Lung Cancer HELPLine 844-360-5864
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.
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.
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.
This grant was funded in part by The Huff Project
Osimertinib is the standard of care for treating non-small cell lung cancer with EGFR mutations. Unfortunately, the tumors inevitably develop resistance to osimertinib. Currently, very few treatment options exist for patients whose cancers have become resistant to osimertinib. Dr. Reuss is conducting a phase 2 clinical trial to test whether two immunotherapy drugs, atezolizumab and tiragolumab, given with a VEGF inhibitor, bevacizumab, are effective in controlling EGFR-positive NSCLC that has become resistant to osimertinib.
Currently available ALK inhibitors are an effective treatment for lung cancer, but tumors can development treatment resistance. In this project, Dr. Bivona will explore a novel way to treat ALK-positive lung cancer by targeting “membraneless cytoplasmic protein granules,” a new mechanism of signaling in ALK-positive lung cancer. His team will use precision medicine approaches that are complementary to current ALK inhibitors and that could improve their efficacy as well as quality of life for patients.
In this project, Dr. Chiarle and his team will generate T cells that have engineered receptors, called TCR receptors (TCR-T cells), that will selectively target and attack the ALK protein that is expressed by tumor cells. Generation of such cells could be a powerful tool to eradicate ALK+ lung cancer cells and form the basis of a TCR-T cell-based clinical trial for patients with TKI-resistant ALK+ NSCLC.
Patients with an ALK-positive lung cancer are typically young. For these patients several oral ALK inhibitors are available as pills, typically alectinib, lorlatinib, and brigatinib. These ALK inhibitors are very effective and well tolerated and most patients respond for long time. However, tumors may progressively develop resistance and start to grow back. In this setting of relapsing disease, few therapeutic options are left because most patients with ALK-positive lung cancer do not respond to existing immunotherapies.
For several years, we have been working to develop immunotherapy tools specifically for patients with ALK-positive lung cancer. In this proposal, the strategy is to re-engineer patients’ naturally occurring immune cells to target ALK selectively expressed by tumor cells. First, we will discover several receptors (TCRs) that T lymphocytes use to recognize ALK and kill tumor cells. Next, we will re-introduce these TCRs into the T lymphocytes to rapidly generate a large pool of killer cells all directed simultaneous against the tumor. The rapid infusion of a large number of TCR-engineered T lymphocytes, called TCR-T cells, will generate a wave of killing toward which the tumor will not have the time to adapt and escape. While the identification of ALK specific TCR might be difficult and elusive, we already discovered a series of very specific TCRs directed against ALK expressed by ALK-positive tumors in mice. Leveraging the discovery of ALK peptides expressed by human tumor cells, we will now discover specific TCRs that recognize ALK in human lung cancer. We will use these TCR-T cells to cure ALK-positive human tumors in combination with ALK inhibitors. We expect that this combination will be extremely powerful to rapidly eradicate tumor cells in the lung as well as in metastatic sites.
About 5-7% of non-small cell lung cancers (NSCLCs) have a rearrangement of the anaplastic lymphoma kinase (ALK) gene. ALK-rearranged NSCLC is typically treated with ALK tyrosine kinase inhibitors (TKIs), but no effective immunotherapies are available for refractory or relapsed tumors. In previous work, we have shown that ALK is an immunogenic oncoprotein that induces specific T cell responses with potent killing activity against ALK+ tumor cells in the lung and in distant metastatic sites, such as the brain. Thus, the lack of efficacy of standard immunotherapy in ALK+ NSCLC can be bypassed by the development of tools to induce ALK-specific T cell responses. Our central hypothesis is that the generation of T cells engineered to express TCRs (TCR-T cells) that selectively target ALK+ NSCLC will be a powerful tool to completely eradicate ALK+ lung cancer cells.
In preliminary experiments, we have shown the feasibility of the cloning of ALK-specific TCRs against an ALK peptide expressed by a mouse model of ALK+ lung cancer. In Aim 1, we will test the potency, the safety and the in vivo efficacy of ALK-specific TCR-T cells obtained by T cells engineered to express TCRs against ALK in a mouse model of ALK+ lung cancer. TCR-T cells will be tested alone or in combination with ALK TKI. Their efficacy will be compared to natural anti-ALK T cells induced by vaccination in mice. In Aim 2, we will discover and study the activity of ALK-specific TCRs against human ALK peptides. We will leverage ALK peptides we previously identified to be expressed by human ALK+ NSCLC. The killing activity of these human specific TCR-T cells will be tested against human ALK+ NSCLC in vitro and in vivo, alone or in combination with ALK TKIs. We expect to identify potent and specific TCRs as leading candidates for a TCR-T cell-based clinical trial for patients with TKI-resistant ALK+ NSCLC.
Lorlatinib is currently the only approved treatment for patients with ALK-positive NSCLC whose cancers have progressed on prior ALK drugs, and for those whose tumors develop resistance, there is a lack of other treatment options other than chemotherapy. In this study, Dr. Qin will evaluate a novel drug called gilteritinib as a treatment in patients with ALK-positive NSCLC whose tumors have developed a resistance to lorlatinib.
Lorlatinib is the only approved ALK-targeted drug for patients with ALK-positive non-small cell lung cancer (ALK NSCLC) who progressed on prior ALK drugs. The average duration of benefit from lorlatinib is seven months before resistance develops. There are currently no approved ALK-directed therapies after lorlatinib.
Our understanding of lorlatinib resistance mechanisms remains limited. However, we know that 1) cancer cells can develop two ALK mutations that block lorlatinib action and 2) cancer cells can activate other pathways so that cancers no longer exclusively rely on ALK.
This proposal addresses ALK resistance directly, with the goal of opening a clinical trial using a novel drug called gilteritinib. Preliminary tests show gilteritinib prevents ALK NSCLC from using alternative pathways to overcome ALK inhibition. First, we propose to obtain tumor-containing samples from patients who are progressing on lorlatinib and perform in-depth sequencing of these cancer cells to thoroughly describe resistance mechanisms in all detectable cancer clones. Next, we will perform drug sensitivity testing on these cancer cells using approved and experimental drugs, including gilteritinib. Finally, we will open a clinical trial using gilteritinib, already approved for treatment of a blood cancer (FLT3+ acute myeloid leukemia). In multiple pre-clinical studies, gilteritinib was able to kill lorlatinib-resistant cells, but this drug has not been given to patients with ALK NSCLC. Our proposal focuses on bringing knowledge obtained from patients’ cancer cells through extensive analysis directly into a clinical trial with a novel drug, maximizing the impact to patients.
Lorlatinib is currently the only approved ALK TKI (tyrosine kinase inhibitor) for patients with ALK NSCLC that have progressed on prior lines of therapy. The clinical benefit of lorlatinib is modest in previously-treated patients with a median PFS of 7 months (1). Mechanisms of lorlatinib resistance are diverse and include novel ALK mutations, compound ALK mutations, and activation of bypass pathways including AXL. Gilteritinib is a dual inhibitor of FLT3/AXL that is approved for relapsed/refractory FLT3+ acute myeloid leukemia (AML). Pre-clinical work using ALK fusion positive cell lines (including those containing compound mutations), patient-derived tumor cells, and in vivo mouse studies all demonstrate the anti-tumor activity of gilteritinib specifically against lorlatinib-resistant ALK NSCLC.
We will recruit patients with ALK NSCLC with progression on lorlatinib and collect patient-derived tumor samples. In addition to surgical, biopsy, or effusion fluid samples, plasma will be collected for isolation of circulating tumor DNA and circulating tumor cells. Whole exome sequencing (WES) will be used to identify molecular alterations that define resistance mechanisms. Ex vivo drug testing will be conducted using our existing platform and will include ALK inhibitors and inhibitors of pathways implicated in resistance such as AXL, MET, mTOR, and MAPK. Results of ex vivo drug testing will be correlated with findings from WES.
Simultaneously, we will open a phase I clinical trial to assess the safety and preliminary efficacy of gilteritinib in patients with lorlatinib-resistant ALK NSCLC. Crucially, clinical endpoints will be correlated with sequencing data and ex vivo drug testing results.
Despite advances in the development of RET inhibitors, patients with RET fusions eventually progress. Immunotherapy has been inefficient in patients harboring RET fusions. However, RET fusion proteins themselves may be immunogenic and give rise to an immune response. Dr. Reuben hypothesizes that RET fusions give rise to immunogenic antigens which can be effectively recognized and targeted by engineered T-cells. This project will identify which antigens can elicit an immune response. This information will be used to engineer customized T-cells to gain the ability to recognize those cancer cells that produce these RET fusion proteins. The ultimate goal is to offer new therapeutic alternatives by expanding the possibility of immunotherapy treatment in the overwhelming majority of NSCLC patients harboring RET fusions.
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.
Many RET-positive cancers become resistant to targeted therapy for reasons not clearly based on genetic changes alone. Dr. Drilon predicts that other causes of resistance include (1) chemical changes (in the “epigenome”) that turn cancer-causing genes on or off and (2) changes in how these cancers look under the microscope (“histology”) that affect cancer behavior. 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.
There is an urgent need to identify new agents or combination therapies to benefit patients whose tumors have developed resistance to current RET inhibitors. Currently, the true extent of RET-dependent (resistance mutations in the RET gene) versus RET-independent mechanisms of resistance is unknown. Dr. Heymach’s team will study mechanisms and biomarkers of RET-independent drug resistance and test different drug combinations to overcome RET inhibitor resistance.