Investigators at Memorial Sloan Kettering are invited to submit research proposals for support from the Druckenmiller Center for Lung Cancer Research. Primary goals of the DCLCR include expanding our understanding of the biology of lung cancer through the support of basic research discoveries, examining novel treatment strategies in preclinical models of lung cancer, and testing promising concepts in patients through clinical trials.
Year 2 - 2017
Project Title: The Tumor Suppressor Function of SETD2 in Lung Tumorigenesis
Recent cancer genome sequencing studies of lung cancer have identified a new cancer gene, SETD2, which is mutated in up to 9% of lung adenocarcinoma. SETD2 encodes an enzyme that modifies histone proteins to regulate gene expression and several other biological processes. However, how SETD2 mutations cause lung cancer remains unclear. We plan to build a mouse model that mimics human lung cancer with SETD2 mutations. Using this model, we will investigate how SETD2 mutations cause lung cancer and identify therapeutic strategies for lung cancer harboring SETD2 mutations.
Project Title: Analysis of circulating tumor DNA to identify clonal resistance mechanisms to targeted therapies in patients with HER2 mutant lung cancers
Memorial Sloan Kettering is actively investigating new agents for the treatment of HER2 mutant lung cancers. This project aims to leverage our latest advances in genetic sequencing of cancer DNA from the blood, or liquid biopsies, to determine mechanisms of de novo and acquired drug resistance to targeted therapies, including ado-trastuzumab emtansine. We will apply the latest computational algorithm FACETS, to map out the evolutionary clonal composition of HER2 and other mutations before and after treatment, to help refine our precision medicine for patients with HER2 mutant lung cancers.
PI: Andreas Rimner, MD
Department of Radiation Oncology
Co-PIs: Alexander Geyer, MD
Department of Pulmonology
Project Title: Biomarker and patient-reported outcomes response to nintedanib for prevention of pulmonary exacerbations after radiation pneumonitis
Radiation pneumonitis is one of the most severe toxicities of radiation therapy to the lungs. It occurs in up to 20% of patients and is only controlled with a long course of steroids such as prednisone. It can result in severe long-term sequelae such as long-term oxygen dependence and frequent reoccurring pulmonary exacerbations, infections and episodes of severe shortness of breath or cough. This study is a prospective, randomized, multicenter phase II study that examines the impact of nintedanib, a novel targeted drug, in addition to steroids in preventing such sequelae in an attempt to improve patients’ long-term quality of life. As part of this study we evaluate physician- and patient-reported outcomes and quality of life as well as biomarkers in the peripheral blood that may correlate with response to treatment with prednisone and nintedanib.
Project Title: Functional Significance of BRMS1 Variant2 SNP rs1052566 in Lung Adenocarcinoma Metastases
BRMS1 is a protein functioning as a metastases suppressor in several solid tumor malignancies. Using a large Lung Adenocarcinoma (LUAD) tissue microarray we show that BRMS1 is an independent predictor of survival and loss of BRMS1associates with invasive histologic subtypes. Single nucleotide polymorphisms (SNPs) are the most common genetic variations and are major determinants of disease susceptibility and response to therapy. We recently identified the SNP rs1052566 homo-variant in BRMS1 variant 2 (v2) is present in 7.5% of LUAD patients and causes an A273V mutation, resulting in enhancement of c-Fos-induced L1CAM transcription and LUAD metastases. The goals of this project are to evaluate the biological significance of SNP rs105226, clarify the mechanism(s) through which BRMS1v2 A273V promotes metastases, and examine the therapeutic efficacy of a c-Fos inhibitor on suppression of SNP rs105226-enhanced LUAD metastasis.
PI: Kathryn Arbour, MD
Medical Oncology Fellowship, Thoracic Oncology Service, Department of Medicine
Project Title: Combination MEK and FGFR inhibition in KRAS mutant NSCLC: A Phase I/II Trial of Trametinib and Ponatinib
While FDA approved therapies now exist for patients with EGFR, ALK, and ROS1 mutations but together, these mutations only account for approximately 30% of all patients with advanced NSCLC. By contrast, KRAS mutations occur in approximately 20% of patients with advanced NSCLC, however there are no targeted therapies that combat KRAS mutated tumors. The only hint of an effective targeted therapy for KRAS mutant tumors is with inhibition of a protein called MEK, which seems to be important in KRAS mutant tumors. Unfortunately, it only shrinks cancer in a small number of patients. Recently published groundbreaking results (from the laboratories of MSKCC collaborators Dr. Scott Lowe and Dr. Neal Rosen) showed that KRAS mutant cancer cells quickly become resistant to MEK inhibitors by activating another protein called FGFR1. Following this observation, further work demonstrated that inhibiting both MEK (via the drug trametinib) and FGFR1 (via the drug ponatinib) killed the KRAS mutant cancer cells. Based on this data, we will conduct a phase I/II study to understand whether it is safe and effective to combine trametinib and ponatinib in people with metastatic KRAS mutant NSCLC.
Year 1 - 2016
Project Title: eIF4A is a New Therapeutic Target in Small Cell Lung Cancer
Our project explores a new and effective mechanism to kill small cell lung cancer cells. Specifically, we found that lung cancer cells cannot tolerate a class of drugs that block the RNA unwinding enzyme eIF4A. This enzyme is needed to turn a specific group of RNAs into proteins and lung cancer cells depend on these proteins. Inhibitors of this enzyme are derived from a natural compound, silvestrol, which is originally found in the Aglaia silvestris tree in Malaysia. We found that synthetic analogues of this compound kill lung cancer cells in the lab and can drive human lung cancers transplanted into mice into remission. The goal of our project is develop this new anticancer mechanism for clinical application.
Project Title: Preclinical development of a DLL3-targeted theranostic for high-grade neuroendocrine lung cancers
DLL3 is a protein that is found on the surface of certain types of aggressive lung cancer cells but is not found on normal cells in adults. We can take advantage of the cancer-specific expression of this protein to improve the treatment of lung cancer in a number of ways. Using an antibody that targets DLL3, this project will develop new ways to precisely image lung cancers and deliver potent therapeutics to the site of the tumor while sparing normal tissues.
Project Title: A Phase 2 Study of MLN0128 in Patients with Advanced Squamous Cell Lung Cancers Harboring NFE2L2 and KEAP1 Mutations
Patients with squamous cell carcinomas of the lung (SQCLC) make up 25 percent of all non-small cell lung cancers, amounting to nearly 40,000 patients per year who are diagnosed with this disease in the United States alone. Unfortunately, targeted therapies for patients with SQCLC do not yet exist. This project, a phase II trial of a novel drug MLN0128 in patients with stage IV SQCLC harboring NFE2L2 and KEAP1 mutations, builds on our earlier genotyping work and preclinical studies that have shown that NFE2L2 and KEAP1, two commonly mutated stress response genes in this disease, are oncogenic and can be inhibited by the TORC1/2 inhibitor MLN0128.
Co-PI: Romel Somwar
Department of Pathology
Project Title: Identifying Mechanisms of Acquired Resistance to RET Inhibition in RET-Rearranged Lung Cancers
Previous work at Memorial Sloan Kettering has identified that targeted therapy drugs that inhibit the protein kinase RET can be effective in patients with lung cancers that are driven by RET fusion oncogenes. These oncogenes arise from the fusion of the functional domain of the RET gene with one of several other genes. Tumors typically develop resistance to drugs that target driver oncogenes; therefore, uncovering how such resistance emerges is essential to developing subsequent therapeutic options. The goal of this project is to identify mechanisms of resistance to the RET inhibitor cabozantinib in tumor biopsy samples as well as in experimental models of cabozantinib-resistant lung cancer that we are developing (new cell lines and patient-derived xenografts). We will search for genetic changes in tumor DNA that may contribute to the development of resistance. By identifying these changes, we hope to find new drugs or therapeutic targets that may be exploited to overcome resistance to cabozantinib or other RET inhibitors in lung cancers driven by RET fusions.
Project Title: Genomic Analysis of Lung Neuroendocrine Tumors in the Context of Detailed Histological, Immunohistochemical, and Clinical Correlation
This project aims to answer several questions pertaining to lung neuroendocrine neoplasms, which we hope will advance the understanding of their biology and facilitate optimal classification and clinical management. First, we aim to identify clinically relevant subgroups within large cell neuroendocrine carcinomas (LCNEC) — a highly aggressive malignancy whose biological relationship with other lung tumors and optimal clinical management remain poorly defined. In our recent studies, we have identified distinct genomic subgroups within surgically resected LCNEC, and we plan to expand these observations to patients with advanced disease to further assess the clinical relevance of these molecular subgroups. Second, we aim to study genomic and histologic alterations occurring during metastatic progression of lung carcinoid tumors — an area that has not been previously investigated in detail. These studies should improve our understanding of the biology of metastatic progression in carcinoids, and may improve the diagnosis and identify potential therapeutic targets.
Project Title: Exploring Novel Treatments for Lung Cancers with Activated ERK Signaling
ERK plays an important role in regulating diverse cellular functions, including the regulation of cell cycle progression and bypass of apoptosis, two key characteristics of cancer cells. ERK also exerts negative feedback, which suppresses signaling from various receptor tyrosine kinases. The goal of this project is to determine the therapeutic benefit of novel ERK inhibitors. We will first determine if these drugs durably inhibit ERK and its downstream effectors in KRAS and BRAF mutant lung cancer models. We will then determine if they inhibit the growth lung cancer patient derived models and determine optimal combination treatment strategies. Finally we will investigate the mechanisms that confer resistance to these drugs.