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Oncogenesis and Tumor Biology: Targeting ASCL1

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Oncogenesis and Tumor Biology: Targeting ASCL1 Oncogenesis and Tumor Biology: Targeting ASCL1 U01 CA213338-01 Developing ASCL1 and NEUROD1 Lineage Oncogene Targeted Therapy for Small Cell Lung Cancer (PI: Minna) John Minna Jane Johnson Melanie Cobb Adi Gazdar Lab Lab Lab Lab Victor Stastny Luc Girard Aiden Karine Demetra Courtney Nguyen Pozo Kelenis Powell Kenneth Huffman Rahul Kollipara Svetlana Earnest Michael Peyton Trisha Savage Pearl Wichaidit U01 CA213338-01 Developing ASCL1 and NEUROD1 Lineage Oncogene Targeted Therapy for Small Cell Lung Cancer (PI: Minna) Major Goal: To systematically classify SCLCs for their dependency on two key lineage oncogenes, ASCL1 and NeuroD1, and develop therapy targeted at these two transcription factors and their key downstream druggable targets. Updating Findings on Lineage Oncogenes ASCL1 and NEUROD1 in SCLC Testing ASCL1 and NEUROD1 targets in SCLC cells and xenografts Identifying a group of transcription factors that cross and auto-regulate one another; testing their requirement for SCLC. Identifying ASCL1 interacting proteins (co-factors) Probing the role of ERK and the ERK-ASCL1 axis in SCLC ASCL1 and NEUROD1 are lineage- specific bHLH transcription factors • They are transcriptional activators. gene • They, or their transcriptional targets, may provide unique, druggable, vulnerabilities in SCLC. • They are required in multiple neuronal and neuroendocrine lineages during normal development. ASCL1 NEUROD1 ASCL1 NEUROD1 • They are not mutated in SCLC but represent lineage- specific TFs required for tumor cell survival. Ascl1-/- Understanding ASCL1 function in SCLC: New Biomarkers and New Targets Cofactors Regulators P P P ASCL1 ASCL1 P P Effectors SCLC growth Identifying downstream transcriptional targets of ASCL1 and NEUROD1 in SCLC Differentially expressed ASCL1 or NEUROD1 genes in ASCL1HI and ChIP-Seq NEUROD1Hi SCLC Associated genes In Progress: models Potential Targets Drop out screen in SCLC cell lines and in xenografts using an shRNA library with a 571 394 subset of these targets. ASCL1 49 NEUROD1 Targets Targets Borromeo et al. 2016 • Some shared, most distinct Understanding ASCL1 function in SCLC: New Biomarkers and New Targets Cofactors Regulators P P P ASCL1 ASCL1 P P Effectors SCLC growth A core TF network may co-regulate genes important for tumor biology Super-enhancers are associated with key cell lineage genes * * * * Borromeo et al. 2016 A core TF network may co-regulate genes important for tumor biology NFIB NKX2.1 CANCER GENE Tumor ASCL1 TARGETS growth MYCL FOXA2 Is the function of each transcription factor interdependent and necessary for tumorigenesis? ASCL1 and FOXA2 bind many of the same sites in a SCLC cell line ASCL1/FOXA2 bound sites ? Is each transcription factor interdependent and Johnson Lab, unpublished necessary for tumorigenesis? Regulatory interactions between a subset of the core TF network H2107 ASCL1high SCLC cells 48 hrs post treatment ASCL1 NFIB NKX2.1 FOXA2 Karine Pozo ASCL1 loss is detrimental to SCLC survival H2107 ASCL1high SCLC cells 1.6 48 hrs post treatment 1.4 1.2 1 0.8 0.6 0.4 80% 95% 95% Cell survival 0.2 - - - Kd Kd Kd 0 Karine Pozo siRNA A core TF network may co-regulate genes important for tumor biology NFIB NKX2.1 ASCL1 CANCER GENE Tumor TARGETS survival MYCL FOXA2 Identifying ASCL1-cofactors in SCLC Co-IP Mass Spec from SCLC (H2107) ASCL1 IgG Nuc Cyto IP IP 247 interactors E15.5 mouse lung E12/E47 ASCL1 ASCL1/PROX1 HEB E2.2 NKX2.1 PROX1 TRIM28 McGovern et al., 2010 CDK2 Karine Pozo Understanding ASCL1 function in SCLC: New Biomarkers and Targets Cofactors Regulators P P P ASCL1 ASCL1 P P Effectors SCLC growth ERK in SCLC and an ERK:ASCL1 Axis • SCLC express relatively low Growth Factors levels of phosphoERK MEK1/2 • SCLC cells (ie H82 and H889) are insensitive to MEK inhibitors ERK1/2 SCLC Melanie Cobb Lab ASCL1 Uses DUSP6 to Set the Amplitude of ERK Signaling Growth Factors • ASCL1 is phosphorylated and can be an ERK substrate MEK1/2 Control +AP + PP2A WB: ERK1/2 ASCL1 ? H889 ? DUSP6 ASCL1 • DUSP6 is an ASCL1 target H889 H2107 H69 H82 H524 H526 H720 SCLC ASCL1 DUSP6 Total ERK Earnest and Cobb; unpublished Ongoing studies on Lineage Oncogenes ASCL1 and NEUROD1 in SCLC Testing ASCL1 and NEUROD1 targets in SCLC cells and xenografts Identified a TF network; testing requirements for SCLC. Identified ASCL1 interacting proteins; testing how they modulate ASCL1 activity Probing the role of ERK and the ERK-ASCL1 axis in SCLC Acknowledgements Johnson Lab Melanie Cobb John Minna Kenneth Huffman Trisha Savage Svetlana Earnest Michael Peyton Mark Borromeo Pearl Wichaidit Rahul Kollipara Longshan Li Karine Pozo Alex Augustyn Demetra Kelenis Aiden Nguyen Adi Gazdar Victor Stastny Luc Girard Funding NCI Lung Cancer Spore UTSW CPRIT NCI: U01.
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