More Research, More Life
We support research that will advance our understanding of RET-driven cancers and increase the number and quality of cancer treatments for all RET patients. We harness the scientific and institutional capacity of a range of partners - including Lungevity, the Happy Lungs Project, and the Hamoui Foundation - to identify and fund research projects demonstrating the greatest potential to benefit RET+ patients.
Current RET Treatment Options + Challenges
Recent FDA approvals for RET-selective tyrosine kinase inhibitors (TKIs) have been pivotal to improving survival and quality of life for patients with RET-driven cancers. Unfortunately, not all patients respond to these targeted therapies, and - for the many who do - cancer progression at some point is likely.
After progression on TKIs, current treatment options are of limited benefit. Chemotherapy, for example, may provide some benefit but with limited duration and greater toxicity. Immune checkpoint inhibitors have provided durable benefits for many lung cancer patients, but RET-driven cancers usually show limited or no response to this type of immunotherapy.
RET-driven cancers are considered a rare cancer subtype, which presents a unique set of research challenges. We have a number of unmet needs pre-clinically that make RET-driven cancers more challenging to study in the lab:
- Understanding co-mutations
- Risk stratification
- Limited cell line availability
- Lack of patient-derived xenograft (pdx) models
RET Research Priorities
An important area of unmet clinical need includes addressing best treatment options before progression such as:
- Risk stratification (early stage RET+ cancers vs advanced stage cancers already treated with TKIs)
- Combination therapies (and possibly targeting drug-tolerant persister cells)
For those who have progressed on targeted therapy, researching next-generation RET TKIs, as well as combination strategies with chemo or other targeted agents is critical. There is also a vital unmet need to create effective immune-oncology approaches that target RET-driven cancers, including:
- Possible cell therapies
- Tumor-infiltrating lymphocytes (TILs)
- Oncolytic viruses
Lastly, it remains a challenge to identify and recruit RET+ patients for clinical trials, as this is considered a rare subtype of cancer. It is imperative to not only advocate for inclusion of RET-driven cancers in clinical trials, but to help promote innovation, possibly through use of Real World Data and Real World Evidence and advocating for innovative trial designs.
In 2022, RETpositive partnered with The Hamoui Foundation and Lungevity to co-fund $1.2 million in research for the following grants:
Targeting lineage plasticity to suppress drug-tolerant persisters (DTP) in RET-positive lung cancer (Dr. Hideo Watanabe, Icahn School of Medicine at Mount Sinai New York)
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.
T cell receptor engineering for the treatment of RET fusion-positive NSCLC (Dr. Alexandre Reuben, University of Texas MD Anderson Cancer Center)
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.
MET and EGFR as biomarkers for amivantamab in overcoming RET TKI resistance (Dr. Tejas Patil, University of Colorado Denver, AMC and DC)
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.
Novel structure-based and combinatorial approaches for RET-fusion NSCLC (Dr. John Heymach, University of Texas MD Anderson Cancer Center)
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.
Identifying non-genomic mechanisms of RET TKI resistance (Dr. Alexander Drilon, Memorial Sloan Kettering Cancer Center New York)
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.
In June 2022, RETpositive partnered with the Happy Lungs Project to co-fund over $1 million in research:
RETgistry: Global registry for the study of resistance to RET inhibition in patients with RET-altered solid tumors (Dr. Jessica Lin, Massachusetts General Hospital; Dr. 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 (Dr. John Heymach, MD Anderson Cancer Center; Dr. Marc Ladanyi, Memorial Sloan Kettering Cancer Center; Dr. 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 (Dr. Justin Gainor, Massachusetts General Hospital; Dr. 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.