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We fund translational research to move knowledge as quickly as possible from basic discovery to treatment of patients.
Since 2002, LUNGevity has invested in 191 research projects at 69 institutions in 24 states and the District of Columbia focusing on early detection as well as more effective treatments of lung cancer.
Dr. Deutsch’s proposal centers around finding better pathologic predictors of response to neoadjuvant IO in early stage NSCLC. She will utilize machine learning/artificial intelligence to test an algorithm that she and her team have developed that assesses percent residual viable tumor (%RVT), which is the amount of tumor left at the time of surgery. Dr. Deutsch will also characterize tissue specimens using a novel immunofluorescence platform to identify cell types and spatial relationships that are associated with patient benefit to immunotherapy+chemotherapy. This approach can help inform which patients should receive a given therapy, how they will respond, and additional possible targets for the development of new therapies.
The introduction of targeted therapies and immunotherapy for early-stage lung cancer is associated with improved survival, but patients can only benefit if they partake in adjuvant and neoadjuvant therapies. Data has shown that inequalities exist for patients with lower socioeconomic status as well as non-White patients when it comes to being referred for and receiving treatment after surgery. These inequalities are likely to increase as new drugs are developed in clinical trials comprised of predominantly white patients. In this project, Dr. Nobel will study the impact of disparities on uptake of adjuvant therapy for NSCLC in a largely minority patient population at Montefiore Medical Center in Bronx, NY. She will provide social support and health literacy to engage patients in their care and collect genetic data about their tumors, which will contribute to future clinical trials that are more inclusive.
In patients with EGFR-mutant NSCLC, tyrosine kinase inhibitors (TKIs) have been an effective treatment, but over time these patients develop resistance to TKIs, leading to tumor relapse. Dr. Yang’s project focuses on cancer cells called drug-tolerant persisters (DTPs), which are implicated in TKI resistance. A gene called HER3 is expressed in DTPs, and Dr. Yang will use specially engineered immune cells, called CAR-T cells, to target both HER3 and EGFR simultaneously. If successful, this approach would result in a bi-specific CAR-T cell that can be further evaluated in clinical trials.
This grant was co-funded by Rising Tide Foundation for Clinical Cancer Research
The objective of this project is to develop a blood test that can improve upon current limitations in lung cancer screening. Dr. Patel and his team have developed a method to accurately measure alterations in DNA that are cancer-specific by looking at levels of methylation of circulating tumor DNA (ctDNA) in the bloodstream. Using this method, Dr. Patel will develop a predictive model to identify patients with lung cancer based on these DNA alterations at a single time point, as well as an algorithm that can track these changes in a patient’s DNA over time. If successful, this could help detect lung cancer earlier in its development, thereby leading to better outcomes for patients.
This project will investigate the role of cells called macrophages, key components of the immune system that have multiple functions, including immune surveillance within a unique communication pathway called hedgehog (Hh). The hedgehog signaling pathway is involved in cell growth and differentiation, as well as maintenance of stem cells and tissue repair. Disruption or inhibition of Hh can create an environment that is less favorable for survival of cancer cells, allowing a patient’s immune system to combat it more effectively. This research has the potential to benefit patients who have been diagnosed with NSCLC, who have not responded to current treatments including immunotherapy by boosting the body’s own defense mechanisms.
This project will investigate novel protein degraders (called PROTACs) as a treatment for RET-positive cancers, and will evaluate their efficacy in vitro and in vivo in prostate and lung cancer. PROTACs are highly specific molecules that degrade unwanted or harmful proteins in cells (in this case, RET tyrosine kinase). This research aims to provide a novel therapeutic approach targeting RET signaling, which could overcome resistance to existing RET inhibitors. If successful, it would be a first-in-class compound for further clinical development.
This project will explore the use of neoantigens to evaluate immunogenic priming of dendritic cells (DC) in RET+ NSCLC. Neoantigens are short protein fragments present only in cancer cells that bind to genetically encoded proteins known as human leukocyte antigens (HLA). Dr. Cummings will use features of HLA to predict which cancer-specific protein fragments best match an individual’s immune system, utilizing a biobank of RET-rearranged NSCLC biospecimens. This approach could help identify optimal immunogenic targets, that could be translated into a pathway for clinical use of personalized DC vaccines.
This project aims to develop new therapeutic approaches for RET-positive cancers, focusing on overcoming resistance to currently available RET inhibitors. Dr. Somwar and colleagues will investigate ways to block the growth of lung cancers with altered RET in a pathway called MAPK (mitogen activated kinase), which is involved in many biological processes involving cell growth and survival. MAPK is implicated in developing resistance to RET inhibitors and finding strategies to target this pathway in combination with RET could benefit many patients who have no approved therapy options after tumor reoccurence.
RET fusions result from abnormal rearrangements of the kinase domain of RET with other non-essential genes and drive tumorigenesis. These oncogenic chimeric tyrosine kinases are found in approximately 2% of non-small cell lung cancer (NSCLC).Two FDA-approved selective RET inhibitors (selpercatinib and pralsetinib) have shown great response rates in lung cancer patients. However, resistance to RET inhibitors inevitably occurs, limiting therapeutic benefit. Multiple mechanisms of resistance to RET inhibitors have been described, including acquired RET solvent front mutations (G810R/S/C/V), and RET-independent mechanisms of resistance due to amplifications of other receptor tyrosine kinases (RTK) including MET, FGFR1 and ERBB2, and alterations in the RAS-MAPK pathway. Some second-generation RET inhibitors that target secondary RET mutations have been recently developed including vepafestinib (TAS0953/HM06) which is currently being tested in phase I/II clinical trials in the US and Japan for RET fusion positive lung cancer. There is a clinical need to identify mechanisms of resistance to vepafestinib and develop strategies to overcome them.
RET with solvent front mutations, amplification of MET/FGFR1/ERBB2 and RAS-MAPK pathway mutations account for >30% of all resistance mechanisms to first-generation RET drugs, and importantly, all of these alterations are expected to activate the RASMAPK pathway. Therefore, a therapeutic strategy that tackles RAS-MAPK pathway activation is expected to benefit >30% of patients who acquire resistance to first-generation RET drugs. Moreover, given that RET fusions, like all tumors arising from activated RTKs engage the RAS-MPAK pathway for oncogenesis, we believe that many treatment-naïve patients may also benefit from a therapeutic strategy that targets RET and the RAS-MAPK pathway.
Our first goal in this proposal is to simultaneously address resistance due to RAS-MAPK pathway alterations and extending the benefit of first-generation RET drugs by developing a combination therapy strategy involving RET and pan-RAS, MEK1/2 or ERK1/2 inhibitors. Our second goal is to decipher mechanisms by which the transcription factor capicua (CIC) regulate RET-driven tumorigenesis and resistance to RET inhibitors. We will perform transcriptomic, epigenic and proteomic profiling to gain insights into RET-ERK-CIC interaction. Our third goal is to identify and target resistance mechanisms to vepafestinib, so that a therapeutic strategy will be in place for when patients being treated with this drug develop resistance.
Our team includes leaders in the field of lung cancer clinical and translation research who have been at the forefront of lung cancer genomics and therapy, developing state of the art therapeutic strategies. We are well positioned to translate the findings from this study to the clinic within two years. These studies have the potential to benefit more than 30% of lung cancer patients with RET fusions.
Small cell lung cancer (SCLC) is difficult to treat, and most patients diagnosed have a poor prognosis. Most patients with SCLC treated with first line chemoimmunotherapy progress within months of immune checkpoint inhibitor (ICI) maintenance therapy. Previous studies in mice have revealed that SCLC treated with iadademstat and maintenance ICI shows enhanced tumor response compared to ICI alone. Dr. Choudhury will conduct a phase II randomized trial investigating this combination in patients with SCLC versus standard of care ICI alone to evaluate progression free survival.
This grant was funded in part by Lung Cancer Initiative
Although the average age at diagnosis is 70, thousands of new patients under 45 are diagnosed with lung cancer every year, most of whom have never smoked. Dr. LoPiccolo hypothesizes that these patients may share inherited genetic changes that predispose them to developing lung cancer at a younger age. In a preliminary analysis of young-onset lung cancer patients, Dr. LoPiccolo has found that approximately 30% of these patients carry rare mutations in known cancer-associated genes. In this study, Dr. LoPiccolo will investigate whether these mutations affect response to targeted or immune-based therapies. This insight is likely to identify risk factors among young lung cancer patients, which could lead to improved screening and treatment options for this population.
Checkpoint immunotherapy has advanced treatment of NSCLC, but the majority of patients do not experience long-term disease control and are at risk for autoimmune-related side effects. In this study, Dr. Tseng will examine specialized cells called CD8+ T that express receptors (KIR+) that suppress autoimmunity to understand how these cells regulate the immune system’s cancer-fighting ability during checkpoint immunotherapy treatment. Insights gained from this study could result in better strategies for improving efficacy while decreasing immune-related side effects.
Lung cancer is the number one cause of cancer-related deaths in the US because it is often found only after it has spread to other organs in the body, decreasing the likelihood of surviving at least 5 years after diagnosis. Only 21% of patients are diagnosed then their lung cancer is early stage, when it is most treatable. The goal of this project is to create a new way to screen for lung cancer using a blood sample that can find early stage disease when patients can still be treated and/or cured. In preliminary work, Dr. Diehn has developed a blood test that can identify tiny amounts of DNA from lung cancer cells and in this study he will improve this test and apply it to patients and healthy controls. If successful, Dr. Diehn’s work has the potential to significantly improve early detection of lung cancer and improve outcomes for patients.
Funded by the American Society for Radiation Oncology
Radiation therapy remains a cornerstone treatment for patients with locally advanced lung cancer, however knowing which patients will respond and which will not respond is still poorly understood. The goal of this project is to analyze genomic and radiomic data from patients with NSCLC to understand how tumors change during therapy and create models to predict therapeutic response that will assist with clinical decision making.
Radiation therapy is the single most utilized anti-cancer agent; nearly 70% of all cancer patients will receive radiation at some point in their cancer journey. Radiation plays a crucial role in almost half of all cancer cures. The sequencing of the human genome, completed nearly 20 years ago, followed by the large scale cancer sequencing effort in The Cancer Genome Atlas (TCGA) have provided an unprecedented understanding of cancers in the primary and metastatic setting. In those same years, medical oncology has undergone three major phase transitions: targeted therapies have changed the way we think many diseases with specific actionable mutations; immunotherapy has revolutionized the treatment of many of those without; and antibody-drug conjugates have increased the specificity of our cytotoxics. Radiation treatment decision making, however, has not seen these same changes from biological influences, instead having relied on advances in medical physics and computer science to drive our advances. While the number of trials has ballooned in radiation oncology of late, spurred on by encouragement, and funding, from pharmaceutical companies interested in the synergy between novel (and profitable) compounds in the form of immune checkpoint inhibitors and antibody-drug-conjugates, with radiation, our understanding of the relative benefits and best choices for individual patients has not seen the same increases. In fact, we have struggled to parse out the differences between these novel combinations and standard chemoradiotherapy in phase II trials, largely because of the combinatorial nature of our trials, and the sheer number of open questions. In this project, we seek to make headway toward personalizing radiation therapy treatment choices. Leveraging our experience in using gene signatures to predict individual patient radiation benefit, together with expertise in radiomics and genomics, we will track the progress and outcomes of patients with non-small cell lung cancer treated with standard of care chemoradiation using high resolution genomic and radiomic measures. The dynamics of these genomics through time will be correlated to the high temporal density radiomics features to allow for translation and generalization to all patients treated with modern technique. Through these complimentary -omic modalities, we aim to leverage our experience in creating signatures of therapeutic response to admit personalized treatment choice in the upfront setting, and opportunities to change course using real- time information gleaned from daily imaging. This pilot project will enable the development of novel multimodal data integration methodologies to interrogate radiation treatment response in a comprehensive manner.
Tyrosine kinase inhibitors (TKI) are a class of drugs that are used to treat EGFR NSCLC. These drugs eventually stop working and some cancer cells called drug-tolerant persisters (DTPs) are implicated in this resistance. Dr. Kobayashi and his team have found that a protein called CD74 plays a role in developing a resistance to osimertinib. In this project, he will investigate whether CD74-expressing cells allow for the development of DTPs and if inhibition of CD74 by combining an antibody-drug conjugate (CD74-MMAE) with osimertinib, prevents resistance. If successful, this has the potential to significantly impact the survival of EGFR patients by allowing them to stay on osimertinib for a longer duration.
In this project, Dr. Reuben and colleagues aim to develop a novel therapeutic strategy harnessing immune response in EGFR-mutant NSCLC. He will use engineered T cells with receptors targeting EGFR antigens to eradicate drug-tolerant persister (DTP) cells, preventing the emergence of resistance following treatment by osimertinib. This work lays the foundation for use of TCR-engineered T cells in treating patients with EGFR mutations.
Although targeted therapies are extremely effective in destroying tumors, they inevitably leave behind a few cancer cells which persist. These are the cells which eventually become resistant to therapy and lead to the death of patients. Although checkpoint blockade immunotherapy has been largely unsuccessful in EGFR-mutant tumors, immunotherapy via cell therapy may offer promise in this setting. EGFR mutations can give rise to short peptides at the surface of tumor cells, called antigens, which allow the immune system to distinguish tumors from their normal counterparts and to specifically destroy them. Importantly, we have identified several antigens that are found solely on or enriched within EGFR-mutant tumors persisting following treatment with EGFR targeted therapies such as osimertinib/Tagrisso. As a result, we have developed a library of receptors which can be engineered into immune cells to allow their direct recognition and destruction of persisting EGFR-mutant cancer cells on the basis of the unique antigens they display. Here, we propose to test a novel approach to eradicate these EGFR-mutant drug persister cells by treating them with engineered immune cells to eliminate the last remaining persister cell and prevent the emergence of resistance following exposure to osimertinib. Our proposal includes two aims: Aim 1 will focus on determining the impact of EGFR-mutant persister cells on the function of immune cells and on their ability to recognize and kill tumor cells. Aim 2 will focus on assessing the ability of receptor- engineered immune cells to eliminate EGFR persister cells when combined with EGFR targeted therapy in vitro and in vivo.
Together, these aims will allow us to determine the therapeutic potential of this novel treatment strategy approach. Our proposal is highly translational, as we have entered into a partnership with Alaunos Therapeutics, a cellular therapy company performing a clinical trial using engineered immune cells at MD Anderson which could facilitate our ability to move these findings into the clinic. Due to the prevalence of the antigens we are targeting (one of which is found in ~90% of lung cancer patients), our approach could extend to almost all patients harboring EGFR mutations.