Dr. Bakalar is developing new methods to discover the millions of interactions between T-cell receptors and foreign antigens that trigger an immune response. In many cancers, such as metastatic melanoma, immunotherapy depends on the ability of T cells to recognize and respond to tumor-specific neoantigens—new proteins found on cancer cells, which let the immune system know that these are not normal cells. Collecting the data on this relationship can help create computational models to predict the antigen-target of a patient’s individual T cell receptor, which could then guide the design of patient-specific cancer vaccines and engineering of new, tumor-targeting T cells.

The RAS oncogene is mutated in 20% of all human cancers. Different types of mutations occur that promote cancer initiation and progression, yet we do not yet understand the specificity of how each mutation affects RAS’ ability to promote cancer. Unfortunately, despite decades of scientific effort, there are no effective therapies to directly target RAS mutant cancers. Dr. Burd proposes novel, mutation-specific studies of RAS in a variety of tumor types, starting with melanoma, thyroid cancer, and acute myeloid leukemia (AML). The reason why each cancer type appears to prefer one RAS mutant over another is unknown; however, she postulates that the subtle differences between mutants are critical for tumor formation.  Her research will lead to new understanding of RAS mechanism and function, resulting in better design of novel therapeutics to target RAS for treatment of cancer.

Dr. Chudnovskiy studies “antigen presentation,” an immune process by which dendritic cells capture antigens at the tumor site, migrate to the tumor-draining lymph nodes, and present tumor antigens to the effector CD4 and CD8 T cells that are responsible for anti-tumor responses. This is the first crucial step in successful cancer immunotherapy.

Immunotherapy has resulted in positive outcomes for patients with melanoma, lung cancer, and other malignancies; however, most patients do not have meaningful responses to this treatment strategy. Tumors that fail to respond to immunotherapy have effectively hidden themselves from detection by the host immune system. Understanding how cancers create an immune-excluded environment promises to lead to the development of more highly effective immunotherapies. Dendritic cells (DCs) play a central role in orchestrating the immune response to cancers by enabling T cells to “see” and destroy cancerous cells. Previous work has shown that melanomas secrete a protein called Wnt5a that potently suppresses DC function and ultimately contributes to the development of immunotherapy resistance. Dr. DeVito will examine certain tumor signaling pathways that have been implicated in driving Wnt5a production and facilitating cancer spreading by suppressing DC function within nearby draining lymph node tissues, which are critical for generating immune responses capable of destroying developing cancers. These studies will further investigate the ability of Wnt5a inhibition to sensitize cancers that are typically resistant to immunotherapy strategies. In addition, he is conducting a clinical trial to determine if the activation of these pathways correlates with immunotherapy failure in melanoma patients. He anticipates that better characterization of pathways that cancers utilize to suppress DC function to thus shut down the immune response will lead to the discovery of novel, more effective immunotherapy strategies, and may identify biomarkers that will improve selection of tailored immunotherapies for specific cancer patients.

Dr. Dong studies how injury and pathogen invasion trigger a chain of inflammatory and repair responses that restore the damaged tissue. Defects in wound repair result in painful, non-healing ulcers that frequently affect aged individuals and diabetes patients. Malignant tumors are particularly severe complications, which often occur at sites of repetitive irritation and chronic wounds. She is investigating the roles of anti-microbial peptides during inflammation and wound healing, and hopes that these studies will provide insights about the cause and prevention of various carcinomas.

Dr. Insco studies advanced melanoma. Melanoma initiation and drug resistance rely heavily on factors that control gene expression. Proteins called Cyclin Dependent Kinases (CDKs) show promise as drug targets in multiple difficult-to-treat cancers and are enabling a method to “drug” the previously “undruggable” process of gene expression. She aims to determine whether any of the transcriptional CDKs could be an effective drug target in advanced melanoma. 

Dr. Kulalert focuses on how the skin is influenced by microbes. The skin is enriched with immune cells and highly innervated; nevertheless, the roles of neuroimmune crosstalk in cancer development and treatment remain largely unexplored. Sensory perception, especially pain sensation, is associated with cancer-related complications as well as chemotherapy. Because the microbiota plays a critical role in maintaining tissue homeostasis in the skin, he will explore whether sensory processing can also be modulated by the host-microbe interactions, particularly in the context of tumorigenesis and cancer treatment. These insights may provide novel tools to alleviate tumor progression and complications linked with cancer and chemotherapy, including pain sensation. 

Therapies that directly target cancer-promoting oncoproteins have revolutionized the treatment of cancer. Cancers, however, are primed to adapt and evolve in the presence of treatment, resulting in an ability to resume growth despite the presence of therapy. Utilizing cutting-edge new techniques that allow the determination of genetic alterations in single cancer cells, Piro aims to understand the principles that govern the evolution of resistance during therapy and identify novel therapeutic interventions that halt this process. His specific focus will be on resistance of lung cancer and melanoma to BRAF-targeted therapies. 

The treatment of metastatic melanoma has been transformed over the past decade with the development of (1) targeted therapies that target a very common gene mutation (BRAF mutations in 50-60% of tumors) in melanoma and (2) two different types of immune therapies that induce the immune system to attack the cancer (CTLA-4 and PD-1 inhibition). However, not all patients respond to either targeted or immune therapy, and there is evidence suggesting that patients who quickly develop resistance on the initial therapy (whether targeted or immune) have worse outcomes (e.g. rapid resistance) when switched to other therapy approaches. Thus, being able to predict which patients will respond to targeted and immune therapies is critically important to personalize therapy and improve patient outcomes. Dr. Liu proposes to address this issue by analyzing large cohorts of melanoma patients treated with targeted and immunotherapy with deep genetic sequencing and molecular characterization of their tumors, developing algorithms to identify molecular features that predict differential response or resistance to therapy. Importantly, he will apply approaches from machine learning to develop and validate a predictive model integrating genetic and clinical tumor characteristics to predict response to therapy in individual patients. The validated molecular features in the model will shed light on the biological mechanisms that underpin response and resistance to therapy, identifying novel therapeutic targets and potential synergistic therapy combinations. Taken together, the success of this proposal will have important biological and clinical implications, informing future drug and combination therapy development as well as impacting clinical care.

Dr. Naik focuses on the fundamentally important interactions between the immune system, microbes, and adult skin tissue stem cells, and the consequences of such interactions for health and disease.  She studies how stem cells in epithelial tissues such as the skin sense and cope with inflammatory stress.  Her goal is to understand how inflammatory signals (either host-generated or microbial) provide adult stem cells with rapid, sensitive, and context-specific information, and how this process can go awry, potentially predisposing stem cells to diseases such as cancer. She hopes that her findings will facilitate the development of novel therapies.