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.
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.