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Synthetic lethality: an old friend with a new job. Finding the Achilles heel of cancer. Yolanda Sanchez, Ph.D. Associate Director Basic Sciences Norris.

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Presentation on theme: "Synthetic lethality: an old friend with a new job. Finding the Achilles heel of cancer. Yolanda Sanchez, Ph.D. Associate Director Basic Sciences Norris."— Presentation transcript:

1 Synthetic lethality: an old friend with a new job. Finding the Achilles heel of cancer. Yolanda Sanchez, Ph.D. Associate Director Basic Sciences Norris Cotton Cancer Center CTOP retreat 2014

2 Three inter-related concepts in Cancer Research: Synthetic lethality Precision/targeted therapy Pathway vs. organ site approach to therapy

3 Synthetic Lethality

4 Viable p53 PTEN k-Ras/NF1 Myc Normal cell Cancer cell Synthetic lethality in yeast and cancer Add drugCross

5

6 Mutations that drive a cell to become cancerous rewire the cell in such a way that they become dependent on normal pathways for survival (Achilles heel). Although we know a lot about the mutations that drive cells to become cancerous we know very little about the vulnerabilities of cells that carry these mutations. Candidate and unbiased approaches to target vulnerabilities of cancer cells.

7 Deregulation of cyclins and proto-oncogenes leads to replication-dependent DNA damage and activation of the DNA damage checkpoint Oncogenes Serrano, M et al., Cell 1997 Di Micco R, et al., Nature 2006 Bartkova, J., et al., Nature 2006 DNA damage during DNA replication

8 Deregulation of cyclins and proto-oncogenes leads to replication-dependent DNA damage and activation of the DNA damage checkpoint Oncogenes Serrano, M et al., Cell 1997 Di Micco R, et al., Nature 2006 Bartkova, J., et al., Nature 2006 P P H Atr Atrip Chk1 Claspin DNA damage during DNA replication

9 Deregulation of cyclins and proto-oncogenes leads to replication-dependent DNA damage and activation of the DNA damage checkpoint Oncogenes Serrano, M et al., Cell 1997 Di Micco R, et al., Nature 2006 Bartkova, J., et al., Nature 2006 P P H Atr Atrip Chk1 Claspin DNA damage during DNA replication Candidate approach: Are high levels of oncogene-mediated DNA damage synthetic lethal in combination with Chk1 inhibition?

10 A hypomorphic allele that genetically mimics pharmacological inhibition of Chk1 Candidate Approach with: Ethan Dmitrovsky Vince Memoli Candice Black Alan Eastman Konstantin Dragnev CMGCC

11 Mutations that drive a cell to become cancerous rewire the cell in such a way that they become dependent on normal pathways for survival (Achilles heel). Although we know a lot about the mutations that drive cells to become cancerous we know very little about the vulnerabilities of cells that carry these mutations. Unbiased approach: to find the molecular Achilles heel of cells rewired by mutations that drive the most difficult tumors to treat.

12 Rubin and Gutmann, NRC 5 (2005) Ras GTPGDP ActiveInactive Neurofibromin Targeting tumors With dysregulated Ras signaling

13 Chemical Synthetic lethal screens IRA2  Chemical library NF mutant Slow growth or death v.s. WT No effect on growth v.s. = HIT NF1 NF1-Δ

14 Chemical Synthetic lethal screens IRA2IRA2  Chemical library NF mutant Slow growth or death v.s. WT No effect on growth v.s. = HIT Wood, M., et al., Mol. Cancer Ther Matt Wood NF1 NF1-Δ

15 DMS106 NF1-  NF1 HTS Results Tier 3 AC 50 Ratio = Highly selective 19 compounds (0.0031%) Selective AC 50 ratio > compounds (0.0046%) AC  M DMS136 NF1-  NF1 AC  MAC  M AC 50 Ratio = N/A

16 Personalized therapy Pathway vs. organ site approach to therapy

17 Ras GTPGDP ActiveInactive Neurofibromin NF % Glioma (including Glioblastoma) Neuroblastoma Lung, breast and ovarian cancer Ras mutations frequent as drivers in cancer -Pancreatic >90% -Lung ~30%. Neurofibromin Molecular “Fingerprint” of Cancer and disease

18 Are compound effects limited to MPNST cell lines, or do activities carry over to other cell lines with activated Ras? Matthew Wood Sondra L. Downey Robert J. Allaway Jennifer Bai Ryan Soderquist

19 Tool compounds inhibit the growth of yeast and human cells lacking NF1 Robert Allaway DMS136 Alice S. Pang

20 Using patient-derived Xenografts to determine whether the molecular “Fingerprint” of Cancer correlates with response to compound X Y X+Z

21 Ras GTPGDP ActiveInactive Neurofibromin Tool compounds synthetic lethal in PDX models of pancreatic adenocarcinoma Robert J. Allaway and Dawn Fischer Neurofibromin Tim GardnerStu Gordon Kerry Smith Arief Suriawinata

22 Matthew Wood Ryan S. Soderquist Shu (Alice) Pang Sondra Downey Robert Allaway Elizabeth Pereira Mandeep Kaur Katherine Michelis Jaya Batra Tyler Melancon Helen Hou John Kim Saryah Azmat Nathan Wong Geisel and NCCC Camilo Fadul Mark Israel Bill Hickey Konstantin Dragnev Murray Korc Lionel Lewis Jack Hoopes Rendy Strawbridge Alex Pletnev Craig Tomlinson Joanna Hamilton Jason Moore Nadia Penrod Casey Greene Kerrington Smith Dawn Fischer Tim Gardner Stu Gordon Arief Suriawinata Cincinnati Children’s Hospital Nancy Ratner UC Drug Discovery Center Sandra Nelson Lisa Merk Bill Seibel Ruben Papoian Johns Hopkins Jeffry L. Corden Fukuoka University, Japan Senji Shirasawa JAX labs, Susie Airhart Carol Bolt Neal Goodwin

23 Robert Allaway Prouty Ultimate 2013!

24 Summary of both screens 10 Lead (tool) compounds 3 Identified target or mechanism of synthetic lethality 2 Identified target with inhibitors in clinical trials.

25 Central Hypotheses 1)Compounds that are synthetically lethal with deletion of the budding yeast IRA2 gene (ira2  ) will have selective inhibitory activity in NF1-deficient human cells. 2)The yeast platform is suitable to identify the target molecules or mechanism of action of these compounds. 1)Some of the compounds identified in our screens will be useful as a starting point to develop therapies for other cancers driven by increased Ras activity (NF1 loss, Ras mutation or increased EGFR signaling).

26 What are the target molecules or processes for an unknown compound? nf1  Compound treatment overexpression library Wood, M., et al., Mol. Cancer Ther * * * * * * A B C E F G D Compound treatment nf1 

27 Loss of NF1 NF1 loss can drive formation of plexiform neurofibromas (PN) which can subsequently develop into malignant peripheral nerve sheath tumors (MPNSTs) JML, pheochromocytomas, and astrocytomas are also linked to NF1 loss TCGA reported that 17-23% of glioblastoma multiforme (GBM) carry NF1 mutations. NF1 loss occurs in 25% of breast cancers and in lung adenocarcinomas it is the 6 th most frequently mutated gene, deleted in 7% of ovarian. NF1 loss by mechanisms other than mutation in glioblastomas and neuroblastomas (Cichowski and colleagues). Friedman, JM (1998)

28 NF1 - TCGA, Nature, 2008; Gene Expr - TCGA, Cancer Cell, 2011 Gene Expression (206) NF1 LoF (19) Machine Learning Prediction Which tumors to test: NF1 loss by mechanisms other than mutation in glioblastomas TCGA


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