Research Database

Lorlatinib is currently the only approved treatment for patients with ALK-positive NSCLC whose cancers have progressed on prior ALK drugs, and for those whose tumors develop resistance, there is a lack of other treatment options other than chemotherapy. In this study, Dr. Qin will evaluate a novel drug called gilteritinib as a treatment in patients with ALK-positive NSCLC whose tumors have developed a resistance to lorlatinib.

Despite advances in the development of RET inhibitors, patients with RET fusions eventually progress. Immunotherapy has been inefficient in patients harboring RET fusions. However, RET fusion proteins themselves may be immunogenic and give rise to an immune response. Dr. Reuben hypothesizes that RET fusions give rise to immunogenic antigens which can be effectively recognized and targeted by engineered T-cells. This project will identify which antigens can elicit an immune response. This information will be used to engineer customized T-cells to gain the ability to recognize those cancer cells that produce these RET fusion proteins. The ultimate goal is to offer new therapeutic alternatives by expanding the possibility of immunotherapy treatment in the overwhelming majority of NSCLC patients harboring RET fusions.

Despite an initial response to the newly approved RET inhibiting drugs, most RET-positive lung cancers become resistant to these drugs and the cancers relapse. Dr. Watanabe’s project will provide anti-relapse therapeutic strategies for RET-positive lung cancer that target newly identified “drug-tolerant persisters (DTPs)”. DTPs are a small population of cancer cells that do not respond to these drugs and therefore start growing, leading to the relapse of these cancers. The role of DTPs in RET-positive lung cancer is not well understood. Dr. Watanabe proposes therapeutic strategies, such as targeting the Wnt and Hippo signaling pathway to overcome the DTP adaptability and prevent relapse before these cells arise.

Many RET-positive cancers become resistant to targeted therapy for reasons not clearly based on genetic changes alone. Dr. Drilon predicts that other causes of resistance include (1) chemical changes (in the “epigenome”) that turn cancer-causing genes on or off and (2) changes in how these cancers look under the microscope (“histology”) that affect cancer behavior. Because these changes affect cell states rather than mutations, this resistance is potentially reversible, defining a key opportunity to maintain, restore, and extend sensitivity to potent and specific RET inhibitors.

There is an urgent need to identify new agents or combination therapies to benefit patients whose tumors have developed resistance to current RET inhibitors. Currently, the true extent of RET-dependent (resistance mutations in the RET gene) versus RET-independent mechanisms of resistance is unknown. Dr. Heymach’s team will study mechanisms and biomarkers of RET-independent drug resistance and test different drug combinations to overcome RET inhibitor resistance.

Two possible pathways that seem to be important for resistance to RET inhibitors are the EGFR and MET signaling pathways. Conventional methods of detecting EGFR or MET resistance may not identify many cases where both pathways are involved. In this study, Dr. Patil will use several different laboratory techniques to better detect and define EGFR and MET resistance. He anticipates that the EGFR and MET pathways can be blocked by a newer drug called amivantamab, which is a bi-specific antibody that specifically targets both EGFR and MET.

Immunotherapy has become a standard treatment regimen for advanced-stage non-small cell lung cancer. However, most patients do not respond. One significant barrier to immunotherapy efficacy is the tumor microenvironment (TME), which contains immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs). MDSCs represent an important tumor immune escape mechanism and play a role in the development and progression of lung cancer. Dr. Owen will be studying how this group of cells can be targeted to improve the effect of immunotherapy.

The use of mindfulness has the potential to address the multiple intersections of stigma in high-risk lung cancer groups inclusive of racial/ethnic and LGBTQ+ communities. A known approach of mindfulness (MOST) that has proven utility in other cancer-related fields has not been examined to a great extent in reducing stigma from lung cancer.

Dr. Riley is testing an innovative community-based participatory research (CBPR) and Multiphase Optimization Strategy (MOST) method to develop a brief virtual mindfulness intervention to decrease intersectional stigma. Dr. Riley will examine the reach, acceptability, and feasibility to underserved intersectional groups, including Black, Latinx, and LGBTQ+ lung cancer patients. This research project has a high likelihood of improving health behaviors and health outcomes for several communities.

The protein SGL2 seems to be produced in higher quantities on abnormal lung cells than on normal lung cells. Dr. Scafoglio is testing whether SGL2 can be used to image lung cancer cells by using a new imaging technology.

Fusion-driven NSCLC is a group of lung cancers that are driven by specific changes in oncogenes. These lung cancers tend to be addicted to these oncogenes. Such fusion-driven NSCLCs are treated with targeted therapies that block the effect of the oncogenes. However, the cancer inevitably comes back because the tumors become resistant. Traditionally, fusion-driven NSCLCs have not been successfully treated with immunotherapy. Dr. Schenk is testing how these cancers can be treated with immunotherapy through another immune pathway—the innate immunity pathway.

The lesbian, gay, bisexual, trans, and queer (LGBTQ) community faces several health disparities, including a higher rate of lung cancer due to increased rates of tobacco use in this group. Dr. Triplette will partner with an urban LGBTQ community center to create and evaluate a tailored lung cancer screening and smoking cessation navigation program to specifically address the needs of this community. By directly partnering with stakeholders and community members, he plans to develop a sustainable program that will assist LGBTQ community members with both screening and cessation that can then be disseminated to improve the health of LGBTQ patients across the country.

Currently, low-dose computed tomography (LDCT) is the only tool for the screening and early detection of lung cancer in individuals who meet screening criteria. LDCT is not very sensitive; often, abnormalities identified in an LDCT scan turn out to be benign. However, ruling out cancer requires an invasive biopsy. Dr. Vachani is testing whether a biomarker signature can be integrated into LDCT screening to improve the sensitivity of LDCT so that patients may be spared unnecessary biopsies.

Despite high tumor response rates, patients treated with EGFR targeted therapies, such as osimertinib, inevitably develop disease progression. Mechanisms of drug resistance remain incompletely understood on both a genomic and proteomic level. The objective of Dr. Lovly’s project is to find new targeted treatments and drug combinations that can tackle cancer evolution and osimertinib resistance.