Your investment in The Happy Lungs Project has resulted in very exciting advances over the past year. Check out the RET Research Update webinar recording and recaps of the 4 research presentations.
We are grateful to Dr. Heymach, Dr. Drilon, Dr. Gainor and Dr. Reuben for sharing such fascinating presentations about their RET-positive cancer research.
Thank you also to the nearly 100 patients, caregivers and family members, clinicians, researchers, and other members of the lung cancer community who joined us for the RET Research Update.
Your investment in The Happy Lungs Project has resulted in exciting research advances. View the webinar recording below.
Recap of the 4 presentations:
Genomic mechanisms of RET inhibitor sensitivity and resistance in RET-fusion positive cancer cells. John V. Heymach (MDACC)
Dr. John Heymach presented some of the updates on the project that he is leading along with Drs. Marc Ladanyi (MSKCC) and Ralf Kittler (UTSW). Dr. Heymach’s team demonstrated that RET fusions are heterogeneous, and the type of fusion can impact RET drug sensitivity. They were able to establish a big panel of RET cancer cell models (>20 models) bearing the different RET fusions found in RET patients and use them to test different RET drugs including selpercatinib, pralsetinib, vandetinib, cabozantinib, and ponatinib between others. They found that unique RET fusions impart differential sensitivities to RET inhibitors, for example, tumors expressing a certain type of RET fusion called KIF-RET (K15, R12) were highly sensitive to selpercatinib, pralsetinib, and ponatinib, whereas cells expressing the RET fusion KIF-RET (K22, R12) were less sensitive to ponatinib. Also, the experiments in the lab showed that the RET inhibitor pralsetinib seems to be more effective than selpercatinib on patients bearing the RET fusion CCDC6. They also used the LentiMutate approach, an innovative approach developed by Dr. Kittler that aims to quickly identify drug acquired RET resistance mutations in the lab. Acquired mutations in the RET molecule that are developed after the treatment with selective RET targeted therapy and produce an alteration on the RET molecule that allow the cancer cell to escape the effects of targeted drugs. They were able to identify secondary acquired mutations on the RET molecule that produce acquired resistance to both RET inhibitors selpercatinib and pralsetinib. Importantly some of these secondary mutations were associated with resistance to selpercatinib but not pralsetinib or vice versa. This study demonstrates that the different RET fusion variants have distinct drug sensitivity profiles and that acquired resistance mutations may be non-overlapping between the RET inhibitors. These data can provide RET cancer patients that become resistant to RET therapies an opportunity to switch to another more effective RET inhibitor. Dr. Heymach also investigated other cancer cell pathways that are independent of RET and can be turned on when RET cancer patients become resistant to RET inhibitors. This is called RET independent resistance. His lab showed that there is a molecule that is overexpressed in the surface of the cancer cells when RET cancer cells become resistant or tolerant to RET inhibitors. They are now working on different strategies to target this molecule.
To read more about resistance to RET therapies visit:
https://happylungsproject.org/resistance-when-ret-non-small-cell-lung-cancer-treatments-stop-working/
RETgistry: Global registry for the study of resistance to RET inhibition in patients with RET-altered solid tumors. Alexander Drilon (MSKCC)
To understand the mechanisms of resistance to RET therapies, Drs. Alexander Drilon and Jessica Lin performed a deep genomic analysis of 118 tumor biopsies obtained from RET patients who progressed on a RET inhibitor. The analysis demonstrated that resistance to RET inhibition can happen by additional mutations in the RET gene that do not allow the RET drug to bind efficiently. These additional mutations were identified in 12% of the patients. Interestingly, they showed that most RET cancer patients who developed RET inhibitor resistance (53% of patients) the resistance was mediated by bypass mechanisms such as activation of alternative cell pathways that produce tumor grow (RET independent resistance). The amplification of the MET gene was the most common one found in this group of patients. Interestingly they showed that the duration of the RET therapy is not related to the development of one type of resistance or another (RET acquired resistance or RET independent resistance). They also performed an analysis of RET patients treated with immunotherapy (PD-1/PD-L1 inhibitors like pembrolizumab) or chemotherapy. They showed that the efficacy of the combination of immunotherapy and chemotherapy was modest in RET patients with a progression free survival of 7.3 months. The efficacy of immunotherapy treatment alone was also very modest with progression free survival of 5 months. They are now working with Lilly to analyze data from clinical trials of RET patients treated with selpercatinib or chemotherapy.
To read more about immunotherapy and other RET therapies visit:
https://happylungsproject.org/current-treatment-options-for-ret-lung-cancer/
How does the tumor microenvironment influence RET+ lung cancer? Dr. Justin Gainor (MGH)
Dr. Gainor performed a deep analysis of the tumor microenvironment of a large panel of NSCLC tumors including RET lung cancer tumors. The tumor microenvironment is defined by the environment surrounding a tumor, which includes various non-cancerous cells, like immune cells that closely interact with the tumor cells and play a critical role in tumor development, progression, and resistance to therapies. His team was able to perform single cell RNA sequencing which is a very innovative technique used to analyze the genes in individual cells from a tumor sample. This technique allows investigators to study not only the tumor cells in a tumor but also the immune cells, the fibroblast, the blood cells, etc. Interestingly they found that some cancer cells present an overexpression of molecules that are in the cell membrane like HER3, TROP2 or MET and that can be targeted by drugs called antibody-drug conjugates (ADCs) that are a type of targeted cancer therapy that combines antibodies, designed to find and bind to specific proteins in the tumor, linked to a chemotherapy agent.
The also studied other cell types within RET tumors and found that there are groups of immune cells (immune hubs) present in RET tumors and that these hubs are good markers for immunotherapy (PD-1/PD-L1 inhibitors). They are now investigating strategies to better induce these immune hubs.
His team also investigated the role of fibroblasts (cells found in tissues that are responsible for the structural integrity and support of tissues in the body) and their interaction with RET cancer cells. Interestingly, they demonstrated that when RET cancer cells and fibroblast are closely together, the RET cancer cells become less sensitive to RET inhibitors.
To read more about immunotherapy and RET lung cancer visit:
https://happylungsproject.org/immunotherapy-and-ret-lung-cancer/
Cell-therapies for the treatment of RET fusion lung cancer. Dr. Alexandre Reuben (MDACC)
Dr. Reuben presented some of the latest updates on the development of cell-based immunotherapies for RET cancer. Immune cell therapies are a class of cancer immunotherapy that is based on the isolation of the immune T cells of the patient that can recognize tumors, their expansion in the lab, and the re-infusion of the selected immune T cells back into cancer patients.
There are several different types of immune cell therapies including the TCR therapy that Dr. Reuben is developing. TCR T-cell therapy utilizes the immune T cells from cancer patient’s blood that are re-engineered in the lab by adding a new T-cell receptor (TCR) that is specially designed to effectively recognize proteins present on the patient’s tumor. When the T cell binds to the tumor cell it destroys it. This therapy has been proven effective in KRAS mutant cancers (8).
Dr. Reuben’s lab identified a part of the RET protein that is overexpressed in most RET tumors. They have isolated and designed specific immune T cells or TCR candidates (5 candidates) that effectively recognize and attack this RET protein. They are now testing these TCR candidates in tumors in the lab and preparing some experiments with RET mouse models. When these TCR candidates are fully validated in the lab the investigators will manufacture the product for the clinic and open a pilot clinical trial.
To read more about new immunotherapy approaches for RET lung cancer visit:
https://happylungsproject.org/immunotherapy-and-ret-lung-cancer/
