The Happy Lungs Project Supported Research
As an organization, we first and foremost seek to support researchers and clinicians in their work toward a cure for Non-Small Cell Lung Cancer caused by the RET mutation. While current treatments like Selpercatinib improve patient outcomes greatly, they are by no means a cure. Some patients develop resistance. Others fail to respond.
We aim to provide the resources necessary to develop treatments for NSCLC caused by the RET mutation, including novel drugs, procedures, and immunotherapies. We will collaborate with those studying the biology of RET-driven malignancies of all types, no matter what their institutional affiliation, so that our efforts can benefit patients afflicted not just by NSCLC, but those suffering from other RET-driven cancers. We will also facilitate development of treatment options for patients who exhibit resistance to existing RET medications. Based upon the advice of our scientific advisory board, we will evaluate late-stage clinical trials which show promise and need funding to complete critical work, as well as novel, early-stage research.
The Happy Lungs Project is pleased to fund research grants to different working groups from MD Anderson Cancer center, Massachusetts General Hospital, and Memorial Sloan Kettering Cancer Center. The working groups will be actively investigating RET fusions with an emphasis in elucidating the mechanisms of resistance to RET targeted therapies and the development of novel effective therapies including T cell immunotherapies. Summaries of the projects are detailed below.
RETgistry: Global registry for the study of resistance to RET inhibition in patients with RET-altered solid tumors
Jessica Lin, Massachusetts General Hospital (MGH)
Alexander Drilon, Memorial Sloan Kettering Cancer Center
While solid tumors driven by oncogenic RET alterations such as RET mutations or fusions are sensitive to RET inhibitors, drug resistance remains a major problem causing disease relapse in most patients. By leveraging the comprehensive genomic assessment of patient tumor or plasma specimens from the “RETgistry” global consortium, this proposal aims to identify drivers of resistance to RET inhibitors that could inform the development of novel treatment strategies. RETgistry involves a multi-centered international study that collects clinical and genomic data from patients with any advanced RET-altered solid tumor treated with RET inhibitors. These analyses will allow us to determine new more effective therapeutic approaches.
Characterize mechanisms of primary resistance to RET inhibitors in lung cancer and test new combinations that overcome the resistance
John Heymach, MD Anderson Cancer Center
Marc Ladanyi, Memorial Sloan Kettering Cancer Center
Ralf Kittler, UT Southwestern Medical Center
RET fusions are caused by chromosomal rearrangements of a region of the RET protein with a portion of another protein, leading to constitutive activation of the RET kinase. Although the most common gene fusion partners are KIF5B and CCDC6, there are many other fusion partners and the variations in fusion partners may impact the sensitivity of these tumors to RET inhibitors. This proposal aims to establish a comprehensive landscape of RET fusions and mutations associated with RET inhibitor resistance. This will allow us to establish functional classification subgroups of RET mutations based on their differential response to RET therapies. We will determine the RET mutations associated with RET inhibitor resistance using innovative approaches and our collection of RET preclinical models. We will also identify key molecular features of RET fusions using computer models developed to model potential alterations in the RET protein that drive RET inhibitor primary resistance.
Develop novel immunotherapeutic approaches for the treatment of RET-positive NSCLC
Justin Gainor, Massachusetts General Hospital (MGH)
Alexandre Reuben, MD Anderson Cancer Center
Current immunotherapies are designed to enhance the immune response to fight cancer. Immunotherapies based on immune checkpoint inhibitors (drugs that block immune checkpoints to allow immune cells to respond more strongly to cancer) have shown good responses in lung cancer patients but unfortunately, they have shown minimal anti-tumor activity in patients harboring RET fusions. Very little is known about the role of the tumor immune microenvironment in response and resistance to immunotherapy in these patients. This proposal aims to elucidate the immune microenvironment landscape of RET-positive lung cancer patients in order to develop novel more effective immunotherapeutic approaches including T cell therapies targeting RET fusions. In these innovative therapies, the immune cells are taken from RET patients, engineered in the lab to better attack the cancer, and reinfused into patients for therapeutic purposes.
Examples of fundable projects include:
Innovative clinical protocols for testing of individualized cancer treatments.
Drug repurposing for mutation-driven cancer – funding this work will allow researchers to test existing drugs and combinations of drugs to determine effectiveness in patients with RET mutations and those with resistance to targeted RET therapies.
Targeted-drug development based upon tumor sequencing and individualized medicine.
Immunotherapy tailored to recognize specific RET epitopes.
Other initial funds were granted to MD Anderson to characterize RET mutations and elucidate resistance mechanisms from newly generated cell lines and animal models and develop novel T cell therapies against RET-fusions. These projects are currently ongoing and will serve in part as a foundation for the new awarded studies.
1. Characterize RET Mutations
Characterize RET mutations and elucidate resistance mechanisms from newly generated cell lines and animal models.
2. Determine RET Sensitivity
Determine the sensitivity of individual patient RET mutations to existing RET inhibitors. Investigate drug repurposing to combat RET inhibitor clinical resistance through novel application of single drugs, or new therapeutic combinations or cocktails of medications.
3. Develop T-cell Receptors
Develop T-cell receptors with therapeutic potential against RET-driven NSCLC, or other cancer vaccine-based strategies.
4. Generate RET Targeted Drugs
Generate new RET-mutation targeted drugs. Use the knowledge gained by characterizing the mutations to design more effective, selective, and more brain-penetrant medications.
We funded these initiatives because they could provide data for rapid advancement of NSCLC care, and potential treatments for those who have developed resistance to current RET inhibitors. However, this research may be applicable to other cancers caused by the RET mutation such as thyroid cancer and colon cancer, as well as other NSCLC caused by other genetic mutations.
Our mission is to find and facilitate the most promising science anywhere in the world which may benefit those facing RET-driven malignancy. The small percentages of RET found in any one form of cancer have made RET positive malignancies difficult to study at any single institution. Thus, RET-related diseases have been under-funded and under-researched. We can change that by supporting and bringing together the clinicians and researchers who are focused upon RET related disease, and in turn, change the outcome for RET+ patients.