VHL Systemic Therapy Eric Jonasch, MD UT MD Anderson Cancer Center
Disclosures Research funding: Exelixis, Merck, Novartis, Pfizer Consulting: Aravive, Aveo, Eisai, Exelixis, Merck, Novartis, Pfizer
VHL- A Regulatory Hub β α Elongin C Elongin B Cul 2 Other substrates Qing Zhang Regulates how the cell Controls the sees its surroundings primary cilium Impacts blood Regulates vessel formation p53 Ohh et al, Mol Cell, Vol 1, 959-968, 1998 Kurban et al, Cancer Res 2006; 66: (3). Pugh et al Narture Medicine 2003 Thoma et al Nature Cell Biology Aug 2009 Roe and Youn Mol Cell May 2006 Kerbel NEJM May 2008 Kuehn et al Ca Res May 15, 2007
VHL Mutation Increases Growth Factors including VEGF HIF- β HIF- α VHL Nucleus Transcription of: VEGF Other angiogenic factors VEGF = vascular endothelial growth factor; HIF = hypoxia-inducible factor.
VHL Loss Results Highly Angiogenic Lesions VEGF VEGF VEGF VEGF Stromal cells VHL-/- Tumor cells VHL-/- VEGF VHL-/-
Can We Block The Consequences of VHL Loss?
Therapeutic Opportunities in the VHL-HIF-VEGF Pathway VHL HIF Tumor cells VEGF
Therapeutic Opportunities in the VHL-HIF-VEGF Pathway VHL HIF Tumor cells VEGF VEGFR inhibitors
Therapeutic Opportunities in the VHL-HIF-VEGF Pathway VHL HIF Tumor cells VEGF inhibitors VEGF VEGFR inhibitors
Therapeutic Opportunities in the VHL-HIF-VEGF Pathway VHL HIF HIF inhibitors Tumor cells VEGF inhibitors VEGF VEGFR inhibitors
Therapeutic Opportunities in the VHL-HIF-VEGF Pathway VHL VHL stabilizers/surrogates HIF HIF inhibitors Tumor cells VEGF inhibitors VEGF VEGFR inhibitors
Moving Towards Better Therapies for VHL Disease
VEGF and VEGFR inhibitors VHL HIF Tumor cells VEGF inhibitors VEGF VEGFR inhibitors
14 Not all TKIs are created equal Fabian, M., Biggs, W., Treiber, D. et al. A small molecule–kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23, 329–336 (2005)
Sunitinib Sunitinib is an oral, small molecule inhibitor of VEGFR 1-3, PDGFR, KIT and other kinases VHL HIF Tumor cells VEGF VEGFR inhibitors
Sunitinib Pilot Study Germline VHL Sunitinib 50mg RECIST 1.1 in RCC or Clinical PO all lesions at 6 VHL 4/2 Schedule months 15 Patients Accrued Jonasch and Matin, Annals of Oncology 2011
Sunitinib Study: Efficacy Lesion site Lesion number PR (%) SD (%) PD (%) 21 0 19(91) 2(9) Hemangioblastoma* Renal cell carcinoma* 18 6 (33) 10(67) 2(10) 9 0 9 (100) 0 Renal cyst Retinal angiomas 7 0 7 (100) 0 Pancreatic NET 5 0 5 (100) 0 Pancreatic cyst 3 0 3 (100) 0 Nine out of 15 patients completed study- most came off study due to poor tolerability *(P=0.014) Jonasch and Matin, Annals of Oncology 2011
Sunitinib Study: Efficacy Lesion site Lesion number PR (%) SD (%) PD (%) 21 0 19(91) 2(9) Hemangioblastoma* Renal cell carcinoma* 18 6 (33) 10(67) 2(10) 9 0 9 (100) 0 Renal cyst Retinal angiomas 7 0 7 (100) 0 Pancreatic NET 5 0 5 (100) 0 Pancreatic cyst 3 0 3 (100) 0 Nine out of 15 patients completed study- most came off study due to poor tolerability *(P=0.014) Jonasch and Matin, Annals of Oncology 2011
Sunitinib Study: Efficacy Lesion site Lesion number PR (%) SD (%) PD (%) 21 0 19(91) 2(9) Hemangioblastoma* Renal cell carcinoma* 18 6 (33) 10(67) 2(10) 9 0 9 (100) 0 Renal cyst Retinal angiomas 7 0 7 (100) 0 Pancreatic NET 5 0 5 (100) 0 Pancreatic cyst 3 0 3 (100) 0 Nine out of 15 patients completed study- most came off study due to poor tolerability *(P=0.014) Jonasch and Matin, Annals of Oncology 2011
Pancreatic NETs Responded Jonasch and Matin, Annals of Oncology 2011
Renal Masses Responded Baseline 12 Weeks 24 Weeks Jonasch and Matin, Annals of Oncology 2011
Hemangioblastomas Did Not Respond Jonasch and Matin, Annals of Oncology 2011
VHL Related Tumors VEGFR VEGF VEGF Stromal cells VHL-/- PDGFR Tumor cells VHL-/- VEGFR VHL-/- EGFR
Are Endothelial Cells in RCC and Hemangioblastomas Driven by Same Growth Factors? VEGFR VEGF VEGF Stromal cells VHL-/- PDGFR Tumor cells VHL-/- VEGFR VHL-/- EGFR
Hemangioblastomas Densely packed, seemingly normal blood vessel channels of varying sizes, separated by stromal cells.
20 Hemangioblastomas Evaluate Status of Different Determine Receptor Types in Differences Between Blood Vessels Hb and RCC Using Laser Scanning Cytometry 20 Renal Cell Carcinomas Jonasch and Matin Annals of Oncology 2011
Wilcoxon ’ s log(Hb) log(RCC) t-test rank test N mean SD N mean SD p-value p-value pVEGFR2 in CD31 Cells 20 11.268 0.498 20 11.752 0.378 0.001 0.003 tVEGFR in CD31 Cell 20 12.977 0.478 20 13.081 0.859 0.639 0.192 pPDGFR in CD31 Cells 20 10.952 0.654 20 10.805 0.839 0.539 0.82 tPDGFR in CD31 Cells 20 13.078 0.659 20 12.842 0.851 0.333 0.947 VEGFR.ratio 20 0.206 0.122 20 0.372 0.431 0.105 0.043 PDGFR.ratio 20 0.145 0.067 20 0.157 0.077 0.608 0.602 VEGF receptor activation state is higher in kidney tumors compared to hemangioblastomas . Jonasch and Matin Annals of Oncology 2011
Wilcoxon ’ s log(Hb) log(RCC) t-test rank test N mean SD N mean SD p-value p-value Tie2 in CD31 Positive Cells 20 12.654 0.455 20 12.63 0.817 0.909 0.883 Tie2 in Tumor Tissue 20 11.598 0.321 20 11.614 0.303 0.866 0.947 FGFR3 in CD31 Positive Cells 20 12.265 0.448 20 12.29 0.961 0.914 0.495 FGFR3 in Tumor Tissue 20 11.439 0.224 20 11.338 0.106 0.075 0.174 pFRS2 in CD31 Positive Cells 20 12.495 0.492 20 11.91 0.989 0.023 0.059 pFRS2 in Tumor Tissue 20 11.452 0.258 20 11.258 0.089 0.003 0.003 pFRS2 (a marker for FGF receptor activation) is higher in hemangioblastomas compared to ccRCC Jonasch and Matin Annals of Oncology 2011
Pazopanib Sunitinib is an oral, small molecule inhibitor of VEGFR 1-3, PDGFR, FGFR and other kinases VHL HIF Tumor cells VEGF VEGFR inhibitors
Pazopanib- Case Study: Response in Hemangioblastoma Kim Jonasch and McCutcheon Targ Oncol 2012
Pazopanib Phase 2 Study Germline VHL Pazopanib RECIST 1.1 in RCC or Clinical 800mg PO all lesions at 6 VHL Daily months Jonasch and Matin The Lancet Oncology 2018
32 Pazopanib Phase 2 Study Jonasch and Matin The Lancet Oncology 2018
33 Pazopanib Phase 2 Study Jonasch and Matin The Lancet Oncology 2018
Pazopanib Phase 2 Study Pancreatic Lesions RCC Hemangioblastomas Jonasch and Matin The Lancet Oncology 2018
Pazopanib: Tumor Response Jonasch and Matin The Lancet Oncology 2018
PT2977/MK6482 VHL HIF HIF inhibitors Tumor cells VEGF
HIF 2 Alpha Blockade HIF- β HIF- α VEGF PT2977 PT VHL Nucleus
Development of a Small Molecule HIF2a Inhibitor Atlas of Genetics and Cytogenetics in Oncology and Haematology UT Southwestern (UTSW) research on HIF- 2 α biology • Identified small molecule binding pocket in PAS-B domain • Established that small molecule HIF-2 α HIF-1 β binding led to inhibition of transcriptional activity Scheuermann et al . PNAS 2009 , 106 :450 Key et al . JACS 2009 , 131 :17647 Scheuermann et al. Nature Chem Biol 2013 , 9 :271 Slide courtesy of Naseem Zojwalla
Development of a Small Molecule HIF2a Inhibitor Atlas of Genetics and Cytogenetics in Oncology and Haematology Initial UTSW HIF-2 α hit not viable lead • Modest cell activity HIF-2 α HIF-1 β • Poor pharmacokinetic properties Metabolic liabilities • • Electrophilic -- Potential for non- specific covalent protein modification Scheuermann et al . PNAS 2009 , 106 :450 Key et al . JACS 2009 , 131 :17647 Scheuermann et al. Nature Chem Biol 2013 , 9 :271 Slide courtesy of Naseem Zojwalla Rogers et al . J Med Chem 2013 , 56: 1739
Development of a Small Molecule HIF2a Inhibitor Atlas of Genetics and Cytogenetics in Oncology and Haematology Further iteration of molecule HIF-2 α antagonist bound to HIF-2 α PAS-B* domain HIF-2 α HIF-1 β HIF-2 α PAS-B* (R247E mutant) domain (green) HIF-1 β PAS-B* (E362R mutant) domain (blue) PT2385 (magenta) Wallace et al . Cancer Res 2016 , 76 :5491 Cho et al . Nature 2016 , 539 :107 Slide courtesy of Naseem Zojwalla Chen et al. Nature 2016 , 539 :112 Courtney et al. J Clin Oncol 2018
Development of a Small Molecule HIF2a Inhibitor Further iteration of molecule HIF-2 α antagonist bound to HIF-2 α PAS-B* domain PT2385 HIF-2 α HIF-1 β Wallace et al . Cancer Res 2016 , 76 :5491 Cho et al . Nature 2016 , 539 :107 Slide courtesy of Naseem Zojwalla Chen et al. Nature 2016 , 539 :112 Courtney et al. J Clin Oncol 2018
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