Unmet Needs VHL Gene and Protein Data Models of Basic Science On - - PowerPoint PPT Presentation

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

The Past, Present, and Future of VHL: A Clinical and Research Perspective

Eric Jonasch, MD Professor of Medicine UT MD Anderson Cancer Center

Coming Up With A Cure: Many Layers of Knowledge are Needed!

Identification of the VHL Gene Description of VHL Protein Function Identifying and Characterizing Additional Genes Disrupted in VHL Disease Development of Relevant Model Systems

Detection Follow up Treatment

Generate Real-World Patient Databases

Unmet Needs

Data Collection Imaging Technology New Therapies Models of Disease Basic Science Screening Tools

• On chromosome 3p25
• 213 amino acid protein
• Binds to Elongin C/B
• Forms “VBC complex”

Elongin C (15kDa) a Elongin B (18kDa)

Cul 2 Modified from Stebbins and Pavletich, Science, Vol 284, 16 April 1999

VHL Gene and Protein

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

Regulates how the cell sees its surroundings

Ohh et al, Mol Cell, Vol 1, 959-968, 1998 Kurban et al, Cancer Res 2006; 66: (3).

Regulates p53 Impacts blood vessel formation Controls the primary cilium

Thoma et al Nature Cell Biology Aug 2009 Pugh et al Narture Medicine 2003 Kuehn et al Ca Res May 15, 2007 Kerbel NEJM May 2008

Elongin C

a b

Elongin B

Cul 2

Roe and Youn Mol Cell May 2006

VHL- A Regulatory Hub

Transcription of: VEGF Other angiogenic factors HIF-a Nucleus HIF-b VHL

VEGF = vascular endothelial growth factor; HIF = hypoxia-inducible factor.

VHL Mutation Increases Production

• f Growth Factors, like VEGF

Tumor cells VHL-/- VHL-/-

VEGF

VHL-/-

VHL Loss Results in Abnormal Production

• f Blood Vessels, Fueled by VEGF

Stromal cells

VEGF VEGF VEGF VEGF

Can We Block The Consequences

• f VHL Loss?

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

Tumor cells VHL-/- VHL-/-

VEGF

VHL-/-

Agents Exist or Are in Development That Block VEGF or VEGF Receptors

Stromal cells

VEGF VEGF VEGF VEGF

Sunitinib Pazopanib Axitinib Bevacizumab

Pazopanib Study: American Society

• f Clinical Oncology 2017

Phase II Study of Pazopanib in Patients with von Hippel Lindau Disease

Eric Jonasch1, Daniel Gombos2, Steven G. Waguespack3, Valerie Marcott4, Diane Liu5, Justin Weldon1, Shelly Bird1, Christine Robichaux1, Nizar Tannir1 Ashley Woodson6, Gregory N. Fuller7, Ian E. Mccutcheon8 and Surena Matin9

Departments of Genitourinary Medical Oncology1, Ophthalmology2, Endocrinology3, Investigational Therapeutics4, Biostatistics5, Cancer Genetics6, Pathology7, Neurosurgery8 and Urology9 at the UT M. D. Anderson Cancer Center, Houston, TX

INTRODUCTION

von Hippel Lindau disease (VHL) is an autosomal dominant disorder. Affected individuals develop vascular neoplastic lesions in multiple sites including the eye, brain, pancreas, adrenal and kidney. Standards of care includes surveillance imaging and surgical

• intervention. We hypothesized that treatment of

VHL related lesions with an antiangiogenic agent would result in shrinkage of all lesion

• types. We chose the multikinase inhibitor

pazopanib to test this hypothesis.

METHODS RESULTS RESULTS

Patients treated with an alternate sunitinib schedule d

RESULTS

Treatment emergent toxicities seen in at least 10 percent of patients PATIENT Patients with clinical features or genetic confirmation of VHL disease, with measurable lesions were treated with pazopanib 800mg PO daily for two 12-week

• cycles. Efficacy was determined by modified

RECIST after two cycles, with overall response the primary endpoint. Patients had the option to continue therapy beyond 24

• weeks. Continuous monitoring for any lesion

progression and drug discontinuation due to toxicity during the whole period of the treatment was planned. Swimmers plot of response by organ site

RESULTS PATIENT CHARACTERISTICS CONCLUSIONS

• Dosing
• N

800mg 13 600mg 12 400mg 6 No dose received 1

• Reason
• ff

therapy

• Transaminitis

4 Other toxicities 3 Progression 3 Patient choice 11 Ongoing treatment 10 Death 1

• Adverse

Event Max Grade 1 Max Grade 2 Max Grade 3 Max Grade 4 Diarrhea 14 9

• Fatigue

11 10 1

• Aspartate

aminotransferase increased 12 5 3

• Alanine

aminotransferase increased 11 4 3 1 Skin hyperpigmentation 18

• Hypertension

4 10

• Nausea

9 3

• Dysgeusia

7 3

• Proteinuria

7 1 1

• Mucositis

5 3

• Leukopenia

7

• 1
• Alopecia

8

• Vomiting

7

• Platelet

count decreased 6

• Hair

pigment change 6

• Rash

4 2

• Anemia

5

• Alkaline

phosphatase increased 4

• Creatinine

increased 4

• Depression

4

• Epistaxis

4

• Hyperglycemia

4

• Hyperthyroidism

4

• Hypoalbuminemia

4

• Hypernatremia

3

• Hypocalcemia

3

• Hypokalemia

3

• This is the largest prospective VHL disease

specific therapeutic study presented to date. Pazopanib resulted in significant and sustained disease control for the majority of VHL patients enrolled on the study, with shrinkage

• r stabilization in the kidney, pancreas and

CNS, along with an acceptable safety profile. A number of patients remain on therapy, with continued response. This agent may be considered as an alternative to surgical intervention in patients with VHL disease.

• Number
• f

patients (%) Total evaluable 31 CR PR 13 (42) SD 18 (58) PD Inevaluable 1

• Renal

(%) CNS(%) Pancreas (%) Lesion Number

• 59

49 17 CR 2 (3)

• PR

29 (53) 2 (4) 9 (53) SD 28 (47) 47 (96) 8

• (47)

PD

• Overall response rate

Best response by organ site Examples of organ specific response Dosing and reason for treatment discontinuation Time to response per organ site and duration of treatment per

• patient. Median duration of treatment was six months.

New Therapies

Pazopanib: Tumor Response

New Therapies

PT

HIF-a Nucleus HIF-b VHL

If VHL Is Broken, Cells Don’t Control HIF

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

PT

HIF-a Nucleus HIF-b VHL

If VHL Is Broken, Cells Don’t Control HIF

PT

HIF-a Nucleus HIF-b VHL

VEGF

If VHL Is Broken, Cells Don’t Control HIF

PT

HIF-a Nucleus HIF-b VHL

VEGF

If VHL Is Broken, Cells Don’t Control HIF

Can we block HIF?

PT

HIF-a Nucleus HIF-b VHL

PT2977

Peloton HIF 2 Alpha Blocker

VEGF

New Therapies

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

PT

HIF-a Nucleus HIF-b VHL

PT2977

VEGF

Peloton HIF 2 Alpha Blocker

New Therapies

PT

HIF-a Nucleus HIF-b VHL

PT2977

VEGF

A clinical trial is being developed to test PT2977 in VHL patients!

New Therapies

Peloton HIF 2 Alpha Blocker

• PT2977 is a next-generation HIF2a blocker that is

administered in pill form.

• A study will be launched in 2018 to test the effect of

PT2977 on kidney and other manifestations in individuals with VHL.

• Primary goal of study will be to see whether kidney

tumors shrink- will also assess impact in other sites.

Peloton HIF 2 Alpha Blocker

New Therapies

VHL Alliance Research Funding

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

VHL Alliance Research Funding

• Over 1 million dollars given for research!
• Review committee consisting of world leaders

in VHL research.

• Strong emphasis on translational research

which will benefit patients sooner rather than later.

Preproposal Requests (May-June) Invitation for Full Review (July) Full Proposal Submission (August) Peer Review and Selection Vetted by internationally recognized experts

Data Collection Imaging Technology New Therapies Models of Disease Basic Science Screening Tools

VHL Models and Novel Therapeutics

Othon Iliopoulos

• Dept. Oncology

Massachusetts General Hospital, Boston MA

2014 Full Project Awardee

Models of Disease

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

• Zebrafish are tiny fish that can be

genetically modified.

• VHL mutation in zebrafish can

represent aspects of human biology.

• Dr. Iliopoulos used zebrafish to discover new

drugs that may rescue consequences of VHL mutation.

• Work is almost complete and will be published

soon.

Salivary, plasma meTanephRines and anxiEty levelS in pheochromocytomaS (STRESS)

A.N.A van der Horst-Schrivers Department of Endocrinology University Medical Center Groningen

2015 Pilot Project Awardee

Screening Tools

Approach and Significance

• The team will assess salivary metanephrine

levels and compare to blood levels to determine accuracy

• If measurement of salivary metanephrines is

just as accurate as blood metanephrines, then this approach will be more time and cost effective for patients/germline mutation carriers and for the treating medical team.

Screening Tools Using a novel mouse model of ccRCC to investigate Hif-1α and Hif-2α inhibition for cancer prevention and therapy

• Prof. Dr. Ian J. Frew

Institute of Physiology, University of Zurich

2015 Full Project Awardee

Models

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

Rationale

• Clear cell renal cell carcinomas (ccRCC) that arise frequently in

patients with von Hippel-Lindau (VHL) disease.

• The generation of mouse models has been a powerful tool

used by scientists to not only understand the genetic causes and biological behaviour of tumors but also to test new therapies that can guide subsequent drug trials in human patients.

Models of Disease

Approach and Significance

• Dr. Frew and his team have recently generated a very good

mouse model of ccRCC, possibly the first that truly represents what happens in patients.

• They will use mouse ccRCC model to determine whether drug

treatment can prevent the formation of new tumors and efficiently treat existing tumors. They will test available compounds that block HIF.

• If successful, this will allow us to more rapidly screen for new

drugs that can treat kidney cancer.

Models of Disease

VHL IT‐Sharing International Consortium (VISIon)

Raymond Kim PI University of Toronto

2016 Pilot Project Awardee

Data Collection

Rationale

• We lack consolidated databases that

aggregate information on VHL genotype- phenotype correlations.

• By creating such a database, it will advance
• ur ability understand why we see specific

patterns of VHL manifestations in patients.

Data Collection

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

Approach and Significance

• Dr. Kim will develop an interactive database to

collect genotypic and phenotypic data on VHL patients worldwide.

• By performing this work, Dr. Kim’s team will

create a template that will allow more rapid collection of VHL genotypes and phenotypes, and will contribute to our understanding of how VHL mutations affects patients.

Data Collection

iPS model for Retinal Hemangioma Pathogenesis

Michael Gorin, MD, PhD UCLA

2016 Full Project Awardee

Models of Disease

Rationale

• No good models currently exist for

hemangioblastomas.

• Induced progenitor stem cells are cells that can be

modulated to develop specific cell types, including those from the eye.

• Knockout of the Vhl gene in specific regions of a

mouse is possible using specific gene modulating techniques.

Models of Disease

Significance

• If successful, this model will provide a

representative model of abnormal retinal cells in VHL.

• This model will allow the Gorin team to test

how retinal hemangiomas influence blood vessels in the eye, and to screen for potential strategies that will overcome blood vessel formation.

Models of Disease

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

VHL Patient Natural History Study

A patient-driven databank dedicated to finding a cure for VHL, BHD, HLRCC, SDH, and related disorders

Data Collection

Origins

• Outcome of 10th International VHL Medical

Symposium (Houston, 2012) – VHLA Research Council

• Collaborative effort includes National

Organization of Rare Disorders (NORD) – NORD = Software Provider – VHLA = Databank Owner

Data Collection

A Complementary Effort

• Joint effort between VHLA and heath care

professionals

• Complementary to existing institutional databanks

– Information best answered by patients, i.e. Lifestyle (diet, exercise, sleep, nutritional supplements, mood, altitude,

• ral health)
• De-identified data available to researchers
• Match participants within a specific research

criteria

• Provide baseline data for clinical trial

Data Collection

Goals

• Further understand natural history

‐ Longitudinal

• International study

‐ Wide range of genotype ‐ Study geographical differences

• Comprehensive patient-driven data

‐ Impact of lifestyle on disease progression and/or tumor growth rate

• Learn from all experimentation
• Learn from commonalities and differences

between disorders

Data Collection

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A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance, 2017 Tampa, FL

Features

• Privacy and Confidentiality: Primary concerns

and factor built into CGIP

• Confidential/Secure
• IRB Approved
• Data curation process incorporated
• Online: no geographic limitations
• Language = English
• No age limitations

Data Collection

Challenges

• Global support and participation by researchers
• Increased awareness among patients

– VHL, BHD, HLRCC, SDH, etc.

• Increasing participation
• Patient follow-through

– Surveys – Medical information

Data Collection

2017 Grant Cycle

Data Collection Imaging Technology New Therapies Models of Disease Basic Science Screening Tools

Past Present and Future

Identification of the VHL Gene Determining how VHL deficiency affect patients Developing new ways to treat VHL disease