Molecular Profile Detail

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Profile Name VHL negative
Gene Variant Detail

VHL negative (loss of function)

Relevant Treatment Approaches mTORC1 Inhibitor VEGFR Inhibitor (Pan) VEGFR2 Inhibitor

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Molecular Profile Indication/Tumor Type Response Type Relevant Treatment Approaches Therapy Name Approval Status Evidence Type Efficacy Evidence References
VHL del renal cell carcinoma predicted - sensitive VEGFR Inhibitor (Pan) VEGFR2 Inhibitor Regorafenib Preclinical - Cell line xenograft Actionable In a preclinical study, Stivarga (regorafenib) inhibited angiogenesis and tumor growth in cell line xenograft models of renal cell carcinoma harboring VHL gene deletion (PMID: 21170960). 21170960
VHL over exp clear cell renal cell carcinoma no benefit VEGFR2 Inhibitor Cediranib + Saracatinib Phase II Actionable In a Phase II clinical study, baseline expression of VHL was not predictive for response to Saracatinib (AZD0530) and Recentin (cediranib) relative to Recentin (cediranib) in patients with metastatic clear-cell renal cell carcinoma (PMID: 26802156). 26802156
VHL mutant islet cell tumor not applicable N/A Guideline Risk Factor Germline mutations in VHL result in von Hippel Lindau syndrome, which is associated with increased risk of developing pancreatic neuroendocrine tumors (NCCN.org). detail...
VHL mutant renal cell carcinoma predicted - sensitive VEGFR2 Inhibitor Sunitinib Phase I Actionable In a Phase I trial, 33% (6/18) of renal cell carcinoma patients harboring a VHL mutation, as determined from archived patient specimens, demonstrated a partial response when treated with Sutent (sunitinib) (PMID: 22105611). 22105611
VHL mutant renal cell carcinoma no benefit VEGFR Inhibitor (Pan) Unspecified VEGFR inhibitor Clinical Study - Meta-analysis Actionable In a meta-analysis of 6 clinical studies, VHL mutation status was not associated with overall response rate (relative risk=1.47, p=0.20), progression-free survival (HR=1.02, p=0.91), or overall survival (HR=0.80, p=0.21) in a total of 633 patients with renal cell carcinoma who received anti-VEGF therapies (PMID: 28103578). 28103578
VHL mutant clear cell renal cell carcinoma not applicable N/A Guideline Risk Factor Germline mutations in VHL result in von Hippel Lindau syndrome, which is associated with increased risk of developing clear cell renal cancer (NCCN.org). detail...
VHL mutant renal cell carcinoma sensitive mTORC1 Inhibitor Everolimus Phase I Actionable In a Phase I study, Afinitor (everolimus), as compared to Apitolisib (GDC-0980), resulted in a greater progression free survival and overall survival in patients with renal cell carcinoma harboring VHL mutations (J Clin Oncol 32:5s, 2014 (suppl; abstr 4525)). detail...
VHL negative renal cell carcinoma sensitive STF-62247 Preclinical Actionable In a preclinical study, STF-62247 induced selective cytotoxicity and inhibited tumor growth of renal cell carcinoma cells lacking VHL (PMID: 18769110, PMID: 18598947). 18769110 18598947
VHL loss renal cell carcinoma sensitive VEGFR Inhibitor (Pan) Bevacizumab Preclinical Actionable In a preclinical study, clear cell renal cell carcinoma xenograft models with VHL loss demonstrated sensitivity to Avastin (bevacizumab) (PMID: 22931246). 22931246
VHL loss renal cell carcinoma sensitive BPTES Preclinical - Cell culture Actionable In a preclinical study, VHL-deficient renal cell carcinoma cells demonstrated growth inhibition and suppression of DNA synthesis in culture when treated with BPTES (PMID: 28346230). 28346230
VHL loss renal cell carcinoma sensitive ELR510444 Preclinical - Cell line xenograft Actionable In a preclinical study, renal cell carcinoma cells deficient for VHL were sensitive to ELR510444 both in culture and in cell line xenograft models (PMID: 22295124). 22295124
VHL loss renal cell carcinoma sensitive BPTES + Olaparib Preclinical - Cell culture Actionable In a preclinical study, the combination of BPTES and Lynparza (olaparib) resulted in a synergistic effect, demonstrating growth inhbition of VHL-deficient renal cell carcinoma cells in culture (PMID: 28346230). 28346230
VHL loss renal cell carcinoma sensitive Olaparib + Telaglenastat Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of CB-839 and Lynparza (olaparib) resulted in a synergistic effect, demonstrating greater reduction in tumor volume compared to either agent alone in renal carcinoma cell xenograft models deficient for VHL (PMID: 28346230). 28346230
VHL loss renal cell carcinoma sensitive Telaglenastat Preclinical - Cell culture Actionable In a preclinical study, VHL-deficient renal cell carcinoma cells demonstrated growth inhibition in culture when treated with CB-839 (PMID: 28346230). 28346230
PTEN loss VHL loss renal carcinoma decreased response Gedatolisib Preclinical Actionable In a preclinical study, human renal carcinoma cells with PTEN loss and VHL loss had a decreased response to Gedatolisib (PKI-587) in culture (PMID: 21325073). 21325073
VHL V155fs kidney cancer predicted - sensitive VEGFR2 Inhibitor Sunitinib + Trametinib Preclinical - Pdx Actionable In a preclinical study, the combination of Mekinist (trametinib) and Sutent (sunitinib) inhibited tumor growth in patient-derived xenograft models of renal cancer harboring VHL V155fs (referred to as V155fs*4) (PMID: 26487278). 26487278
VHL inact mut renal cell carcinoma predicted - sensitive mTORC1 Inhibitor Everolimus Phase II Actionable In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Afinitor (everolimus) had a trend towards improved in progression free survival when stratified by the presence (median PFS=8.6 months, n=15) or absence (median PFS=5.5 months, n=16) of deleterious VHL mutations (PMID: 26951309). 26951309
VHL inact mut clear cell renal cell carcinoma conflicting PT2399 Preclinical - Pdx Actionable In a preclinical study, PT2399 had variable impact on tumor growth in clear cell renal cell carcinoma (ccRCC) cell line and patient-derived xenograft (PDX) models with defective VHL, with decreased tumor growth in a VHL-defective ccRCC PDX model and some VHL-defective ccRCC cell line xenograft models, and no tumor suppression in other cell line xenograft models (PMID: 27595393). 27595393
VHL inact mut hemangioblastoma sensitive Belzutifan FDA approved Actionable In a Phase II trial that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in an overall response rate of 32% (16/50, 1 complete response, 15 partial responses) in patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma harboring germline VHL mutations, 69% (11/16) of patients with retinal hemangioblastoma experienced improvement (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). detail...
VHL inact mut hemangioblastoma sensitive Belzutifan Guideline Actionable Welireg (belzutifan) is included in guidelines for patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma that do not require immediate surgery (NCCN.org). detail...
VHL inact mut renal cell carcinoma predicted - sensitive VEGFR Inhibitor (Pan) Alpha 2 Interferon + Bevacizumab Clinical Study - Cohort Actionable In a retrospective analysis, VHL alterations did not impact overall survival or objective response in renal cell carcinoma patients treated with a VEGF-targeted therapy, including Avastin (bevacizumab) and Alpha 2 Interferon combination therapy, but were associated with a prolonged time to progression (PMID: 16827904). 16827904
VHL inact mut pancreatic endocrine carcinoma sensitive Belzutifan FDA approved Actionable In a Phase II trial that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in an overall response rate of 80% (16/20, 1 complete response, 15 partial responses) in patients with Von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors harboring germline VHL mutations (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). detail... detail...
VHL inact mut renal cell carcinoma no benefit GDC-0980 Phase II Actionable In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Apitolisib (GDC-0980) had no difference in progression free survival when stratified by the presence (n=5) or absence (n=17) of deleterious VHL mutations (PMID: 26951309). 26951309
VHL inact mut retinal hemangioblastoma sensitive Belzutifan Phase II Actionable In a Phase II trial, Welireg (belzutifan) treatment was safe and resulted in an overall response rate of 32% (16/50, 1 complete response, 15 partial responses) in patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma harboring germline VHL mutations, 69% (11/16) of patients with retinal hemangioblastoma experienced improvement (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). detail...
VHL inact mut renal cell carcinoma sensitive Belzutifan FDA approved Actionable In a Phase II trial that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in a confirmed partial response (PR) in 36% (22/61) and unconfirmed PR in 11% (7/61) of patients with Von Hippel-Lindau disease-associated localized renal cell carcinoma harboring germline VHL mutations, median duration of response was not reached in responders (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). detail... detail...
TP53 R248W VHL inact mut clear cell renal cell carcinoma resistant PT2399 Preclinical - Cell culture Actionable In a preclinical study, TP53 R248W was associated with resistance to PT2399 in VHL-defective clear cell renal cell carcinoma cell lines in culture (PMID: 27595393). 27595393
Clinical Trial Phase Therapies Title Recruitment Status Covered Countries Other Countries