VHL Syndrome and Hemangioblastoma Management

Transcription

1 VHL Syndrome and Hemangioblastoma Management Eric Jonasch Professor of Medicine UT MD Anderson Cancer Center Fourteenth International Kidney Cancer Symposium Miami, Florida, USA November 6-7,

2 Outline What is VHL disease Follow up for VHL patients Treatment interventions by organ site Clinical trials in VHL disease Fixing broken VHL- ongoing research

3 VHL Gene and Protein On chromosome 3p amino acid protein Forms VBC complex E3 ubiquitin ligase for HIF1a and HIF2a a Elongin C (15kDa) Elongin B (18kDa) Cul 2 Modified from Stebbins and Pavletich, Science, Vol 284, 16 April 1999

4 VHL Mutation Replicates the Hypoxic State HIF-b HIF-a Transcription of: VEGF Other angiogenic factors VHL Nucleus VEGF = vascular endothelial growth factor; HIF = hypoxia-inducible factor.

5 Clear Cell Kidney Cancer -Clear and eosinophilic cells with substantial vascularity.

6 Hemangioblastomas -Densely packed, seemingly normal blood vessel channels of varying sizes, separated by stromal cells. -Stromal cells carry VHL mutations; endothelium wildtype.

7 VHL- A Regulatory Hub b Elongin C a Elongin B Cul 2 Regulates how the cell sees its surroundings Regulates p53 Controls the primary cilium Impacts blood vessel formation Ohh et al, Mol Cell, Vol 1, , 1998 Kurban et al, Cancer Res 2006; 66: (3). Roe and Youn Mol Cell May 2006 Thoma et al Nature Cell Biology Aug 2009 Kuehn et al Ca Res May 15, 2007 Pugh et al Narture Medicine 2003 Kerbel NEJM May 2008

8 Manifestations and Surveillance Screening/Surveillance Approximately 1/ live births worldwide VHL disease produces nonmalignant and malignant lesions in multiple organs Regular surveillance is critical for patient wellbeing Management requires an integrated team Ho and Jonasch JNCCN 2015

9 Approximately 75 percent showed progression after 8 years. Male gender, partial VHL deletions associated with larger tumor burden.

10 Treatment for VHL related lesions Standard of care in 2015 involves invasive procedures. Retinal hemangioblastomas: laser ablation, photocoagulation, surgical excision Renal cell carcinoma: If approaching or exceeding 3cm, surgical resection, thermal ablation Pancreatic neuroendocrine tumors: surgical resection if larger than 3cm. Pheochromocytomas: resection Hemangioblastomas: resection if symptomatic

11 Coming Up With A Cure: Many Layers of Knowledge are Needed! Identification of the VHL Gene Description of VHL Protein Function Therapeutic Avenues Generate Real-World Patient Databases Identifying and Characterizing Additional Genes Disrupted in VHL Disease Development of Relevant Model Systems

12 Particpation Cancer in Our Genes International Patient (CGIP) Databank A patient-driven databank dedicated to finding a cure for VHL, BHD, HLRCC, SDH, and related disorders Collaborative effort includes National Organization of Rare Disorders (NORD) NORD = Software Provider VHLA = Databank Owner Month

13

14

15 Kim and McCutcheon Targeted Oncology 2012

16 40 patient study Patients with genetically confirmed or clinical diagnosis of VHL eligible Treatment with pazopanib for six months with option to continue. To date, 29/40 patients enrolled.

17 Novel Treatment Approaches

18 Zbar et al Human Mut 1996;8(4): Can We Fix Broken VHL? Approximately one third of VHL lesions are point mutations

19 Point Mutations Destabilize pvhl Flag tagged VHL transfected into incubated with cycloheximide or lactacystin Schoenfeld and Burk PNAS 2000

20 786-0 Some Mutant VHL Isoforms Possess Residual Functionality WT P45L V74D R82P L89H S111N HIF2a VHL Zhiyong Ding and Peter German

21 Differential Stability of VHL Can Be Measured in a Cellular System WT W117A R167W R167Q Zhiyong Ding and Shanshan Bai

22 Screened Prestwick compound library of agents that are in clinical use. Several compounds raised VHL levels. Studies underway assessing the mechanism of action behind VHL elevation.

23 R167Q mutation found in the elongin C binding region of VHL, and prevents VBC complex formation. Is most common VHL mutation in VHL disease patients. You can genetically raise level of VHL by C-terminal tagging gene.

24 Ding and Jonasch Ca Research 2014 VHL Mutational Isoforms Influence Renal Cell Carcinoma Growth Group A: parental line Group B: with L117A mutation and a C-terminal Venus tag *Isofluorane Anesthesia, 1 x 10 7 /100µl PBS, sc into both flanks, 21G, per cell line. *Treatment to begin 2 weeks post tumor implantation. Group C: with R167Q mutation and a C-terminal Venus tag Group D: with R167Q mutation and no tag

25 Ding and Jonasch Ca Research 2014 Bortezomib raises VHL levels and lowers HIF and GLUT1 levels

26 Phase II Study of Carfilzomib in Patients with Refractory Renal Cell Carcinoma Genotype VHL in patient tissue Phase II 40 patient study. Clear cell RCC. Failed at least one prior therapy. Correlate to clinical outcome 12 patients enrolled. No major responses Genotype-phenotype correlation underway

27 VHL Disease: Summary and Next Steps Careful adherence to screening protocols is essential for the wellbeing of VHL patients in We have a lot to learn about genotype-phenotype correlations in VHL disease. We need to develop accurate model systems of VHL to define actionable therapeutic pathways. Using models, our ultimate goal is to devise treatment strategies that prevent development of VHL related lesions in the first place.

28 Peter German Xiande Liu Shanshan Bai Mianen Sun Zhiyong Ding

29 Acknowledgements VHL Clinic Surena Matin Steven Waguespack Ian McCutcheon Dan Gombos Ashley Woodson Kamran Ahrar Greg Fuller Marcia Holloway Maisha Amusa Lab Zhiyong Ding Peter German Shanshan Bai Mianen Sun Xiande Liu Lijun Zhou Nanomedicine Group Wah Chiu Judith Frydman William Mobley David Housman W.E Moerner