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.

Non-small cell lung cancers are frequently driven by specific genetic alterations that can be targeted by precision medicine therapies. However, these therapies often result in partial responses, allowing some cancer cells to survive and become fully resistant to therapy. This ultimately limits patients' long-term survival. Dr. Blakely focuses on a particular type of lung cancer that is driven by mutations in the EGFR gene. This type of lung cancer frequently develops in younger patients who are non-smokers. Treatment of this disease with the targeted therapy osimertinib results in partial (incomplete) responses in the vast majority of cases. His goal is to understand why responses to this treatment are almost always incomplete, and to identify new targets for therapies to be used in combination with osimertinib. Ultimately, the goal of this research is to identify novel combination therapy strategies that can improve the depth and duration of response to targeted therapies, allowing patients to live longer.

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.

Dr. Jin's research focuses on the interaction between the nervous system and the immune system in cancer, with a particular focus on the crosstalk between the sensory neurons and the tumor microenvironment (TME) in lung cancer. While nerves have long been viewed as passive bystanders in cancer, solid tumors are innervated by distinct branches of the nervous system that respond to internal and environmental stimuli. However, it remains poorly understood how the nervous system regulates tumor-associated immune cells, and what factors in the TME shape tumor innervation and neuro-immune interactions. Dr. Jin will combine genetically engineered mouse models with diverse approaches in cellular immunology, cancer genetics, and functional manipulations of neuronal circuits to elucidate the molecular and cellular mechanism of neuro-immune crosstalk in the lung TME, and to explore how we can target specific neural pathways to improve cancer immunotherapy.

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.

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.

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.

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.

Kinase proteins, which regulate the activity of other proteins, are a major class of cancer therapy targets, with over 65 FDA-approved drugs targeted against them. However, tumors can evolve resistance to kinase-targeting therapies, and it remains difficult to predict whether a specific tumor will resist a particular kinase-targeting drug. Dr. Singh will use protein structural models and biophysical predictions to analyze how kinase mutations cause cancers to resist therapy. As these computationally intensive calculations could require decades on a single desktop computer, he will use a computing platform called Folding@home, which harnesses idle computer time donated by citizen scientists around the world to run the calculations. By developing new algorithms to predict whether a known mutation will resist a kinase-targeting drug, Dr. Singh hopes to advance precision oncology to allow clinicians to predict a treatment's chance of success given a patient's tumor profile. While his work primarily focuses on resistance to the drug crizotinib, used to treat non-small-cell lung carcinomas, his approaches can be extrapolated to other tumors and cancer targets. Dr. Singh received his BA and his PhD in computational and molecular biophysics from Washington University in St. Louis.

Molecular dynamics (MD) simulations are computational microscopes that model and capture atomically detailed protein motions. To analyze MD simulations, Dr. Singh will construct Markov State Models, network representations of a protein's conformational landscape, and couple them with information theoretic measures of communication between mutated residues and drug binding sites. Alchemical Free Energy calculations will predict the impact of mutation on a drug's binding energy using artificial "alchemical" intermediates to measure the energetic cost of mutating a residue.

Immunotherapies using checkpoint inhibitors have shown amazing results in certain solid cancers. However, there are vast differences in treatment outcomes for patients who have remarkably similar cancers (based on histology and genetics) and many patients develop resistance. In addition, predicting who will benefit from the treatment has been unreliable. Recent research found that the diversity and specific quality of microbes that colonize the intestines (the gut microbiome) can impact the success of cancer immunotherapy, but there is no consensus about the underlying mechanisms. Dr. Upadhyay aims to build a mouse model of lung cancer that replicates the previous findings and then dissect the intricate biology between the gut microbiota and tumors in the lung. He plans to further define the cells and molecules involved, with the hope that more effective immunotherapy treatments can be designed for patients.