2023 Happy Lungs Project RET research update
On Friday December 8th, the Happy Lungs Project held a scientific research update where some of our funded investigators Drs. John Heymach, Alexandre Drilon, and Alexandre Reuben shared the latest progress on their projects aimed at investigating new therapies for RET-inhibitor resistant disease and developing new immunotherapies for RET cancer. Some of the progress included the following:
Dr. Heymach showed a detailed characterization of RET positive lung cancer tumors and the results of a big drug screening effort that included the testing of specific RET inhibitors and second-generation RET compounds currently on clinical trials. By the analysis of large databases, the team identified unique RET fusions that impart differential sensitivities to RET inhibitors. They also identify a set of RET mutations that are drug specific on RET positive cancer cell lines that confer resistance to RET inhibitors by using the innovative Lentimutate approach. Importantly these acquired resistance mutations may be non-overlapping between the RET inhibitors.
Dr. Drilon presented the analysis of biopsies from 89 RET cancer patients with progression on a RET inhibitor, that is part of the large effort of creating a registry of RET cancer patients across numerous medical institutions in order to provide insight into mechanisms of resistance. They demonstrated that resistance to RET inhibition can happen by a wide variety of mechanisms and the majority of the resistance is mediated by the activation of alternative pathways in the tumors. Importantly, this form of resistance can be targeted by targeted therapies (like in the case of MET amplifications) or combination therapies currently in development.
Dr. Reuben showed some of his work on developing new T cell therapies for RET cancers and specifically some of the advances in the generation of TCR therapies against antigens found in RET tumors. They identified RET-specific antigens that arise from the RET fusion breakpoints and from other more consistent regions of the RET molecule. Importantly, they were able to demonstrate that these RET antigens identified are immunogenic, are able to drive a T cell response, and are great candidates for the development of new adoptive TCR therapy for RET tumors. They also performed an analysis of RET positive tumors and identified the transcription factor FOXM1 that is expressed in RET tumors and overexpressed in RET inhibitor resistant tumors. The development and the preclinical testing of FOXM1 TCR therapies that can be used against RET tumors is currently ongoing.
The Happy Lungs Project wants to sincerely thank all the investigators and speakers to make this possible and to all the attendees for their time and participation.
Learn more about The Happy Lungs Supported RET Cancer research here.