We fund translational research to move knowledge as quickly as possible from basic discovery to treatment of patients.
Since 2002, LUNGevity has invested in 200 research projects at 69 institutions in 24 states and the District of Columbia, for a total of $55,743,471.02.
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.
The veteran population is disproportionately affected by lung cancer and relatively few patients that are eligible participate in lung cancer screening. This low participation is due to barriers such as provider bias, structural racism, patient mistrust, and fear of diagnosis. In this project, Dr. Navuluri proposes to develop and test an electronic shared decision-making aid and referral tool to improve equity in lung cancer screening (LCS). She will pilot test the aid to assess its feasibility and usability among patients and providers within the Durham VA system.
This project proposes to develop novel therapeutic approaches to treat advanced EGFR-mutant NSCLC. CAR-T cell therapy is a type of immunotherapy treatment that uses genetically altered T cells to find and destroy cancer cells more effectively. TROP2 is a protein that is over expressed on the surface of NSCLC and is a target of the antibody-drug conjugate (ADC), sacitizumab-govitecan, which is FDA-approved to treat other solid tumors. Dr. Brea hypothesizes that TROP2-directed CAR-T targeting of EGFR-mutant NSCLC will be superior to standard Osimertinib treatment.
In this project, Dr. Trovero will study the role of METTL3, an RNA modifying protein that is thought to promote tumor initiation and progression. She will evaluate the function of METTL3 by increasing or decreasing its activity in vivo. Results from this study will help establish METTL3 as a possible therapeutic target for lung cancer, and pave the way for understanding the relationship between RNA modifiers and cancer biology.
Among mRNA modifications, N6- Methyladenosine (m6A) is the most abundant, catalyzed by a complex that includes methyltransferase-like 3 (METTL3). Although the function of m6A in cancer remains understudied, Gregory’s lab provided functional evidence of METTL3 as an oncogenic protein, promoting translation of oncogenes to promote lung cancer cell growth, survival, and invasion in human cancer cell lines. Lung adenocarcinoma (LUAD) is the most common form of lung cancer, with a survival rate of about 18%, highlighting the need for more effective treatments and understanding LUAD biology.
Our hypothesis: METTL3 is a novel oncogenic factor in lung cancer and plays a key role in tumor initiation and progression. I will test the role of METTL3 in a LUAD mouse model, and in tumor organoid culture system.
Aim 1: Determine the effects of METTL3 manipulation on tumor progression in a LUAD mouse model. Lentivirus will be used to knockdown or overexpress METTL3 simultaneously with activation of oncogenic Kras in the LUAD mouse model for comparison of tumor number, size and histopathological features.
Aim 2: Test the effects of METTL3 on early-stage lung cancer by manipulating METTL3 expression in a tumor organoid model of cancer initiation. Alveolar epithelial (AT2) cells from Kras mice will be infected with Cre and shMETTL3 or METTL3 cDNA to initiate early-stage lung cancer in organoid cultures, to assess organoid size, proliferation and differentiation features.
This proposal could establish METTL3 as a therapeutic target for lung cancer and pave the way for understanding links between epitranscriptome and cancer biology.
Dr. Benjamin’s research focuses on improving the rates of lung cancer screening. Currently, there is interest in “centralizing” lung cancer screening into self-contained programs or one-stop shops, with dedicated support staff and clinical personnel to coordinate shared decision-making, scheduling imaging, and arranging appropriate follow-up care. However, it is poorly understood how these centralized programs compare to “decentralized” screening that is coordinated by primary care physicians directly with their patients. Dr. Benjamin seeks to utilize nationwide longitudinal data from multiple lung cancer screening programs from the Veterans Affairs Healthcare System to evaluate and compare the performance of centralized versus decentralized screening programs, with particular focus on highlighting their effectiveness within various racial and income groups.
Dr. Ocadiz Ruiz proposes to develop a bioengineered scaffolding and test it in mouse models. If successful, this research could progress to a phase 1 clinical trial and lay the groundwork for a new technology to be used in individuals with increased risk of lung cancer. This technology has to potential to make biopsies and consequently, early detection, easier.
Lung cancer is the leading cause of cancer related death among women and men and the second most diagnosed cancer in the world, causing 1.8 million deaths annually. Surgical resection of the primary tumor is the standard of care whenever possible. However, 90% of lung cancer deaths are caused by metastases months-to-years after surgery. Current screening tools such as high-resolution Computed Tomography (CT) and Positron Emission Tomography (PET) can only identify tumors that have reached a detectable size, that often correlates with advanced disease. However, this technology carries side problems, including the false positive rate that led to follow-up tests and invasive procedures that confers additional risks to patients.
Therapeutic strategies targeting specific driver mutations have emerged in recent years for the treatment of metastatic non-small cell lung cancer and have improved survival, yet the initial identification of these molecular alterations depends on biopsies of metastatic lesions after the resection of the primary tumor. For biopsy, the metastatic lesion must be large enough to be detectable by clinical imaging tools, and this large lesion indicates a relatively advanced stage of disease. Biopsy of these lesions is often difficult from both location and patient-safety perspective. An emerging option is a blood draw or liquid biopsy to obtain circulation tumor DNA (ctDNA) for mutation analyses, yet the ctDNA is not abundant in circulation until relatively large metastases have already formed.
Therefore, novel, efficient, and affordable approaches are needed for disease surveillance. We propose a high sensitive, minimally-invasive and efficient cell capture device for easy isolation of tumor cells at early stages of disease, whose analysis can identify targeted therapeutics that can be applied while the disease burden and heterogeneity are low. Furthermore, this technology would increase the coverage of the eligible population and reduce the clinical costs by using histopathology analysis of the sentinel implant. This device is a porous biomaterial scaffold that, when implanted, is vascularized, and infiltrated by immune cells and subsequently cancer cells, acting as a synthetic sentinel niche that provides information about the disease development and progression. Our previous studies in breast and pancreatic cancer models have demonstrated that tumor cells are detectable early after tumor initiation and during the progression of the disease. A comparative analysis of scaffolds and ctDNA showed that the implant captured and therefore detected cancer cells before positive detection of ctDNA.
We will determine the genomic and transcriptomic prolife of inoculated lung cancer cells in PDX’s murine model at early time points. We anticipate that the tumor cells captured by the scaffolds will recapitulate the genotype of the parental PDX. The scaffold safety will be investigated in a Phase I clinical study of metastatic lung cancer patients implanted with our scaffold, with biopsy and subsequent removal to analyze captured cells. Sequencing analysis will be applied to captured cancer cells to assess their genomic and transcriptomic profile. We foresee the use of these bioengineered implants for surveillance in high-risk lung cancer patients, with analysis of the collected cells employed to identify personalized therapeutic strategies to improve patient outcome.
This grant was co-funded by Stand Up to Cancer, LUNGevity, and the American Lung Association
Lung cancer is the leading cause of cancer death globally, primarily due to challenges in early detection. With funding from Stand Up to Cancer, LUNGevity Foundation, and the American Lung Association, a multidisciplinary team called the Lung Cancer Interception Dream Team was formed in 2017 to tackle this challenge, uniting expertise from various fields to enhance lung cancer interception and prevention.
This initiative includes the development of a lung pre-cancer genome atlas (PCGA) aimed at understanding molecular changes linked to the progression of pre-cancerous lesions to lung carcinoma. With continued funding from LUNGevity Foundation and the American Lung Association, the team plans to establish a temporal atlas for premalignant lung adenocarcinoma by utilizing robot-assisted bronchoscopy to collect samples from patients with ground glass opacities (GGOs) suspected of lung cancer. This effort will not only help identify these lesions but also facilitate the targeted delivery of intervention agents.
By gaining insights into progression-associated molecular alterations and cellular interactions, the team aims to significantly advance lung cancer interception strategies - catching cancer at its earliest stages and treatment it before it grows and spreads. Ultimately, the goal is to provide personalized interception approaches for individuals at risk of developing lung cancer.
Cancer interception is catching cancer at its earliest stages and treatment it before it grows and spreads. Our current lack of effective lung cancer interception methods stems from an incomplete understanding of the early molecular events in lung cancer development, Through the 2017 Stand Up To Cancer – LUNGevity Foundation – American Lung Association grant, a multidisciplinary team called the Lung Cancer Interception Dream Team has established the Lung Pre-Cancer Genome Atlas (PCGA), identifying immune and epithelial changes linked to who normal cells become pre-malignant cancer cells. With a second round of funding from LUNGevity Foundation and the American Lung Association, the team will be building on these foundational findings and enhance their efforts by developing a temporal atlas of genomic (DNA-level changes), transcriptomic (RNA-level), and epigenetic changes in pre-malignant lung adenocarcinoma lesions through longitudinal sampling. The team hypothesizes that these lesions exhibit specific genomic, transcriptomic, and epigenetic alterations, with some evading immune detection and advancing to invasive cancer. Ultimately, the insights gained will provide valuable resources for the research community and significantly impact early-stage lung cancer interception.
We lack effective lung cancer interception approaches due to our incomplete understanding of the earliest molecular events associated with lung carcinogenesis, which leave clinicians with few tools to manage precancerous lesions that may be found on CT screening. Our multidisciplinary Lung Cancer Interception Dream Team has made significant progress in establishing a Lung Pre-Cancer Genome Atlas(PCGA) where we have begun to identify immune and epithelial alterations associated with premalignant disease progression. To extend our findings in order to refine targets for lung cancer interception trials, we are proposing to extend our on-going PCGA efforts with two important aims 1) Develop a temporal atlas of premalignant lung adenocarcinoma via establishment of a cohort of longitudinally-sampled ground glass opacities (GGOs) collected with robot-assisted bronchoscopy, representing premalignant and minimally-invasive lung adenocarcinomas and 2) based on our current findings and feedback from our previous reviewers, we will expand our profiling to include spatial and epigenetic profiling of precancerous lesions and minimally invasive carcinoma in biopsy samples collected from the GGO cohort and our Pre-Cancer Genome Atlas 2.0 cohorts. We hypothesize that premalignant lesions bear specific genomic, transcriptomic and epigenetic aberrations, and a subset of these lesions escape immune surveillance and progress to invasive cancer. Our team, will apply spatial profiling using imaging mass cytometry and spatial transcriptomics will allow us to uncover the tissue architecture of the molecular processes associated with progression which in turn will help delineate the cell-cell interactions underlying these processes. Epigenetic profiling via single cell ATAC and bulk DNA methylation sequencing will allow us to overlay information about transcriptional regulation with the other ‘omic data to better understand the regulation of processes associated with progression. Critical to the success of the proposal is the multidisciplinary expertise of the team, involvement of patient advocates and the extensive preliminary data supporting the feasibility of the proposed approaches. The insights gained from successful completion of this project and the data that will made available to the research community will serve as a foundational resource for other investigators in the field and will result in a significant and sustained impact on the interception of early-stage lung cancers.
Around one in three patients with non-small cell lung cancer are diagnosed with early-stage disease, where surgery is offered as curative therapy. Unfortunately, the cancer can recur in 50%-60% of patients. The rate of recurrence is higher in patients whose tumors have certain mutations, such as mutations in the KRAS gene. Dr. Marrone and her team will be conducting a phase 2 trial to test whether treatment with a KRAS G12C blocking drug, adagrasib, given as a single drug or in combination with an immunotherapy drug, nivolumab, before a patient undergoes surgery can delay or prevent recurrence in patients whose tumors have a KRAS G12C mutation.
Alterations in the BRAF gene can lead to the development of non-small cell lung cancer. BRAF fusions are a type of BRAF gene alterations. These fusions are powerful growth stimulators of lung cancer. Currently, no treatment exists for cancers that harbor these BRAF fusions. Dr. Offin will be testing a series of new drugs in preclinical cell line and animal models of lung cancer. The ultimate goal of his project is to identify new drugs that can be tested in clinical trials.
