[PPT] - Defining Vulnerabilities of T-cell Lymphomas: we are close to the PowerPoint Presentation

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Defining Vulnerabilities of T-cell Lymphomas: we are close to the finalization…of the beginning

David Weinstock dweinstock@partners.org http://weinstock.dfci.harvard.edu

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Company name Research support Employee Consultant Stockholder Speakers bureau Advisory board Other Travera X X Founder Novartis X X Dragonfly X Aileron X Abbvie X Astra Zeneca X Surface Oncology X Monsanto Expert Witness Genentech Expert Witness Verastem X Daiichi X DxTerity X

Disclosures

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MSKCC Stanford Dana-Farber/BWH

Clinical Core Phase I and II Surgery Pathology Core Characterization, Banking, NGS, Spectral Imaging Model Generation Core PDX development Cell line generation Transgenic models Patient-Derived Xenografts (PDX) Primary lymphomas & PDX cell lines PDX clinical trials Targeted agents T-cell differentiation Lymphomagenesis 2D 3D In vitro drug response

Nebraska Weill-Cornell

Industrial and Academic Partners

GATA-3

Translational Discovery in Peripheral T-Cell Lymphomas

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Wu et al. Cancer Cell 2015 Crescenzo et al. Cancer Cell 2015 Townsend et al. Cancer Cell 2016 Yoda et al. Nature Medicine 2016 Dunford et al. Nature Genetics 2017 Horwitz et al. Blood 2018 Murakami and Weinstock. Nature 2018 Buchner et al. Cell 2018 Ng et al. Nature Communications 2018 (in press) Ng et al. Blood 2018 (in press) Intlekofer et al. Nature 2018 (in press)

3 years of progress

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Cutting edge in genomics-based drug selection

Letai. Nature Med 2017

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Personalized Medicine for Cancer: Genetic Testing

Letai et al. Nat. Med. (2017); Vivek Prasad, Nature. (2016); Friedman et al. Nat. Rev. Cancer (2015)

Personalized Medicine for Infectious Disease: Antibiotic Susceptibility Testing Highly successful for some cancers but unavailable for most Highly successful across a wide range of organisms and drugs

Proliferation is a functional biomarker

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Ng et al. Nat Comm 2018 (in press)

Vulnerability screening to define targets

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Aileron Therapeutics

Targeting both MDM2 and MDMX

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Murakami and Weinstock, Nature 2017

Patient-derived xenografts to model human cancer

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Patient Cutaneous NK/T

CD3 CD8 CD56 EBER

Mouse tumor

CD3 CD8 CD56 EBER

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20 40 60 80 100 120 140 160 50 100 Days Survival Survival(%) vs. p=0.0002 vs. p=0.0036

Randomization upon engraftment Pharmacodynamics Biomarkers

Defining biomarkers, toxicity and resistance

Townsend et al. Cancer Cell 2016

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T-ALL AML B-ALL AUL BPDCN Mantle cell lymphoma Double-hit lymphoma Marginal zone lymphoma Follicular lymphoma Transformed follicular lymphoma Diffuse large B-cell lymphoma High-grade with MYC rearr

Enabling Research on Human Cancer

Alveolar Soft Part Sarcoma Inflammatory myofibroblastic tumor Neurofibroma Osteosarcoma Rhabdoid tumor Solid pseudopapillary tumor Wilms Tumor Merkel cell carcinoma 400 Solid Tumors from Novartis HSTL Primary cutaneous CD30+ TCL T-PLL AITL ALK+ ALCL ALK- ALCL Mycosis Fungoides Sezary Syndrome Cutaneous NK/TCL Extranodal NK/TCL PTCL, NOS ATLL

Many, many people and especially Giorgio Inghirami

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Public Repository of Xenografts (www.PRoXe.org)

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