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 only partial responses to treatment, 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. He will use next-generation sequencing to identify all of the mutations present in patients' tumors in order to understand which ones may be allowing cancer cells to survive EGFR inhibition and will specifically assess the role of alterations in genes that control cellular division. He will also utilize an innovative phase II clinical trial to treat EGFR-mutant lung cancer patients with osimertinib prior to surgery and will use state-of-the-art single cell RNA sequencing technology to understand which factors within cancer cells, or immune cells that infiltrate the tumor, allow for cancer cells to persist.  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.

Non-small cell lung cancer (NSCLC) is a particularly aggressive type of lung cancer, and mesothelioma is an equally aggressive cancer of the lining of the lung. Despite recent therapeutic advances, approximately 190,000 and 3,000 Americans respectively succumb to these cancers each year, emphasizing the urgent need for more effective treatments. Therapies that use cancer-recognizing immune T cells are especially promising. T cells specifically bind particular tumor-associated molecules (antigens) and kill bound cancer cells through proteins called "T cell receptors" (TCRs). Once an appropriate tumor antigen-specific TCR has been identified, genetic engineering can be used to add that TCR to a patient's T cells, thus educating them to recognize the cancer. The educated immune cells are then infused into patients, where they can seek out and destroy cancer without damaging normal tissues.

Dr Chapuis' studies will target Wilms' tumor antigen 1 (WT1), found not only on NSCLC and mesothelioma cancer cells but also on leukemia cells. She previously led studies of this approach for leukemia, which is now showing promise in the clinic for patients. Her new studies aim to develop a similar safe and effective immunotherapy for patients with deadly lung cancers, with the ultimate goal to entirely bypass the current need for toxic drug and radiation treatments.

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.

Adenocarcinoma is the most common type of lung cancer. Approximately 10% of patients with lung adenocarcinoma will have a tumor that simultaneously carries mutations in genes called KRAS and LKB1. Patients that have a lung cancer harboring both these mutations develop resistance to chemotherapy more rapidly, are more likely to develop brain metastases, and have a worse overall prognosis. Currently, there are no targeted therapies available for patients with this type of lung cancer. Mutations in genes like KRAS and LKB1 lead to a rewiring of normal cellular processes that results in cancer. Importantly, this rewiring also makes tumors more dependent on certain cellular functions. These functions represent cancer-specific vulnerabilities that can be targeted to disrupt tumor growth. In order to identify these vulnerabilities in lung cancers with mutations in both KRAS and LKB1, Dr. Ferrarone is utilizing the CRISPR/Cas9 DNA editing technology on a genome-wide scale. Using CRISPR, he will introduce gene “knockouts” in lung cancer cells carrying both KRAS and LKB1 mutations to see which genetic disruptions are most lethal to the cancer. Identification of the most significant tumor vulnerabilities may lead to the development of new targeted therapies to treat this type of lung cancer.

Dr. Gardner is studying acquired resistance to targeted therapies in lung cancer. Many targeted therapies used in cancer treatment are capable of controlling disease for a period of time, but in most cases, the disease finds a way to resist or adapt. For instance, some patients treated with epidermal growth factor receptor (EGFR) inhibitors for adenocarcinoma develop resistance to this class of drugs when their cancer transforms to small cell lung cancer (SCLC). Dr. Gardner is investigating this process using both human and mouse models of lung cancer to identify therapeutic approaches that may treat, prevent, or reverse this type of acquired resistance.

Dr. Hayes is focused on understanding and identifying mechanisms of resistance to cancer therapies.  Why some cancers respond to some therapies at first, but later become unresponsive, is not well understood. Small cell lung cancer is an ideal cancer to investigate how and why chemotherapy, the oldest and most prescribed cancer regimen, initially causes tumor reduction but ultimately fails after some period of time. She will use a multifaceted approach to interrogate chemotherapeutic resistance with the goal of identifying new methods to enhance patient treatment.

The recent discovery that the immune system can be used to treat cancers has revolutionized treatment and given new hope for long-term response and survival to patients with lung cancer. Research so far has demonstrated that there are some predictors of response to immunotherapy, such as tumor mutation burden which is increased in patients most likely to benefit from immunotherapy. Dr. Hellmann will focus on gaining a deeper understanding of how responses are initiated, why they can remain so durable, and what are the features that characterize resistance when it occurs.  He aims to use this information to build better immunotherapy strategies in the future for patients with lung cancer - to broaden the number of patients who can benefit, to improve the depth and durability of response, and have rational strategies for overcoming resistance if it occurs.

Dr. LaFave is studying how mutations in the SWI/SNF chromatin remodeling complex affect the initiation and progression of non-small cell lung cancer (NSCLC). Mutations in several SWI/SNF components have been identified in a variety of solid tumors; however, it remains unclear how their disruption contributes to tumor progression. She aims to develop novel NSCLC cell line and murine models to study the impact of SWI/SNF alterations. She will map the chromatin landscape in these models in order to characterize epigenetic changes that contribute to altered gene expression. These studies will lead to a greater understanding of SWI/SNF biology, potentially identifying novel therapeutic approaches for NSCLC patients.    

Dr. Li is focusing on quantifying how different tumor suppressor genes interact to determine the mechanisms underlying cancer growth. Using mouse lung adenocarcinoma as a model system, she is developing high-throughput experimental approaches to quantify the combinatorial effects of inactivating tumor suppressor pairs. This approach may enable an in-depth understanding of the pathways that underlie cancer progression and potentially hint at new therapeutic targets.