Recent Advances in Cancer Research and Therapeutic Approaches. Leonidas C. Platanias, MD, PhD

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1 Recent Advances in Cancer Research and Therapeutic Approaches Leonidas C. Platanias, MD, PhD

2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University

3 Cancer "the veins stretched on all sides as the animal the crab has its feet" Edwin Smith Papyrus 1600 BC - Ancient Egypt Hippocrates of Kos BC Aulus Cornelius Celsus 25 BC- 50 AD

4 Advances in Cancer Research and Treatment - Past Radiation Therapy late 1800s Niels Ryberg Finsen Wilhelm Conrad Röntgen Pierre and Marie Curie 1900 Finsen Lab

5 Advances in Cancer Research and Treatment - Past Chemotherapy 1940s Combination Chemotherapy 1960s Sidney Farber George Canellos-Vincent DeVita-Robert Young (1971)

6 Advances in Cancer Research and Treatment - Past Stem Cell Transplant 1970s Georges Mathé E. Donald Thomas

7 Advances in Cancer Research and Treatment Precision Medicine Nanotechnology Epigenetics Immunotherapy

8 Precision Medicine and Therapeutic Targeting 8

9 One Size does not fit all

10 Lung Cancer- Molecular Abnormalities

11 Current Approach

12 Future Approach

13 Integrative Genomic Analysis of Wilms Tumor Nature Genetics 2017 J Clin Oncol 2016, Clin Cancer Res 2016, Cancer Cell 2015, Nature Comm 2015 The genetic landscape of Favorable Histology Wilms Tumor E. Perlman ARRA TARGET; U10CA98543 Genomic Core Robert H. Lurie Comprehensive Cancer Center of Northwestern University 13

14 Integrative Genomic Analysis of Wilms Tumor Nature Genetics 2017 J Clin Oncol 2016, Clin Cancer Res 2016, Cancer Cell 2015, Nature Comm 2015 The combination of two rare mutations results in poor clinical outcome E. Perlman mirnapg and SIX mirnapg only others SIX only SIX 1/2 DROSHA XPO5 DICER1 DGCR8 ARRA TARGET; U10CA98543 Genomic Core Robert H. Lurie Comprehensive Cancer Center of Northwestern University 14

15 mrna abundance (normalized) Therapeutic Targets of Growth Factor Pathways in Acute Myeloid Leukemia Increased HoxA9/10 correlates with Fgf2-dependent cytokine hypersensitivity in AML Clinical trial: 5-Azacitidine + Nintedanib MII-EII mrna expression: CD34+ bone marrow cells (control versus AML low versus AML high ) L. Platanias J. Altman E. Eklund HoxA9 HoxA10 Fgf2 Fgf-R PI3K Akt Gsk3β βcatenin Cdx4 c-myc cyclind1 survivin Proliferation / survival 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0 ** * ** * # # # # # # & & && HoxA9 HoxA10 Fgf2 B3 Integrin ^ ^^ ^ ^^ Control AML low Hox AML high Hox R01CA195642, R01CA077816, R01CA Flow Cytometry, Developmental Therapeutics, Mouse Histology and Phenotyping, Proteomics, High Throughput Analysis, ChemCore Robert H. Lurie Comprehensive Cancer Center of Northwestern University 15

16 Advances in Cancer Research and Treatment Epigenetics and Nuclear Dynamics

17 Histone H3 Lysine to Methionine Mutants in Malignancies Nature Genet 2017; Science 2014; Nature Med 2017; Genes Dev 2017 Scientific Accomplishment: Aim 2 A. Shilatifard N. Kelleher (MOM) C. D. James (TRIST) S. Goldman (TRIST) R01CA089455; P41GM108569; R35CA Proteomics Core Facility, Developmental Therapeutics Core, Quantitative Data Sciences Robert H. Lurie Comprehensive Cancer Center of Northwestern University 17

18 Advances in Cancer Research and Treatment Nanotechnology

19 Tumor weight (mg) Nanotechnology - From the lab to the treatment of solid tumors Sci Transl Med 2013; PNAS 2017; J Am Chem Soc 2015, Genes & Dev 2015 Chad Mirkin (CAPS) Alex Stegh (TRIST) First in Human - Phase 0 clinical trial BCL2L12- targeting SNAs NCT ongoing - 3 patients enrolled so far Anticipated accrual 8 patients and then move to Phase I 150 Crossing the blood brain-barrier in animal models sirna-based SNAs P< mirna-based SNAs P< Priya Kumthekar (TRIST) 0 sico sibcl2l12 0 Co-miR mir-182 U54 CA151880, R01CA208783, the American Cancer Society Research Scholar Award Flow Cytometry, Mouse Histology and Phenotyping, Pathology, Center for Advancer Microscopy 19

20 Tumor Environment and Immunotherapy

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24 The Case for Cancer Cellular Therapy Presented By Carl June at 2016 ASCO Annual Meeting

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26 Checkpoint Inhibitors

27 CAR T cells

28 CAR T manufacturing and administration *large range on timing for processing Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-cd19 chimeric antigen receptors. Nat. Rev. Clin. Oncol. doi: /nrclinonc

29 Future Approaches in Cancer Therapy New Immunotherapeutic Modalities New Targeted Agents Combinations of Therapeutic Approaches We are still missing something significant in order to develop definitive curative treatments for all cancers Robert H. Lurie Comprehensive Cancer Center of Northwestern University 29

30 Thank You 30