α and HIF-2α)-and upregulation of HIF-dependent transcripts are critical to promote tumor formation. For this reason, drugs such as the HIF signaling inhibitor belzutifan have emerged as promising clinical agents for treatment of VHLD patients prone to ccRCC. However, other biological consequences of VHL loss are independent of HIFα degradation, and in some cases independent of the VHL ubiquitin ligase activity. Non-canonical activities of VHL include regulation of microtubule stability, mitotic progression, and ciliation, as well as formation of the extracellular matrix (ECM); the degree to which disruption of these activities contributes to VHLD is currently not well understood. This review provides a concise update of the current literature on VHLD pathogenesis, the relationship of VHL structure and protein interactions to the spectrum of phenotypes associated with VHLD, and current and proposed treatment, prevention, and interception of cancer formation for VHLD patients.
2026-08-05 | Case Report: Diagnosis and treatment report and literature review of 2 cases of VHL-deficient renal cell carcinoma.
Von Hippel-Lindau (VHL) disease is a rare familial autosomal dominant disorder with an incidence rate of approximately 1 in 36,000. It primarily results from mutations or inactivation of the VHL tumor suppressor gene located on chromosome 3p25-p26. The hallmark of this disease is hereditary hemangioblastoma, which can affect multiple organs and systems, including the brain (commonly infratentorial), spinal cord, retina, and internal organs such as the kidneys, adrenal glands, and pancreas. Less commonly, lesions may include papillary cystadenomas and endolymphatic sac tumors (ELST), which can form in the epididymis or broad ligament. The leading causes of death in these patients are hemangioblastomas and renal cell carcinoma of the central nervous system. Due to the multidisciplinary nature of the disease, diagnosis and management require a multidisciplinary team (MDT) consultation and collaboration among various specialties. Clinical diagnosis, genetic implications, and prognosis must be assessed comprehensively, with genetic testing confirming the diagnosis. Cases of VHL are exceptionally rare in clinical practice, and there remains a significant unmet need for effective treatments, particularly in rare tumors. Misdiagnosis and mistreatment are common, and repeated surgical interventions can exacerbate kidney damage. Early and accurate diagnosis, followed by proactive treatment, can significantly improve prognosis. Recently, our department admitted two patients with VHL-deficient renal cell carcinoma. Through surgery, radiofrequency ablation, and subsequent targeted therapy, the therapeutic outcomes were highly favorable. This report introduces the treatment of these two cases and provides a literature review on the current progress in the diagnosis, treatment, and prognosis of VHL-deficient renal cell carcinoma. Additionally, it discusses data on the screening of VHL patients and their close relatives, while emphasizing the optimization of individualized management for renal cell carcinoma to enhance the understanding, diagnosis, and treatment of the disease.
2026-07-28 | Endovascular Embolization in Neurovascular Disease: Material Science, Multimodal Management, and Future Horizons.
Background & Objectives: Endovascular embolization has matured into a sophisticated, precision-guided discipline that is central to the management of complex neurovascular pathologies. This review synthesizes contemporary treatment strategies, evaluating the advanced material characteristics of conventional inert liquid polymers, specifically non-adhesive ethylene vinyl alcohol (EVOH) copolymers and adhesive cyanoacrylates, alongside their targeted clinical applications in brain arteriovenous malformations (bAVMs), dural arteriovenous fistulas (dAVFs), hypervascular intracranial tumors, and chronic subdural hematomas (CSDHs). Furthermore, it examines the critical material and hemodynamic constraints that limit these agents in cerebral aneurysm repair. Methods: A comprehensive literature synthesis through 3 July 2026 was integrated with peer-reviewed clinical illustrations to evaluate both procedural mechanics and the necessity of post-procedural physiological management. Review Findings: Embolization serves a critical dual role: as a definitive curative therapy and as an essential preoperative or radiosurgical adjunct. As demonstrated by recent clinical validations, technical angiographic success must be closely coupled with vigilant neurocritical oversight to manage profound, localized hemodynamic shifts. While these conventional methods represent established clinical practice, the field is evolving away from inert mechanical occlusion toward a highly integrated approach. The convergence of stimuli-responsive "smart" hydrogels and endovascular robotics is being evaluated for potential roles in transforming these interventions into dynamic, bioactive platforms capable of modulating disease-specific mechanisms, such as Rat Sarcoma-Mitogen-Activated Protein Kinase (RAS-MAPK) and Bone Morphogenetic Protein (BMP) signaling in bAVMs or the Von Hippel-Lindau/Vascular Endothelial Growth Factor (VHL/VEGF) axis in hypervascular tumors. This review further analyzes landmark data, including the Squid Trial For the Embolization of the Middle Meningeal Artery for Treatment of Chronic Subdural Hematoma (STEM) trial for CSDH, providing a synthesis for translating these advanced material sciences into standardized, multidisciplinary neurointerventional care.
2026-07-09 | Regression of retinal capillary hemangioblastoma with systemic belzutifan in von Hippel–Lindau disease: a case report
Purpose To report a case of retinal capillary hemangioblastoma (RCH) regression in a patient with von Hippel–Lindau (VHL) disease following treatment with systemic belzutifan. Case presentation A 49-year-old female with VHL disease presented with a retinal capillary hemangioblastoma in the left eye that had been previously treated with laser therapy. She subsequently developed a new retinal lesion and interval growth of a renal intraparenchymal mass, for which systemic belzutifan was initiated. Four months after treatment initiation, a reduction in the size of the retinal lesions was observed, along with decreased perfusion and vascularity. Conclusion Systemic belzutifan therapy for VHL disease may induce regression of retinal capillary hemangioblastomas and can be effective as either a primary or an adjunctive treatment modality.
2026-07-05 | Discovery of SD-2301 as a Highly Potent and Selective PROTAC STAT3 Degrader Capable of Achieving Complete Tumor Regression with Single Administration
High Resolution Image Download MS PowerPoint Slide STAT3 is a promising therapeutic target for human cancers and other diseases. Herein, we report our development of novel STAT3 proteolysis-targeting chimera degraders using high-affinity STAT3 and Von Hippel-Lindau 1 ligands, which led to the discovery of SD-2301 as a highly potent, selective, and efficacious STAT3 degrader. SD-2301 achieved DC 50 = 4 nM and D max of >95% and is >100 times more potent than SD-36 and SD-91. SD-2301 is highly selective for inducing STAT3 degradation over other Signal Transducer and Activator of Transcription members. SD-2301 inhibited cell growth with IC 50 = 5–11 nM in the SU-DHL-1 and SUP-M2 lymphoma cell lines. SD-2301 displayed an excellent pharmacokinetic profile in mice and achieved rapid and persistent depletion of STAT3 protein in native and xenograft tumor tissues in mice. SD-2301 was capable of achieving complete and long-lasting tumor regression in vivo and is a promising STAT3 degrader for the treatment of human cancers and other human diseases.
gene therapies
2026-08-03 | Diabetic ketoacidosis associated with pancreatic involvement in a patient with von Hippel-Lindau syndrome: a case report
Background Von Hippel–Lindau (VHL) disease is a rare autosomal dominant disorder predisposing individuals to multisystem neoplasms. While pheochromocytoma is a well-recognized endocrine manifestation of VHL, pancreatic involvement leading to clinically significant endocrine dysfunction is less frequently emphasized. We report a case of VHL syndrome in which diabetic ketoacidosis (DKA) occurred in the context of underlying pancreatic pathology, highlighting a potential but underexplored metabolic complication in these patients. Case summary A 31-year-old man came to the emergency department with a three-year history of polydipsia, polyuria, and hyperglycemia, and was diagnosed with diabetic ketoacidosis (DKA). His history included resection of cerebellar hemangioblastoma in 2009 and again in 2017, as well as subtotal pancreatectomy (head and body) for pancreatic lesions in 2017. At that time, his blood glucose was normal. His mother and maternal aunt both had hemangioblastoma. During this admission, we found severely impaired islet function in the residual pancreatic tail. Autoimmune diabetes was ruled out by negative anti-GAD, anti-IA-2, and anti-ZnT8 antibodies. There was no sign of infection or steroid use. Genetic testing showed a heterozygous deletion in exon 3 of the VHL gene, confirming VHL syndrome. With no other triggers identified, we attributed the DKA to acute decompensation from markedly reduced beta-cell reserve, likely due to both prior pancreatic resection and chronic VHL-related pancreatic disease. However, without serial imaging or histopathology to confirm progressive changes in the remnant tail, we could not establish a definitive causal relationship. Conclusion This case highlights that DKA can occur as an acute metabolic decompensation in patients with VHL-related pancreatic disease, particularly in those with prior pancreatic resections and progressive beta-cell loss over time. Nevertheless, the exact pathophysiological link between VHL-associated pancreatic involvement and the onset of DKA remains speculative and likely multifactorial. Clinicians should maintain vigilance for endocrine pancreatic insufficiency in VHL patients who present with unexplained hyperglycemia, even in the absence of a prior diabetes diagnosis. Further studies and accumulated case evidence are needed to clarify the mechanisms and risk factors for DKA in this specific population.
2026-02-05 | [A Family case of von Hippel-Lindau syndrome].
Von Hippel-Lindau syndrome (FHL) is a rare autosomal dominant disease that leads to the formation of multiple organ tumor syndrome. The pathology is primarily caused by the inactivation of the VHL gene, which is located on chromosome 3 (3p25/26) and encodes ubiquitin ligase, which destroys hypoxia-induced factor-1α (HIF-1α). The genetic defect leads to the accumulation of HIF-1a protein, activating key carcinogenic pathways, and activated cytokines cause abnormal proliferation of tumor cells and oncogenesis. To date, more than 500 mutations have been registered in VHL. FHL syndrome is characterized by various tumors, including hemangioblastomas of the retina and central nervous system, pheochromocytomas, clear cell renal cell carcinoma, cystic adenoma and others. In the presented clinical description, pheochromocytoma was initially diagnosed in the patient's mother, and 2 months later in the eldest son. Subsequently, the results of a molecular genetic study made it possible to verify the diagnosis, since in the gene in exon 3 of VHL, a single nucleotide was replaced in the heterozygous state of C.500 G>A, leading to the replacement of the amino acid p.R167Q. Identification of the VHL gene mutation required genetic counseling of all family members, during which a similar mutation was identified in the younger brother. Surgical treatment is the main method of treating FHL syndrome, but advances in genetic research technologies provide new opportunities for the treatment of tumors associated with this syndrome.
2026-01-21 | Hemangioblastoma of the Kidney-A Comprehensive Clinical, Pathological, and Genetic Analysis of Four Cases.
Hemangioblastoma (HB) is a benign central nervous system (CNS) tumor associated with mutations in the von Hippel-Lindau (VHL) gene. Although rare outside the CNS, the pathological and genetic features remain poorly understood. We analyzed four renal hemangioblastomas (RHB). Demographics, clinical presentation, and follow-up data were collected. After assessing hematoxylin and eosin-stained slides, immunophenotyping was conducted using CA9, α-inhibin, AE1/AE3, CD10, CD56, PAX8, S100, MelanA, HMB45, CD117, FH, SDHB, and brachyury antibodies, alongside mismatch repair (MMR) deficiency examination. Additionally, whole-exome sequencing (WES) was performed in 3 tumors. Our cohort comprised 3 male and 1 female patients, with a median age of 49 years. No data on VHL disease were available. Well-circumscribed tumors (median size: 25.5 mm) displayed clear vacuolated cytoplasm with a vascular component. Immunostaining revealed expression of PAX8, α-inhibin, AE1/AE3, S100, and cytoplasmic brachyury. WES analysis detected no pathogenic mutations. No cancer-related deaths or progressions were observed. Histologically, RHB resembles low-grade ccRCC and shares expression of PAX8, pancytokeratin, and CA9. However, RHB is uniquely positive for α-inhibin, S100, and lacks VHL alterations. Its favorable prognosis underscores the importance of distinguishing it from ccRCC to prevent unnecessary treatments. Further research is warranted to elucidate the underlying genetic mechanisms.
2025-12-27 | Phenotypic variability in von Hippel-Lindau disease, efficacy of therapy, and prognosis. A review of the literature
Von Hippel-Lindau disease is an inherited cancer predisposition that occurs due to an incorrect structure or a lack of the von Hippel-Lindau protein.Von Hippel-Lindau disease is known to have a noteworthy phenotypic variability and an elevated risk of developing tumors.A multitude of publications have demonstrated the correlation of the severity of a disease with a patient's genotype.Missense mutations in exon three are associated with one of the most severe outcomes, including the elevated risk of clear cell renal cell carcinoma and pancreatic neuroendocrine tumors.Deletions in exon one significantly raise the risk of developing pheochromocytomas.The review proved the importance of tailoring the therapeutic strategy to the genetic profile of the patient.Belzutifan shows high efficacy in treating patients with mutations in exon three.The development of gene therapy, which is currently in preclinical testing, could become a groundbreaking approach to treatment.Heterogeneity of VHL gene mutations leads to high phenotypic variability in the disease.It directly modulates the disease course, treatment efficacy, and prognosis.Early molecular diagnostics and personalized therapy based on the genetic profile are critical for improving patient care.Further studies and the improvement of modern therapeutic approaches, including gene therapy, are necessary.
2025-11-13 | Manipulation with Mutational Status of VHL Regulates Hypoxic Metabolism and Pro-Angiogenic Phenotypes in ccRCC Caki-1 Cells.
Clear cell renal cell carcinoma (ccRCC), accounting for 80-90% of renal malignancies, is frequently driven by VHL inactivation-either through mutation or promoter hypermethylation-resulting in constitutive HIF2α activation and pseudohypoxic signaling. VHL gene inactivation is a hallmark of von Hippel-Lindau syndrome, a hereditary disorder predisposing patients to ccRCC and other tumors, underscoring its central role in disease pathogenesis. While VHL dysfunction promotes aggressive tumor phenotypes, the therapeutic potential of VHL restoration remains underexplored. Here, using the Cas9 induced VHL-mutation in the Caki-1 cell line model, we demonstrate that VHL inactivation augments hypoxia-like pathways and enhances anaerobic glycolysis. Rescue of functional VHL reversed these activation patterns and modulated the expression of genes associated with angiogenesis. Using single cell transcriptomics, we show that the VHL-positive and -negative Caki-1 cells are characterized with different proportions of benign and aggressive cells as seen by analysis of specific gene expression. Furthermore, the identified angiogenesis-related genes were linked to affect clinical outcomes in ccRCC patients, suggesting that VHL restoration may mitigate high-risk molecular features.
proteins
2025-10-03 | Revealing a Heterozygous FCGR1A Variant in a Patient with Uveal Melanoma and Von Hippel-Lindau Syndrome: A Rare Case Report.
To report a rare case of uveal melanoma (UM) and Von Hippel-Lindau (VHL) syndrome in a patient who underwent whole exome sequencing (WES) to identify the possible genetic cause of the disease. A 54-year-old patient was referred to the eye clinic at the Rassoul Akram Hospital in 2016 due to complaints of blurry vision. In addition to UM, he later developed retinal capillary hemangioblastomas in his eye and a central nervous system hemangioblastoma. Proband had a family history of prostate cancer, breast cancer, skin cancer, and acute myeloid leukemia. After analyzing the Sanger sequencing and multiplex ligation-dependent probe amplification of the VHL genes, no mutations were found, leading to the decision to perform WES. WES disclosed a heterozygous known pathogenic nonsense variant: c.274C>T (p.Arg92*) in exon 3 of gene FCGR1A. Our examination indicated that FCGR1A: c.274C>T (p.Arg92*) may have contributed to the co-occurrence of UM and VHL disease. In the future, FCGR1A could be a promising therapeutic approach for retinal cancer due to its role in several cancers and retinal degeneration. To gain a better understanding of its pathogenesis mechanism, it is recommended to conduct functional analysis using appropriate animal models before using the variant in genetic counseling.
2024-09-27 | Somatostatin receptor 2A expression in von Hippel-Lindau-related hemangioblastomas.
Central nervous system hemangioblastomas are the most prevalent manifestation of von Hippel-Lindau (VHL) disease and remain the main cause of mortality. Surgical resection is the primary treatment strategy, but is not always possible, and should be used as restrictively as possible. There is an unmet need for less invasive treatment strategies, such as targeted therapy. Expression of somatostatin receptor 2A (SSTR2A) in VHL-related hemangioblastomas has been described earlier, but the extent of expression in a larger population has yet to be determined. The authors hypothesize that a substantial subset of VHL-related hemangioblastomas show SSTR2A expression, which may serve as a potential new treatment target. Patients who were surgically treated for a VHL-related hemangioblastoma from 1990 until 2021 at the UMC Utrecht were included. Clinical data was derived from a clinical database. Tissue samples were histopathologically examined with use of hematoxylin and eosin staining, and immunohistochemical analysis of SSTR2A expression was performed. Forty-three tissue samples were obtained from 26 patients. Nine showed strong positivity for SSTR2A expression, whereas 13 showed moderate and 15 sparse expression. Three samples showed no expression of SSTR2A. The distribution showed right-skewedness favoring a strong expression. SSTR2A expression colocalized with endothelial markers and not with stromal cells. Additionally, within-patient variability for SSTR2A expression was described in 14 patients. SSTR2A is expressed in varying degrees in the majority of VHL-related hemangioblastomas. Future treatment with somatostatin analogues or even peptide receptor radionuclide treatment may be considered for SSTR2A-positive cases.
2024-09-01 | A nature-inspired HIF stabilizer derived from a highland-adaptation insertion of plateau pika Epas1 protein
Hypoxia-inducible factors (HIFs) play pivotal roles in numerous diseases and high-altitude adaptation, and HIF stabilizers have emerged as valuable therapeutic tools. In our prior investigation, we identified a highland-adaptation 24-amino-acid insertion within the Epas1 protein. This insertion enhances the protein stability of Epas1, and mice engineered with this insertion display enhanced resilience to hypoxic conditions. In the current study, we delved into the biochemical mechanisms underlying the protein-stabilizing effects of this insertion. Our findings unveiled that the last 11 amino acids within this insertion adopt a helical conformation and interact with the α-domain of the von Hippel-Lindau tumor suppressor protein (pVHL), thereby disrupting the Eloc-pVHL interaction and impeding the ubiquitination of Epas1. Utilizing a synthesized peptide, E14-24, we demonstrated its favorable membrane permeability and ability to stabilize endogenous HIF-α proteins, inducing the expression of hypoxia-responsive element (HRE) genes. Furthermore, the administration of E14-24 to mice subjected to hypoxic conditions mitigated body weight loss, suggesting its potential to enhance hypoxia adaptation.
2024-06-01 | RESPONSES TO SEQUENTIAL SURGERY AND INTERFERON THERAPY OF THE NEUROENDOCRINE PANCREATIC CANCER METASTASES IN A FEMALE PATIENT WITH VON HIPPEL-LINDAU DISEASE
Abstract. Introduction. The article provides a literature review on the epidemiology, diagnosis, and treatment of neuroendocrine tumors. The morpho-functional classification by WHO 2022 is presented with the division of neuroendocrine tumors into three groups. Justifications are given for the choice of instrumental methods of topical diagnostics and the need for determining universal and specific biochemical markers in blood serum or plasma. The principles are indicated for choosing the advanced methods of treating neuroendocrine tumors. Aim. To review the scientific literature on neuroendocrine tumors, providing our own clinical observations. Materials and Methods. Russian- and English-language literature sources on this disease were searched for in the databases, such as PubMed, Medscape, Cochrane Library, and eLibrary. Clinical case of our female patient V., 36 years old, with von Hippel-Lindau disease (heterozygous mutation R167W of the VHL gene). Results and Discussion. As an example, we describe a clinical case of surgical treatment followed by long-term use of interferons in a female patient with neuroendocrine pancreatic cancer with metastases to the liver and retroperitoneal lymph nodes. Histological examination of the surgical material revealed highly differentiated neuroendocrine cancer with low malignant potential. A screening examination of the genetic syndrome components revealed a heterozygous mutation R167W of the VHL gene. Her survival under treatment exceeded 9.5 years, including more than 4.5 years from the start of interferon therapy. This pathology occurred in a young woman with one of the rare genetic multiorgan hereditary forms of neuroendocrine tumors, Von Hippel-Lindau disease that manifested itself as a combination of benign (retinal angiomatosis of both eyes and adenomas of both adrenal glands) and malignant diseases (pancreatic cancer). Conclusions. The given clinical example demonstrates that in a patient with highly differentiated metastatic pancreatic cancer, after distal subtotal resection of the pancreas, splenectomy, retroperitoneal lymphadenectomy, followed by treatment with interferons, life expectancy was more than 9.5 years, including more than 4.5 years from the start of therapy with interferons only. Despite the numerous side effects of interferons described in the literature, the patient tolerated the treatment well. At the same time, a connection between the hypothyroidism detected in the patient and treatment with interferons cannot be ruled out, since dysfunction of the thyroid gland is one of its side effects.
2022-05-11 | Immunohistochemical Expression Pattern of Theragnostic Targets SSTR2 and PSMA in Endolymphatic Sac Tumors: A Single Institution Case Series
Endolymphatic sac tumors are rare neoplasia characterized by slow growth. However, their clinical impact should not be underestimated, considering their potential for local aggressive behavior and strong association with von Hippel-Lindau syndrome. Therefore, early detection with emerging theragnostic examinations such as 68Ga-DOTATATE-PET/CT might improve patient management and reduce morbidity.We report the clinicopathological features of seven endolymphatic sac tumors. In this cohort, we performed immunohistochemical analysis of somatostatin receptor 2A (SSTR2A) and prostate specific membrane antigen (PSMA) protein expression patterns; two targets providing rationale for novel imaging modalities such as PSMA- or SSTR-targeted PET.The tumor cells of all cases were negative for prostate specific membrane antigen and somatostatin receptor 2A, however immunolabeling was consistently detected in intratumoral endothelial cells of endolymphatic sac tumors for PSMA (7/7 cases, 100%), and for SSTR2A (5/7 cases, 71%).Our results show a high rate of PSMA and SSTR2A expression in the tumor vasculature of endolymphatic sac tumors. PSMA and SSTR2A can be targeted with appropriate radioligands for diagnostic and therapeutic purposes. This finding provides a rationale for prospective clinical studies to test this approach as a sensitive screening tool for patients with suspected endolymphatic sac tumors including an improved management of von Hippel-Lindau syndrome.
antibodies
2026-06-08 | Concurrent Von Hippel-Lindau disease and enhanced S-cone syndrome leading to a distinct retinal phenotype.
Von Hippel-Lindau (VHL) disease and Enhanced S-cone syndrome (ESCS) are rare inherited disorders that independently predispose to vision-threatening retinal pathology through distinct mechanisms: VHL through hypoxia-induced activation of several angiogenic factors, which lead to the development of retinal capillary hemangioblastoma (RCH), and ESCS by disrupting photoreceptor development through NR2E3 variants. We describe the coexistence of these two conditions in a pediatric patient, confirmed by multimodal imaging, electroretinography, and genetic testing. A retrospective case report. A 13-year-old girl presented with poor vision in both eyes, mainly in dim light. Fundus examination revealed multiple small hypopigmented areas distributed nasally and temporally along the inferior arcades in both eyes, and multiple small RCHs distributed in all quadrants with superonasal exudations and macular choroidal neovascular membrane (CNVM) in the left eye. Full-field electroretinography (ff-ERG) showed nonrecordable rod responses, broadened rod-cone and cone responses, and a markedly reduced 30-Hz flicker amplitude. While the right eye was successfully managed conservatively, targeted focal laser and intravitreal anti-vascular endothelial growth factor (VEGF) therapy led to regression of neovascular lesions and visual improvement in the left eye. Whole-exome sequencing identified a heterozygous VHL c.452T > C (p.Ile151Thr) variant and a homozygous NR2E3 c.932G > A (p.Arg311Gln) variant. Both VHL disease and ESCS manifested their characteristic retinal findings of RCH, along with the typical electrophysiological features and the CNVM associated with ESCS.
2025-11-08 | Bifurcate Regulation of Hematopoietic Homeostasis and Bone Osteogenesis by VHL-HIF2α-Controlled Adipocyte Function.
Adipocytes play a pivotal role in maintaining metabolic and immunological homeostasis. Here, this work shows that VHL-HIF2α (VHL is Von Hippel-Lindau) axis in mature adipocytes regulates hematopoiesis and osteogenesis. Genetic ablation of VHL in adipocytes triggers profound systemic autoinflammation and abnormal hematopoiesis, concomitant with fat mass decrease and pathological elevation of bone mass. On one hand, VHL deficiency results in aberrantly high stem cell factor (SCF) expression in adipocytes, which exerts a negative role for hematopoietic homeostasis through disrupting hematopoietic stem cell (HSC) quiescence. In vivo anti-CD117 monoclonal antibody treatment ameliorates the hematopoietic defects in VHL-deficient mice. On the other hand, direct HIF2α binding to hypoxia-response elements in the Rarres2 locus enhances chemerin production in adipocytes, which facilitates mesenchymal stem cell (MSC) osteogenesis via Wnt/β-catenin activation. Pharmacological chemerin neutralization through CMKLR1 inhibition using α-NETA mitigates osteogenic activity both in vitro and in vivo. This work thus identifies chemerin as the pivotal molecular nexus connecting hypoxic adipocyte dysfunction to pathological osteosclerosis. The findings uncover a hypoxia-driven signaling network in adipocytes that orchestrates cross-talk with both HSCs and MSCs to regulate systemic homeostasis, thereby revealing therapeutic targets for disorders associated with adipocyte dysfunction.
2025-09-19 | Quantitative analysis of the anti-VEGF effect for retinal capillary hemangiomas and vasoproliferative tumors.
PurposeTo assess the effect of anti-VEGF intravitreal injection (IVI) on vascularity and size of retinal angiomas using quantitative analysis of color fundus images.MethodsColor fundus images of retinal angiomas underwent RGB analysis with ImageJ software. White intensity (mean RGB values) and red ratio (red value/sum of green and blue values) were calibrated to obtain the white intensity and red indices, respectively. The lesion-disc area ratio was assessed for size changes.ResultsSeventeen image sets of 10 angiomatous lesions were analyzed: 6 retinal hemangiomas from 4 eyes (4 patients) with Von Hippel-Lindau disease (VHL) and 4 retinal vasoproliferative tumors (VPT) from 4 eyes (4 patients). Overall, the white intensity index increased from 1.34 to 1.5 (P = 0.001), and the red index decreased from 1.14 to 0.85 (P < 0.001) post-IVI. In the VHL group, white intensity increased from 1.41 to 1.58 (P = 0.013), and the red index decreased from 1.04 to 0.84 (P < 0.001). In the VPT group, white intensity increased from 1.17 to 1.36 (P = 0.031) and red index decreased from 1.39 to 0.87 (P = 0.156) after IVI. Lesion-disc area ratio decreased significantly in both groups.ConclusionAnti-VEGF induces whitening and reduces the red component of angiomas, diminishing vascularity and facilitating subsequent invasive treatments.
2025-02-12 | Carbonic anhydrase-9-targeted near-infrared photoimmunotherapy as a theranostic modality for clear cell renal cell carcinoma.
Carbonic anhydrase-9 (CA9) is highly expressed in clear cell renal cell carcinoma (ccRCC) cells despite no expression in normal kidney tissues. Thus, CA9 has been proposed as a theranostic target for radioligand therapy (RLT). However, ccRCC tends to be radioresistant and may not effectively respond to RLT. Alternatively, CA9 can be targeted for near-infrared photoimmunotherapy (NIR-PIT) of ccRCC. Here, we sought to test NIR-PIT using CA9 in a preclinical model of ccRCC to determine its potential as a therapeutic strategy. Tissue microarray analysis showed that membrane CA9 was expressed in the majority of ccRCC cases. In vitro, CA9-targeted NIR-PIT induced cell membrane damage and cell killing in all CA9-expressing ccRCC cell lines specifically, UOK154, UOK220, and UOK122. In vivo, CA9-targeted NIR-PIT significantly inhibited tumor growth and prolonged survival in UOK154 and UOK220 subcutaneous xenograft models. Notably, 70%-80% of mice achieved complete remission after a single treatment of NIR-PIT. Additionally, remaining tumors after the first NIR-PIT persistently expressed CA9, suggesting that remaining tumors can be treated with repeated NIR-PIT. Furthermore, CA9-targeted NIR-PIT induced significant cytoplasmic damages on ccRCC cells in UOK154 orthotopic xenograft models. In conclusion, CA9-targeted NIR-PIT, which allow for safe and repeated application on the same lesion, is a promising treatment for ccRCC, especially in the management of multiple primary ccRCC (e.g., von Hippel-Lindau syndrome) and oligometastatic ccRCC.
2025-01-20 | Mathematical Modeling and Simulation of Tumor-Induced Angiogenesis in Retinal Hemangioblastoma
Retinal Hemangioblastoma (RH) is the most frequent manifestation of the von Hippel-Lindau syndrome (VHL), a rare disease associated with the germline mutation of the von Hippel-Lindau protein (pVHL). An emblematic feature of RH is the high vascularity, which is explained by the overexpression of angiogenic factors (AFs) arising from the pVHL impairment. The introduction of Optical Coherence Tomography Angiography (OCTA) allowed observing this feature with exceptional detail. Here, we combine OCTA images and a mechanistic model to investigate tumor growth and vascular development in a patient-specific way. We derived our model from the agreed pathology for RH and focused on the earliest stages of tumor-induced angiogenesis. Our simulations closely resemble the medical images, proving the capability of our model to recapitulate vascular patterning in actual patients. Our results also suggest that angiogenesis in RH occurs upon reaching a critical dimension (around 200 um), followed by the rapid formation of stable vascular networks. These findings open a new perspective on the crucial role of time in antiangiogenic therapy in RH, which has resulted in ineffective control. Indeed, it might be that when RH is diagnosed, angiogenesis is already too advanced to be effectively targeted with any effective means. Moreover, our simulations suggest that vascularization in RH is not a continuous process but an inconstant development with long, stable phases and rapid episodes of vascular sprouting.
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2025-07-29 | Overexpression of BDNF and uPA Combined with the Suppression of Von Hippel-Lindau Tumor Suppressor Enhances the Neuroprotective Activity of the Secretome of Human Mesenchymal Stromal Cells in the Model of Intracerebral Hemorrhage.
Nerve tissue damage is an unsolved problem in modern neurology and neurosurgery, which prompts the need to search for approaches to stimulate neuroprotection and regeneration of neural tissue. Earlier we have shown that the secretome of human mesenchymal stromal cells (MSCs) stimulates rat survival, reduces the severity of neurological deficits, and decreases the volume of brain damage in a hemorrhagic stroke model. A significant disadvantage of using the MSC secretome is the need to concentrate it (at least 5-10 fold) to achieve appreciable pharmacological activity. This increases the cost of obtaining clinically applicable amounts of secretome and slows down the clinical translation of this technology. Here, we created a number of genetically modified human MSC cultures, including immortalized MSCs and those with hyperexpression of brain-derived neurotrophic factor (BDNF) and urokinase-type plasminogen activator (uPA) and with suppressed expression of Von Hippel-Lindau tumor suppressor (VHL), and we evaluated the pharmacological activity of their secretomes in a model of intracerebral hemorrhage (ICH) in rats. The secretome of MSCs immortalized by hyperexpression of the catalytic subunit of human telomerase (hTERT) revealed neuroprotective activity indistinguishable from that of primary MSC cultures, yet it still required 10-fold concentration to achieve neuroprotective efficacy. The secretome of MSC culture with combined hyperexpression of BDNF and uPA and suppressed expression of Von Hippel-Lindau tumor suppressor even without additional concentration reduced the severity of neurological disorders and decreased brain lesion volume in the ICH model. The secretomes of MSCs with separate overexpression of BDNF and uPA or suppression of VHL had no such effect or, on the contrary, revealed a toxic effect in the ICH model. Presumably, this may be due to an imbalance in the representation of individual growth factors in the secretome of genetically modified MSCs, which individually may lead to undesirable effects in damaged nervous tissue, such as increased permeability of the blood-brain barrier (under the influence of pro-angiogenic factors) or neural cell apoptosis (due to an excess of neurotrophic factors). The obtained data show that genetic modification of MSC cultures can enhance or alter the therapeutic activity of their secretomes, which can be used in the creation of promising sources of biopharmaceutical substances.
2023-12-16 | Outcomes of and indications for renal transplantation in patients with von Hippel Lindau disease.
Von Hippel-Lindau (VHL) is a hereditary cancer syndrome characterized by bilateral, multifocal renal masses. The cumulative impact of extirpative surgery can depreciate renal function and render patients anephric. In the larger end-stage renal disease population, renal transplant offers both excellent quality of life and functional renal replacement. This case control study aims to examine and compare oncologic and functional outcomes of patients who have undergone renal transplant as renal replacement therapy (RRT) to those who remain anephric. Patient charts were retrospectively reviewed of patients with germline testing confirmed VHL between 1980 and 2022 for transplant, all prior surgical history (within and outside the NCI), renal function and graft outcomes. Overall survival (OS) was determined from years after radical nephrectomy, and graft time was defined as years of graft function from initial transplant until failure or patient death. Graft survival was determined as time between transplant(s) to last follow up. Kaplan-Meier analysis was conducted to compare graft times of anephric VHL patients to those with transplanted kidneys. A total of 23 VHLD patients were identified as either anephric or candidates for transplant. Out of this cohort, 11 total VHLD received 12 total kidney grafts. Median wait time from nephrectomy to transplant was 22.6 months (IQR: 1.02-40.25 months). Median age at transplant was 32 years (IQR: 23-54 years). OS at 5 and 10 years of anephric patients who did not receive a transplant was 33% and 16.7%, respectively. OS rates of the transplant cohort at 10, 15, and 20 years were 91%, 78%, and 58% years, respectively. Median graft time was 161 months (IQR: 56-214 months). Graft survival at 10, 15, and 20 years was 69.8%, 69.8%, and 26.2%, respectively. We demonstrate that transplant recipients have decreased mortality with no difference in cancer recurrence compared to those who do not receive renal transplant for RRT. This data can aid in informing providers of the optimal window for early RRT planning in VHL, while also improving patient counseling.
2022-12-16 | CD70-Targeted Micelles Enhance HIF2α siRNA Delivery and Inhibit Oncogenic Functions in Patient-Derived Clear Cell Renal Carcinoma Cells.
The majority of clear cell renal cell carcinomas (ccRCCs) are characterized by mutations in the Von Hippel−Lindau (VHL) tumor suppressor gene, which leads to the stabilization and accumulation of the HIF2α transcription factor that upregulates key oncogenic pathways that promote glucose metabolism, cell cycle progression, angiogenesis, and cell migration. Although FDA-approved HIF2α inhibitors for treating VHL disease-related ccRCC are available, these therapies are associated with significant toxicities such as anemia and hypoxia. To improve ccRCC-specific drug delivery, peptide amphiphile micelles (PAMs) were synthesized incorporating peptides targeted to the CD70 marker expressed by ccRCs and anti-HIF2α siRNA, and the ability of HIF2α-CD27 PAMs to modulate HIF2α and its downstream targets was evaluated in human ccRCC patient-derived cells. Cell cultures were derived from eight human ccRCC tumors and the baseline mRNA expression of HIF2A and CD70, as well as the HIF2α target genes SLC2A1, CCND1, VEGFA, CXCR4, and CXCL12 were first determined. As expected, each gene was overexpressed by at least 63% of all samples compared to normal kidney proximal tubule cells. Upon incubation with HIF2α-CD27 PAMs, a 50% increase in ccRCC-binding was observed upon incorporation of a CD70-targeting peptide into the PAMs, and gel shift assays demonstrated the rapid release of siRNA (>80% in 1 h) under intracellular glutathione concentrations, which contributed to ~70% gene knockdown of HIF2α and its downstream genes. Further studies demonstrated that knockdown of the HIF2α target genes SLC2A1, CCND1, VEGFA, CXCR4, and CXCL12 led to inhibition of their oncogenic functions of glucose transport, cell proliferation, angiogenic factor release, and cell migration by 50−80%. Herein, the development of a nanotherapeutic strategy for ccRCC-specific siRNA delivery and its potential to interfere with key oncogenic pathways is presented.
2015-09-17 | Computational and experimental characterization of dVHL establish a Drosophila model of VHL syndrome.
The von Hippel-Lindau (VHL) cancer syndrome is associated with mutations in the VHL gene. The pVHL protein is involved in response to changes in oxygen availability as part of an E3-ligase that targets the Hypoxia-Inducible Factor for degradation. pVHL has a molten globule configuration with marginal thermodynamic stability. The cancer-associated mutations further destabilize it. The Drosophila homolog, dVHL, has relatively low sequence similarity to pVHL, and is also involved in regulating HIF1-α. Using in silico, in vitro and in vivo approaches we demonstrate high similarity between the structure and function of dVHL and pVHL. These proteins have a similar fold, secondary and tertiary structures, as well as thermodynamic stability. Key functional residues in dVHL are evolutionary conserved. This structural homology underlies functional similarity of both proteins, evident by their ability to bind their reciprocal partner proteins, and by the observation that transgenic pVHL can fully maintain normal dVHL-HIF1-α downstream pathways in flies. This novel transgenic Drosophila model is thus useful for studying the VHL syndrome, and for testing drug candidates to treat it.
2015-05-12 | Hypoxia-inducible factor as an angiogenic master switch.
Hypoxia-inducible factors (HIFs) regulate the transcription of genes that mediate the response to hypoxia. HIFs are constantly expressed and degraded under normoxia, but stabilized under hypoxia. HIFs have been widely studied in physiological and pathological conditions and have been shown to contribute to the pathogenesis of various vascular diseases. In clinical settings, the HIF pathway has been studied for its role in inhibiting carcinogenesis. HIFs might also play a protective role in the pathology of ischemic diseases. Clinical trials of therapeutic angiogenesis after the administration of a single growth factor have yielded unsatisfactory or controversial results, possibly because the coordinated activity of different HIF-induced factors is necessary to induce mature vessel formation. Thus, manipulation of HIF activity to simultaneously induce a spectrum of angiogenic factors offers a superior strategy for therapeutic angiogenesis. Because HIF-2α plays an essential role in vascular remodeling, manipulation of HIF-2α is a promising approach to the treatment of ischemic diseases caused by arterial obstruction, where insufficient development of collateral vessels impedes effective therapy. Eukaryotic initiation factor 3 subunit e (eIF3e)/INT6 interacts specifically with HIF-2α and induces the proteasome inhibitor-sensitive degradation of HIF-2α, independent of hypoxia and von Hippel-Lindau protein. Treatment with eIF3e/INT6 siRNA stabilizes HIF-2α activity even under normoxic conditions and induces the expression of several angiogenic factors, at levels sufficient to produce functional arteries and veins in vivo. We have demonstrated that administration of eIF3e/INT6 siRNA to ischemic limbs or cold-injured brains reduces ischemic damage in animal models. This review summarizes the current understanding of the relationship between HIFs and vascular diseases. We also discuss novel oxygen-independent regulatory proteins that bind HIF-α and the implications of a new method for therapeutic angiogenesis using HIF stabilizers.
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Drug Discovery Landscape
4 orphan drug designations for Von Hippel-Lindau disease, including 1 approved therapy.
4 orphan drug designations for Von Hippel-Lindau disease, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Belzutifan | small molecules | EMA | Merck Sharp & Dohme B.V. | |
belzutifan [Welireg] | small molecules | FDA | Approved | Merck Sharp & Dohme, LLC |
Propranolol hydrochloride | small molecules | EMA | — | Consejo Superior de Investigaciones Cientificas (CSIC) |
3-(3,5-Dimethyl-1H-2ylmethylene)-1,3-dihydro-indol-2-one | small molecules | FDA | — | Sugen, Inc. |
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