2017 Chabner Colloquium Answering the Big Questions in Cancer Research Annual Meeting Abstracts

1 – PARP Inhibitor Resistance and Acquired Vulnerability in Ovarian Cancer ALAN D’ANDREA, SUSAN F. SMITH CENTER FOR WOMEN’S CANCERS, DANA-FARBER CANCER INSTITUTE, HARVARD MEDICAL SCHOOL, BOSTON, MASSACHUSETTS, USA Large-scale genomic studies have demonstrated that approximately 50% of high-grade serous ovarian cancers (HGSOCs) harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. The most commonly altered HRR genes are BRCA1 and BRCA2, followed by other Fanconi anemia genes. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to PARP-inhibitors (PARPi) through the mechanism of synthetic lethality. PARP inhibitor resistance has emerged as a vexing clinical problem for the treatment of BRCA1/2-deficient tumors.Themost prevalentmechanism of PARPi resistance is secondary events that cancel the original HRR alteration and restore HRR proficiency. PARPi resistance also develops without restoration of HRR proficiency through enhanced replication fork stabilization. We recently made the surprising observation that BRCA2-deficient tumor cells can stabilize their replication forks and become resistant to PARPi by downregulating the expression of variousmethyltransferases, such asMLL3/4 and EZH2. Reduced histonemethylation limits the nucleolytic degradation of the forks. A molecular understanding of PARP inhibitor resistance mechanisms may allow the generation of a new class of drugs, or a repurposing of existing drugs, whichmay reverse this resistance and extend the use of PARP inhibitors tomore tumor types. Abstract 2 – Assessing DNA Repairs in Clinical Trials2 – Assessing DNA Repairs in Clinical Trials TED HONG, MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MASSACHUSETTS, USA Historically, tumors were classified as being radiation sensitive or radiation resistant based on organ of origin and histology. However, significant heterogeneity in response to radiation therapy can exist for any type of tumor, ranging from no response to pathologic complete response. Efforts have primarily focused on genotype of tumor, with KRAS and KRAS/TP53 mutants being identified as remarkably radiation resistant. More recently, a radiation sensitivity index, based on expression of 10 hub genes identified by correlation with surviving fraction after 2 Gy (SF2), has been shown to predict radiation resistance in a number of clinical situations. Future efforts will involve further characterization of expression preand post-radiation to better identify potential future personalization opportunities with radiotherapy. Abstract 3 – Roles of Inhibition of ATR/ATM in Cancer Therapy3 – Roles of Inhibition of ATR/ATM in Cancer Therapy LEE ZOU, MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MASSACHUSETTS, USA PARP inhibitors (PARPi) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. We used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRi) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRi also overcomes the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers. The Oncologist 2017;22(Supplement 1):S1–S4 www.TheOncologist.com Oc AlphaMed Press 2017 Abstract 4 – Developing Therapies for Ras-Driven Cancers4 – Developing Therapies for Ras-Driven Cancers KAREN CICHOWSKI, BRIGHAM AND WOMEN’S HOSPITAL, HARVARD MEDICAL SCHOOL, BOSTON, MASSACHUSETTS, USA Although selective kinase inhibitors have changed the standard of care in cancers that are driven by oncogenic kinases, there are currently few treatment options for malignancies that lack a “targetable” oncogenic driver. Ras-driven cancers are particularly problematic: agents that target individual Ras effector pathways are largely ineffective, and successful therapeutic combinations have not yet been identified; therefore, it is imperative that we rationally conceptualize and test new therapeutic combinations that (a) function to suppress orthogonal pathways in tumors, (b) converge on specific cancer cell vulnerabilities, and/or (c) exploit multiple therapeutic modalities. In this presentation, therapeutic strategies designed to co-target Ras effector kinases, epigenetic regulators, and/or immunoregulatory proteins will be discussed. By dissecting the mechanism by which promising combinations are working in preclinical models, we have uncovered nodal points of convergence between these distinct pathways and have identified new vulnerabilities that can be targeted in Ras-driven tumors. Abstract 5 – Is FGFR Inhibition an Effective Target in Gastrointestinal Tumors?5 – Is FGFR Inhibition an Effective Target in Gastrointestinal Tumors? LIPIKA GOYAL, MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MASSACHUSETTS, USA FGFR gene aberrations are seen in 10%–20% of patients with intrahepatic cholangiocarcinoma (ICC), a rare and rapidly fatal malignancy of the intrahepatic bile ducts for which no targeted therapies are approved. The FGFR inhibitor BGJ398 displayed an encouraging overall response rate of 22% in a phase II trial in this population, but the durability of response was limited.We recently identified the first evidence of clinical acquired resistance to FGFR inhibition through serial plasma and biopsy analysis of patients with FGFR2 fusion-positive ICC who were treated with BGJ398.This presentation will review the current landscape of FGFR inhibitors and FGFR resistance in cholangiocarcinoma. Abstract 6 – Intergenic Fusions as Frequent Drivers in Advanced HR1 Breast Cancer6 – Intergenic Fusions as Frequent Drivers in Advanced HR1 Breast Cancer LEIF ELLISEN, MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MASSACHUSETTS, USA Most primary breast cancers express estrogen receptor and progesterone receptor and are responsive to therapies that target the estrogen response pathway. Nevertheless, a substantial minority of women treated for primary hormone receptor positive (HR1) disease exhibit hormonal therapy resistance, evidenced by the eventual development of metastatic disease. The pathways that confer hormonal therapy resistance have been studied extensively, yet our understanding of them remains relatively limited.We sought to uncover novel genetic drivers of HR1 breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24 of 173) of unselected patients with advanced HR1 breast cancer. Fluorescence in situ hybridization analysis confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of multiple novel kinase fusions in nontransformed cells activates phosphoprotein signaling and dramatically deregulates cell proliferation and survival in three-dimensional culture, while expression in models of HR1 breast cancer modulates estrogen-dependent growth and transcription and confers resistance to hormonal therapy in vitro and in vivo. Strikingly, decreased time-to-recurrence and shorter overall survival were observed in patients with rearrangement-positive versus rearrangementnegative tumors. Correspondingly, fusions were uncommon (<5%) among a cohort of 300 patients with nonmetastatic HR1 breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR1 breast cancer. S2 Oc AlphaMed Press 2017 Abstract 7 – Genomic and Functional Characterization of Patient-Derived Xenograft Models of Small Cell Lung Cancer7 – Genomic and Functional Characterization of Patient-Derived Xenograft Models of Small Cell Lung Cancer ANNA FARAGO, MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MASSACHUSETTS, USA Small cell lung cancer (SCLC) remains one of the most aggressive subtypes of lung cancer, and treatment strategies for this disease have remained virtually unchanged for more than 30 years.We have developed a platform for studying SCLC by generating patientderived xenograft models from both biopsy specimens and circulating tumor cells. We have characterized the genomic features of these models by whole exome sequencing to show that they faithfully recapitulate the genomics of the patient tumor, and further transcriptional and proteomic characterization is under way. Furthermore, we have developed models from patients at serial time points over the course of their treatments in our clinic, and we show drug sensitivities in the models accurately recapitulate the patient experience.We therefore argue that this platformwill be a powerful tool for comparative therapeutic studies and biomarker development in SCLC. Abstract 8 – Antibody Drug Conjugates for Triple-Negative Breast Cancer: Targeting Positive in the Negative8 – Antibody Drug Conjugates for Triple-Negative Breast Cancer: Targeting Positive in the Negative ADITYA BARDIA, MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MASSACHUSETTS, USA Triple-negative breast cancer (TNBC) refers to tumors that lack expression of estrogen receptor, progesterone receptor, and HER2; patients with metastatic TNBC