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

VHL Gene and Protein

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).

Regulatesp53

Impacts blood vessel formation

Controls the primary cilium

Thoma et al Nature Cell Biology Aug 2009Pugh et al Narture Medicine 2003

Kuehn et al Ca Res May 15, 2007Kerbel NEJM May 2008

Elongin C

ab

Elongin B

Cul 2

Roe and Youn Mol Cell May 2006

VHL- A Regulatory Hub

Transcription of:VEGFOther angiogenic factors

HIF-a

Nucleus

HIF-b

VHL

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

VHL Mutation Increases Production of Growth Factors, like VEGF

Tumor cells

VHL-/-

VHL-/-

VEGF

VHL-/-

VHL Loss Results in Abnormal Production of Blood Vessels, Fueled by VEGF

Stromal cells

VEGF

VEGF

VEGF

VEGF

Can We Block The Consequences of VHL Loss?

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

SunitinibPazopanibAxitinibBevacizumab

Pazopanib Study: American Society of 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 N800mg 13600mg 12400mg 6Nodosereceived 1 Reasonofftherapy

Transaminitis 4Othertoxicities 3Progression 3Patientchoice 11Ongoingtreatment 10Death 1

AdverseEvent MaxGrade1 MaxGrade2 MaxGrade3 MaxGrade4Diarrhea 14 9

Fatigue 11 10 1

Aspartateaminotransferase

increased 12 5 3

Alanineaminotransferaseincreased 11 4 3 1

Skinhyperpigmentation 18

Hypertension 4 10

Nausea 9 3

Dysgeusia 7 3

Proteinuria 7 1 1

Mucositis 5 3

Leukopenia 7 1

Alopecia 8

Vomiting 7

Plateletcountdecreased 6

Hairpigmentchange 6

Rash 4 2

Anemia 5

Alkalinephosphataseincreased 4

Creatinineincreased 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

or 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.

Numberofpatients(%)

Totalevaluable 31CR 0PR 13(42)SD 18(58)PD 0Inevaluable 1

Renal(%) CNS(%) Pancreas(%)

LesionNumber

59 49 17

CR 2(3) 0 0

PR 29(53) 2(4) 9(53)

SD 28(47) 47(96) 8(47)

PD 0 0 0

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 ResponseNew

Therapies

PTHIF-a

Nucleus

HIF-b

VHL

If VHL Is Broken, Cells Don’t Control HIF

A Clinical and Research Perspective Eric Jonasch, MD

VHL Alliance, 2017 Tampa, FL

PTHIF-a

Nucleus

HIF-b

VHL

If VHL Is Broken, Cells Don’t Control HIF

PTHIF-a

Nucleus

HIF-b

VHL

VEGF

If VHL Is Broken, Cells Don’t Control HIF

PTHIF-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

A Clinical and Research Perspective Eric Jonasch, MD

VHL Alliance, 2017 Tampa, FL

PTHIF-a

Nucleus

HIF-b

VHL

PT2977

VEGF

Peloton HIF 2 Alpha Blocker New Therapies

PTHIF-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

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

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 VHLmutation.

• 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 metanephrinelevels 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 AwardeeModels

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 AwardeeData

Collection Rationale

• We lack consolidated databases that aggregate information on VHL genotype-phenotype correlations.

• By creating such a database, it will advance our ability understand why we see specific patterns of VHL manifestations in patients.

Data Collection

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

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, oral 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

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