More Research, More Life

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. Learn more.

RET fusions are a challenging subset of non-small cell lung cancers (NSCLC). Although initial efforts with multikinase inhibitors resulted in limited success, subsequent development of selective RET inhibitors has bolstered responses for patients harboring these genomic alterations. Despite these advances, patients with RET fusions eventually progress, highlighting the need for additional therapies. Immunotherapy has been inefficient in patients harboring RET fusions. However, RET fusions themselves may be immunogenic. T cells recognize proteins at the surface of cancer cells called antigens, upon which they can specifically destroy tumors. Importantly, fusions constitute a particularly immunogenic antigen type which could be the key to clinical responses. Although T cells harbor millions of different receptors capable of recognizing different antigens, they can be genetically-engineered to recognize an antigen of interest. As such, we hypothesize that RET fusions give rise to immunogenic antigens which can be effectively targeted by engineered T cells. To address our hypothesis, we will identify antigens derived from tumors harboring RET fusions, receptors capable of killing tumors with these antigens and engineer T cells to gain this ability. Our work could be of benefit to patients progressing on selective RET inhibitors. Our goal is to generate a library of TCRs which could be used off-the-shelf to target the two dominant RET fusions (KIF5B-RET=75%; CCDC6-RET=25%) in order to offer new therapeutic alternatives to the overwhelming majority of NSCLC patients harboring RET fusions. Learn more.

Improved understanding of the genetics of non-small cell lung cancer (NSCLC) has led to the recognition that certain mutations in NSCLC can be effectively treated with targeted therapy. Unlike chemotherapy, targeted therapy interferes with how a cancer grows and spreads by blocking a specific mutation that a cancer cell needs to survive. An important mutation in NSCLC is the RET gene rearrangement. There have been several targeted treatments (such as selpercatinib and pralsetinib) that are highly effective in controlling RET+ NSCLC. While we can achieve durable long-term control with these RET targeted therapies, ultimately resistance is inevitable. An important category of resistance is called bypass signaling. This is when the cancer activates and recruits a different pathway to grow and survive in the presence of a RET inhibitor. Two possible pathways that seem to be important for resistance are the EGFR and MET pathways. Our main hypothesis is that EGFR and MET pathways are recruited by RET+ cancer cells in the presence of a RET inhibitor as a way for the cancer to survive and escape the effects of the targeted treatment. We suspect that the conventional methods of detecting EGFR or MET resistance may not identify many cases where both pathways are involved. In this proposal, we will attempt to use several different laboratory techniques to better detect and define EGFR and MET resistance. We anticipate 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. I wrote an investigator initiated clinical trial that has been approved and funded by Janssen. In this clinical trial, we will have a dedicated cohort for RET+ patients and combine amivantamab with their prior RET targeted therapy. We hope this study will provide insights into the nature of EGFR and MET signaling as resistance mechanisms. Learn more.

RET fusions are oncogenic drivers that are heterogeneous among patients and can occur in approximately 2-3% of lung cancer cases. The treatment of RET fusions has been revolutionized by the development of RET-targeted agents (selperactinib and pralsetinib), but inevitably resistance emerges, and the treatment of resistant disease is a clinical challenge. Resistance is caused by additional mutations in the RET gene (RET-dependent) or changes in other genes/proteins that cause tumor cell growth, but bypass RET inhibition (RET-independent). New studies are urgently needed to identify new agents or combination therapies to benefit these patients. Recently, our team successfully developed a system to classify distinct mutations based on their impact on protein structure and drug sensitivity in EGFR driven lung cancer. We hypothesize that this approach could be used to match patients with RET alterations to the best drugs for each alteration. Building on our previous experience, in this proposal we aim to developing a functional “atlas” of RET fusions and establish a structure/function-based classification approach that would inform clinicians of the best treatment options for RET fusion NSCLC and resistant disease. Further, we will determine mechanisms and biomarkers of RET-independent drug resistance and rational drug combinations to overcome RET inhibitor resistance. These studies will be translated to better guide patient selection and rationale drug combinations for future clinical studies. To this end, we have built a multidisciplinary team with strong expertise in cancer genomics, molecular modeling, and a track record of rapidly translating advances from the laboratory into clinical trials. Learn more.

Understanding how RET-positive lung cancers become resistant to targeted therapy is crucial. Most of what we know is limited to how these cancers develop secondary mutations (like changes in RET itself) that cause resistance. This knowledge is insufficient. Many RET-positive cancers become resistant to targeted therapy for reasons not clearly based on genetic changes alone. To develop new treatments, we need to know what causes resistance in these cancers. The goal of this project is to bridge this knowledge gap. We predict that other causes of resistance include (1) chemical changes (in the “epigenome”) that turn cancer genes on or off and (2) changes in how these cancers look under the microscope (“histology”) that affect cancer behavior. We hope to characterize these changes and expand our anticancer arsenal by developing new strategies to treat patients whose RET-positive lung cancers develop resistance in these ways. 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. Learn more.