Lung Cancer

Current Projects
Debadrita Bhattacharya, PhD

Intra-tumoral heterogeneity (ITH), or the evolution of distinct cell types within a tumor, underlies most fatal features of cancer and presents a great therapeutic challenge. Using small cell lung cancer (SCLC), a highly heterogeneous and lethal form of lung cancer, as a model, Dr. Bhattacharya [Robert Black Fellow] will study how ITH arises during cancer progression. She will employ emerging genomics techniques to characterize the cellular subtypes that comprise SCLC tumors and identify “druggable” transcription factors which, if targeted, could reduce tumor heterogeneity in this cancer. By profiling thousands of cells from treatment-naïve and therapy-resistant tumors, Dr. Bhattacharya aims to identify the “master-regulators” of the cellular subtypes that expand upon treatment in SCLC. She will then evaluate the role of these factors in human patient-derived cell lines, with the goal of uncovering novel mechanisms underlying ITH in human cancers. Dr. Bhattacharya received her PhD from Cornell University and her BS from the University of Calcutta.

Project title: "Investigating molecular and cellular mechanisms of intra-tumoral heterogeneity in small-cell lung cancer"
Institution: Stanford University
Named Award: Robert Black Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Julien Sage, PhD
Cancer Type: Lung
Research Area: Epigenetics
Laura Crowley, PhD

Fibroblasts are one of the earliest known cell types and they contribute to many of the most burdensome lung diseases, including cancers, fibrosis, and emphysema; however, they are surprisingly poorly understood. Dr. Crowley [HHMI Fellow] will examine the different types of fibroblasts in the mouse lung to determine where they come from and how they function normally, as well as how they change with injury and disease. This will establish an important baseline for how these cells function in mice and also provide critical, long-term insights into how these cells may function in humans, where lung diseases are very difficult to treat and are among the leading causes of mortality worldwide. Though her work will directly analyze the fibroblasts and microenvironment around lung tumors, her findings could translate to many other solid tumor contexts. Dr. Crowley received her PhD from Columbia University, New York and her BA from Colby College, Waterville.

Project title: "Identifying fibroblast stem cells in organ maintenance, repair, and cancer"
Institution: Stanford University
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Mark A. Krasnow, MD, PhD
Cancer Type: Lung
Research Area: Stem Cell Biology
Luisa F. Escobar-Hoyos, PhD

Current pancreatic cancer chemotherapies are not effective, and targeted therapies are only applicable in about 5% of cases. Furthermore, pancreatic cancers cause immune cell stress, limiting the success of immunotherapies in this disease. Using animal models and tumor samples from pancreatic cancer patients, Dr. Escobar-Hoyos [William Raveis Charitable Fund Innovator] has discovered that changes in RNA splicing, a process that controls protein diversity in cells, are crucial for pancreatic cancer development, therapy resistance, and disruption of anti-tumor immunity. She plans to dissect the molecular role of RNA splicing in pancreatic cancer, which likely drives the disease's lethality. She seeks to develop a novel anti-RNA splicing therapy with dual action-a targeted therapy against tumor cells coupled with an immunotherapy to restore immune cell anti-tumor activity-to more effectively treat pancreatic cancer patients.

Project title: "Understanding RNA splicing in tumor-cell adaptation and anti-tumor immunity"
Institution: Yale University School of Medicine
Award Program: Innovator
Cancer Type: Breast, Lung, Pancreatic
Research Area: Cancer Genetics
Alex M. Jaeger, PhD

Recent advances in genomic and proteomic technologies have ushered in a new era of antigen-specific immunotherapies, including cancer vaccines. Such therapies depend upon immune system recognition and processing of antigens-proteins or fragments of proteins displayed on the cancer cell surface. However, our understanding of the principles that govern antigen presentation across cell types throughout the tumor microenvironment (TME) remains limited. Dr. Jaeger's research uses sophisticated mouse models to understand how cells present and process antigens in healthy lung tissue and the lung cancer TME. These studies will advance our understanding of how different patterns of antigen presentation activate different T cell pathways and identify opportunities to engineer next-generation immunotherapies. The fundamental insights gained from these studies will be broadly applicable to multiple cancer types.

Project title: "Engineering approaches to exploit MHC-II antigen presentation in cancer"
Institution: H. Lee Moffitt Cancer Center
Named Award: William Raveis Charitable Fund Innovator
Award Program: Innovator
Cancer Type: Lung
Research Area: Tumor Immunology
Xiuning Le, MD, PhD

Mutations in the EGFR gene were identified as the first targetable mutations in lung cancer about two decades ago. Since then, multiple targeted therapies have been approved and prolonged many lives. However, about 15% of EGFR mutations are atypical and do not have a current approved targeted therapy. Dr. Le is leading multiple clinical trials to address this unmet need. With new treatments potentially entering the clinic, new mechanisms of treatment resistance will likely evolve. Dr. Le aims to comprehensively characterize resistance mechanisms and compare resistance predisposition across different types of EGFR-linked lung cancers. She will leverage cutting-edge techniques to determine the mutations at single-cell level and develop rational therapeutic strategies to overcome resistance. This project has the potential not only to bring new FDA-approved treatments to patients but also establish clinical strategies to predict and target major resistance mechanisms.

Project title: "Structure- and lineage-based classification and targeting of resistance in EGFR-mutant NSCLC"
Institution: The University of Texas MD Anderson Cancer Center
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): John V. Heymach, MD, PhD
Cancer Type: Lung
Research Area: Cancer Genetics
Tadashi Manabe, MD, PhD

Lung cancer remains the leading cause of cancer mortality. Substantial breakthrough discoveries, including the identification of lung cancer-specific genetic drivers (e.g., EGFR mutations, EML4-ALK fusion genes) and the development of molecular inhibitors of these pathogenic factors, have improved outcomes for patients with advanced-stage lung cancer. However, lung cancer cells eventually acquire resistance to these molecular inhibitors, resulting in progressive disease. Dr. Manabe’s [Connie and Bob Lurie Fellow] research focuses on protein compounds formed by the self-assembly of oncogenic fusion proteins such as EML4-ALK. These compounds initiate a signaling pathway that causes abnormal cell proliferation in cancer. Dr. Manabe will explore the newly discovered structures of signaling proteins with the goal of developing molecular therapies that enhance precision medicine strategies and improve the control of lung cancer. Dr. Manabe received both his MD and PhD from Keio University School of Medicine.

Project title: "Characterization of oncogenic kinase signaling by membraneless cytoplasmic protein granules"
Institution: University of California, San Francisco
Named Award: Connie and Bob Lurie Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Trever G. Bivona, MD, PhD
Cancer Type: Lung
Research Area: Signal Transduction
Matthew G. Oser, MD, PhD

Although small cell lung cancer (SCLC) is initially highly responsive to chemotherapy, the disease recurs in nearly all patients in less than a year. There are currently no approved targeted therapies for when the cancer returns. Previous studies have demonstrated that SCLCs require sustained neuroendocrine differentiation for survival, suggesting that targeting this process could be a good therapeutic strategy. Dr. Oser will use SCLC patient-derived xenograft models and a novel SCLC genetically engineered mouse model to identify new enzymes required for neuroendocrine differentiation and to develop targeted therapies that can block this process. He aims to identify molecular targets that could be developed into new lasting therapies for SCLC patients.

Project title: "Dissecting and therapeutically exploiting synthetic lethality between NOTCH and TRIM28 to drive anti-tumor immunity in SCLC"
Institution: Dana-Farber Cancer Institute
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): William G. Kaelin, Jr., MD
Cancer Type: Lung
Research Area: Experimental Therapeutics
Manuel Osorio Valeriano, PhD

Human cells compact their vast genomes into the small confines of the nucleus by wrapping their DNA into a highly complex structure called chromatin. Packaging DNA into chromatin, however, affects all nucleic acid-transacting machines (e.g., transcription factors) that need to access the genomic information stored in the DNA. NuRD is a large multi-subunit protein complex that plays a major role in making chromatin either accessible or inaccessible. Dysregulation of NuRD and aberrant targeting of the complex can result in the emergence of several types of cancers, including breast, liver, lung, blood, and prostate cancers. Dr. Osorio Valeriano’s [Philip O'Bryan Montgomery, Jr., MD, Fellow] work will reveal mechanistic aspects of NuRD-mediated chromatin regulation and pave the way for the development of novel therapeutic approaches that target cancers more effectively. Dr. Osorio Valeriano received his PhD from Philipps University and his MSc and BSc from the National Autonomous University of Mexico.

Project title: "Molecular and structural basis of gene expression regulation by the nucleosome remodeling and deacetylase (NuRD) complex in human cancer"
Institution: Harvard Medical School
Named Award: Philip O’Bryan Montgomery Jr. MD Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Lucas Farnung, PhD, and Danesh Moazed, PhD
Cancer Type: Blood, Gastric, Breast, Lung, Prostate
Research Area: Structural Biology
Shreoshi Sengupta, PhD

Studies have shown that lung tumors are sustained through the formation of new blood vessels from pre-existing ones in a process called angiogenesis. Moreover, tumor cells secrete signaling proteins that help them communicate with each other and evade immune detection. However, most of these studies have been on late-stage lung tumors; our understanding of cell-cell interactions in the tumor environment during lung cancer initiation and early stages remains poor. Dr. Sengupta plans to identify the gene expression patterns in tumor cells, endothelial cells (blood-vessel-forming cells), and immune cells over time to understand how they engage in this cellular crosstalk, promoting tumorigenesis. She also plans to examine cell-cell interactions in early-stage lung cancer using organoids, or artificially grown miniature organs. This line of investigation will help understand the mechanisms underlying tumor initiation and lead to novel biomarkers that can help detect lung cancers earlier. The findings will also help identify novel therapeutic targets that can be inhibited to improve patient responses and survival. Dr. Sengupta received her PhD from Indian Institute of Science, Bangalore and her MS and BS from University of Calcutta, Kolkata.

Project title: "Decoding cell-cell interactions aiding angiogenesis and immune evasion in early-stage lung cancer"
Institution: Boston Children's Hospital
Award Program: Fellow
Sponsor(s) / Mentor(s): Carla F. Kim, PhD
Cancer Type: Lung
Research Area: Cancer Genetics
Fyza Y. Shaikh, MD, PhD

Immunotherapy has significantly changed how lung cancer and melanoma are treated. Unfortunately, only a small percentage of patients experience long-lasting responses. Gut bacteria have emerged as a potential predictor of how patients will respond to immunotherapy and may even be adjusted to enhance the effect of immunotherapy. Dr. Shaikh aims to identify features of the gut microbiome that correlate with immunotherapy responses. She will focus on both individual bacteria as they change over the course of treatment and the metabolites made by the entire bacterial community in the colon. The goal of this project, since gut bacteria can be modified, is to develop microbiome-based treatments to be used in combination with immunotherapy to improve response rates or overcome immunotherapy resistance for patients.

Project title: "Defining microbiome stability and longitudinal shifts as biomarkers of tumor response to immune checkpoint inhibitors across multiple malignancies"
Institution: The Johns Hopkins University School of Medicine
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Cynthia L. Sears, MD, and Drew M. Pardoll, MD, PhD
Cancer Type: Lung, Skin
Research Area: Immunotherapy
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