High levels of oxidative stress are a hallmark of many cancers; while it has long been appreciated to be a major impediment to cancer proliferation, the molecular mechanisms underlying its role in this process remain poorly understood. Using cutting-edge proteomic techniques, Dr. Bar-Peled is investigating how cancer cells respond to oxidative stress and exploring the different signaling pathways required by cancer cells to reduce the oxidative stress burden. His research may provide therapeutic avenues for targeting certain lung cancers.

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.

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.

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 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. The proposed project will 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.

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. Gan focuses on brain metastasis in lung and breast cancer, a major cause of death for these patients. She is applying the latest single-cell technologies and developing computational tools to dissect how tumor cells interact with resident brain cells to mediate the progression of metastasis. This research aims to better understand the formation of brain metastasis which may lead to new therapeutic strategies for prevention.

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.