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.
PI: Etay Ziv, MD, PhD
Department of Radiology, Interventional Radiology Service
Project Title: Discovering metabolic vulnerabilities in aggressive lung cancer subtypes with NRF2 dysregulation
A subset of non-small cell lung cancers (approximately 25%) harbor NRF2 pathway mutations that result in NRF2 over-expression. These tumors are associated with aggressive disease, treatment resistance and poor prognosis. Despite this sober outlook, preliminary data from our lab points to metabolic dependencies of these tumors that can potentially be exploited therapeutically. Funding from the Druckenmiller Lung Center at MSK will help identify the most potent metabolic dependencies of these tumors in order to develop novel therapeutics for this treatment-resistant cohort
PI: Triparna Sen, PhD
Department of Medicine
Project Title: Targeting Replication Stress Vulnerabilities in Small Cell Lung Cancer (SCLC)
Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, accounting for approximately 15% of all lung cancers, with approximately 20,000 cases diagnosed annually in the U.S. The current standard-of-care first line treatment of SCLC, with combination of platinum doublet and immune checkpoint blockade, is only beneficial for a small fraction of patients. We propose research that addresses the urgent need for more effective drug combinations to treat SCLC. Because SCLC cells proliferate at such a high rate and can survive even when their DNA is damaged, DNA replication often stalls, inducing a state called replication stress. We have previously established that proteins that regulate replication stress response (RSR) are viable therapeutic targets for SCLC and drugs targeting RSR work even better when combined with immunotherapy. In this project, we will test whether exacerbating replication stress prevent SCLC cells and tumors from growing and investigate the effects of these drugs on the immune-modulating properties of SCLC cells and immune responses to SCLC tumors. The study will use both preclinical models and samples from patients on SCLC clinical trials. This project is especially likely to advance the treatment of SCLC given the strengths of our team and the resources available at our institution. We can readily translate our findings into clinical trials to support effective and durable immunotherapy regimens for SCLC, an aggressive, recalcitrant tumor with little to no treatment advancement in >30 years.
PI: Eduardo Lacayo, MD
Department of Radiology, Interventional Radiology Service
Project Title: An Efficacy and Safety Study of Pembrolizumab plus Cyroablation in Malignant Pleural Mesothelioma (MPM)
Malignant pleural mesothelioma (MPM) is an aggressive malignancy in which local disease progression is the main cause of morbidity and mortality. Even with aggressive multimodality therapy for early stage disease, local recurrences are quite common and cause substantial morbidity. Combination pemetrexed and cisplatin is the only treatment regimen that is FDA-approved for mesothelioma. While the National Comprehensive Cancer Network (NCCN) guidelines support the use of pembrolizumab and nivolumab +/- ipilimumab for recurrent/progressive disease, response rates are modest and no survival benefit has been established. Currently there are no FDA-approved therapies after front-line therapy. A tremendous unmet need persists, and the bar for therapeutic efficacy is low. Percutaneous thermal ablation is a minimally invasive, image-guided technique that produces irreversible tumor tissue destruction through the application of either heat or cold energy. Cryoablation of tumor tissue may help activate tumor-specific T cells by elevating the presentation of tumor antigens to the immune system. In situ tumor cell death caused by thermal ablation up-regulates the immune system causing tumor suppression of metastatic sites. After thermal ablation, tumors can serve as their own antigenic vaccine, and the addition of immunotherapy provides further pro-inflammatory stimuli to activate immune-mediated tumor rejection signals. Therefore, combining thermal ablation with immunotherapies that target antigen presenting cells or modulate T-cell function may provide a synergistic effect by increasing the antitumor response and maintaining tumor suppression of distant metastases. Thus, we will evaluate the safety and efficacy of combining Cryoablation and Pembrolizumab for the treatment of recurrent/progressive malignant pleural mesothelioma
PI: Alvaro Quintanal-Villalonga, PhD
Department of Medicine, Molecular Pharmacology Program
DCLCR Fellowship Award
Project Title: Defining and overcoming resistance in TWIST1-upregulated chemo resistant small cell lung cancer tumors
Small Cell Lung Cancer (SCLC) is the most aggressive subtype of lung cancer, with very limited treatment options that typically result in only short-term responses. SCLC treatment options include platinum-based doublet chemotherapy with the recent addition of immunotherapy, which results in only short-term responses due to the rapid development of chemotherapy resistance. Thus, the identification of molecular mechanisms leading to chemoresistance, and of novel therapies to increase response is an unmet clinical need in this setting. In this project, we will characterize mechanisms of chemoresistance by studying SCLC clinical samples, and we will identify novel therapies sensitizing SCLC tumors to chemotherapy through the use of preclinical SCLC models.
PI: Juan Osorio, MD
Department of Medicine
DCLCR Fellowship Award
Project Title: Fc Receptors as Modulators of Tissue-Specific Activity of Ant-PD-1/PD-L1 Antibodies in Lung Cancer
While antibodies targeting the PD-1/PD-L1 axis can lead to durable clinical responses in patients with lung cancer, only a minority of patients achieve this benefit. Several clinical factors impact response to therapy and particularly, we recently found that site of metastasis (e.g. lymph node vs. liver) influence response to PD-1/PD-L1 blockade. In this project, we aim to understand tissue-specific immune factors, particularly the Fc receptor repertoire, which may mediate distinct metastatic-site responses to anti-PD-1/PD-L1 antibodies. Furthermore, this strategy will inform the development of next generation Fc-enhanced antibodies, potentially customized to target specific metastatic sites which have been traditionally resistant to standard anti-PD1/PD-L1 agents.
PI: Jan Remsik, PharmD, PhD
Human Oncology & Pathogenesis Program
DCLCR Fellowship Award
Project Title: Lung cancer-induced disruption of developmental signaling in pre-metastatic leptomeninges
Leptomeningeal metastasis (LM) is a fatal neurological complication of lung cancer that is characterized by the spread of cancer cells into the cerebrospinal fluid (CSF) and results in rapid neurologic disability and death. The steps of leptomeningeal colonization and signaling pathways involved in this highly conserved process are virtually unknown. We hypothesize that primary lung tumor secretomes disrupt the integrity of blood-CSF barrier. To elucidate this possibility and characterize the pre-metastatic leptomeninges, we will employ single-cell and advanced molecular biology techniques to provide complete spatiotemporal resolution of this phenomenon with subsequent application in clinical practice and therapy for lung cancer patient at high risk of LM development.
PI: Dana Tsui, MD PhD
Center for Molecular Oncology
Project Title: Noninvasive cell-free RNA analysis of actionable fusions transcripts to guide treatment strategy in lung cancers
A subset of lung cancers is driven by changes in the RNA molecules called gene fusions, which involves two genes fused together to enhance their function. Identifying these fusions are crucial to guide precision therapies that are highly effective against these fusions. Current methods for identifying these fusion genes in the clinic rely mostly on tumor biopsies, and are proven useful for diagnosis, prognosis, and treatment selection. However, tumor biopsies are risky to obtain, and often inaccessible, particularly in lung cancers. Our project involves developing a blood test to look for these clinically important fusions by screening for RNA molecules that are shed by the tumor into blood plasma. A blood sample is easy and safe to collect, allowing physicians to more effectively administer matching treatments, thereby improving patient care and outcomes.
Project Title: Targeting cellular heterogeneity in lung cancer
Lung tumors are composed of diverse cellular societies, in which the phenotype, or state, of each tumor cell is influenced by a myriad of cell-autonomous and cell-extrinsic factors. How cellular diversity arises in tumors is a critical question in cancer biology: Heterogeneous tumors are comprised of cellular states that promote resistance to therapy and eventually lead to reconstitution of the tumor by treatment-resistant cancer cells. This project aims at increasing our understanding of the remarkable phenotypic heterogeneity of cancer cells within lung tumors. Our goal is to discover pathways that drive distinct cellular phenotypes and to develop new therapeutic concepts aimed at reducing cellular heterogeneity in tumors.
Project Title: Prediction and detection of response to treatment in locally advanced esophageal adenocarcinoma
Esophageal adenocarcinoma is a relatively rare, but aggressive disease with a 5-year survival under 20%. Limited progress has been made since the Dutch CROSS trial (2012) established that neoadjuvant chemoradiotherapy followed by surgery leads to a modest increase in survival in patients with locally advanced disease. Approximately 25% of patients exhibited a pathologic complete response (pCR) to chemoradiation in this trial, and subsequent studies have confirmed a significantly greater survival benefit in this group of up to 60% at 5 years. Thus, our study aims to develop and validate strategies to predict, detect, and ultimately augment the pCR rate to neoadjuvant treatment using next generation sequencing assays and circulating cell-free tumor DNA.
Project Title: Understanding and Targeting Spliceosomal Gene Mutations in Lung Cancer
Recent studies have identified the surprising finding that ~10% of patients with non-small cell lung cancer carry mutations in components of the “spliceosome.” The spliceosome carries out RNA splicing, the process wherein genetic information is read from DNA and then used to make proteins. Our group has recently identified that mutations in the spliceosome actually promote lung cancer cell growth by altering the RNA splicing process and that cells carrying these mutations are sensitive to a new class of drugs that perturb splicing. Funding from the Druckenmiller Lung Center at MSK will help identify exactly how RNA splicing factor mutations promote lung cancer growth and bring this novel treatment approach closer to use in lung cancer patients.
Project Title: Next-gen CAR T cells resistant to lung cancer-mediated immunoinhibition
Chimeric antigen receptor (CAR) T-cell therapy is a form of immunotherapy that genetically enhances patient’s own T cells to specifically target cancer cells. CAR T cells specific for the B-cell marker CD19 have achieved remarkable response rates in CD19-positive blood cancers leading to the recent FDA-approval of CAR T-cell therapy for acute lymphoblastic leukemia and non-Hodgkin lymphoma. In contrast to blood-derived tumors, targeting solid tumors such as lung cancer represent unique challenges, including a cytokine and cellular immunosuppressive tumor microenvironment that hampers cancer immunotherapy. In this project we will develop a reproducible patient-derived lung cancer microenvironment model that will improve our understanding of CAR T-cell efficacy in the presence of a human immunosuppressive environment, identify inhibitory factors affecting CAR T-cell efficacy, and aid us in developing the next generation of CAR T cells.
Project Title: Optimizing CAR T-cell therapy in a clinically-relevant murine model of lung cancer
Chimeric antigen receptor (CAR) T-cells represent a powerful new approach to cancer therapy in which a patient’s T-cells are engineered to kill tumor cells. While this approach has been effective in leukemias and lymphomas, it has not been successful to date in solid tumors such as lung cancer. In this project, we will build a mouse model of lung cancer that reflects the biology of human lung tumors, but that expresses the CD19 antigen that is the target of FDA-approved CARs for leukemias and lymphomas. This model will allow us to use validated CD19-targeted CARs test the function of T-cells in solid tumors, and to design better CAR T-cells for lung cancer.
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.
Co-PI: John Poirier, PhD
Thoracic Oncology Service
Molecular Pharmacology Program
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.
PI: John Poirier, PhD
Thoracic Oncology Service
Molecular Pharmacology Program
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.