Current Grants

Each year, LCRF selects a group of grant recipients that demonstrate promise and ingenuity in their work. After receiving seed funding from LCRF, these researchers are often better prepared to demonstrate proof of concept and secure additional funding from governmental and other sources.

Learn more about current grant recipients below.

2019 LCRF Research Grant on Disparities in Lung Cancer

Stanford University

Principal Investigator:

Manali Patel, MD, MPH

Research Project:

Reducing Disparities in Lung Cancer through Community Partnerships

Summary:

Scientific advances continue to reduce rates of new lung cancer cases and death from the disease. However, populations with low income as well as racial and ethnic minorities continue to experience high rates of lung cancer cases and lung cancer death. One potential cause for ongoing disparate outcomes from lung cancer includes inequitable receipt of evidence-based lung cancer care. Studies over the past decade repeatedly show lower receipt of stage-appropriate lung cancer care among low-income and minority populations as compared with non-Hispanic white and the more affluent. Previously, we demonstrated the role of social support in improving lung cancer survival for Hispanic populations and developed a novel approach, the CARE (Community health workers Activate, Reach, and Engage) intervention, to utilize social support to engage patients in their care and improve access to end-of-life cancer care for low-income and minority patients with advanced stages of cancer. The objective of this project is to refine, implement, and evaluate CARE with patients and caregivers in community oncology practices to increase access to evidence-based lung cancer recommendations from diagnosis until the end-of-life. The hypothesis is that this approach is feasible and acceptable in the community and can improve patients’ quality of life and reduce lung cancer outcome disparities.

University of Colorado Denver AMC

Principal Investigator:

Betsy C. Risendal, PhD

Research Project:

Improving Preventive Care to Address Lung Cancer Disparities

Summary:

National data suggest that only 4% of people who could benefit have received lung cancer screening, and that differences in the uptake of screening may further widen existing disparities in lung cancer survival. In pilot work funded by the Specialized Program in Research Excellence (SPORE) in Lung Cancer at the University of Colorado Cancer Center, significant barriers to implementing lung cancer screening programs were identified at the patient, provider and system-level. In the current project funded by the Lung Cancer Research Foundation, these barriers will be addressed by providing education, technical assistance and outreach to increase the uptake and delivery of this life-saving preventive screening.

2018 Lung Cancer Research Foundation Annual Grant Recipients

Icahn School of Medicine at Mount Sinai

Principal Investigator:

Jalal Ahmed, MD, PhD

Research Project:

Targeting the tumor microenvironment to advance CAR T cell therapy for lung cancer

Summary:

Lung cancer remains the leading cause of death from cancer. These data compel us to develop novel approaches to address this challenging disease. Chimeric Antigen Receptors (CAR) are engineered receptors that can redirect the killing activity of T cells to targets of interest and have had dramatic results in the treatment of B cell leukemia. However, the application of this technology to lung cancer remains challenging in part due to suppressive tumor microenvironments that are seen even at the earliest stages of disease. Early tumors are infiltrated with immunosuppressive cells including macrophages and T regulatory cells, and have a reduction in effector T cells. Furthermore, radiation therapy can alter tumor microenvironments and stun the growth of tumors. These observations raise the potential for a synergy from combination of radiation therapy and CAR T cell therapy to kill lung tumors. To test this hypothesis, Dr. Ahmed will use a genetic engineering protocol using CRISPR/Cas9 technology that can produce mouse CAR T cells with high efficiencies. This approach will allow him to test CAR T cells in a novel mouse model with an intact immune system and tumor microenvironment. He will use this model to determine if radiotherapy can modify the inflammatory state of the tumor microenvironment and improve CAR T cell killing of lung tumors. Ultimately, Dr. Ahmed hopes to demonstrate the potential of this CAR T cell-lung cancer platform to test novel combination therapies. In future work, he will apply this model to further dissect the ways in which the tumor microenvironment blocks attack from immune cells, to test new CAR T cell combination therapies, as well as to test the safety and efficacy of a multitude of novel CAR technologies that are under active development.

Dana-Farber Cancer Institute

Principal Investigator:

Chiara Ambrogio, PhD

Research Project:

Functional and Therapeutic role for RAS dimerization

Summary:

KRAS is one of the most commonly mutated oncogenes in human cancer, with selectively high frequency in tumors of the lung (30% of patients). KRAS mutant tumors are associated with poor prognosis, yet there are no effective therapies to specifically treat cancers expressing the KRAS oncogene. No direct inhibitor of mutant KRAS has been approved so far and first-line therapy for patients with advanced KRAS mutant disease remains systemic chemotherapy with associated toxicity and therapeutic limitations. Therefore, an urgent need remains for innovative and effective therapeutic strategies to improve outcomes for KRAS mutant cancer patients. Dr. Ambrogio focuses her research on KRAS dimerization, a recently discovered biological feature of KRAS which represents an actionable vulnerability for mutant KRAS. She will use genetic-defined tools to broaden the current understanding of the biology of KRAS in cancer with the ultimate goal of developing new therapeutic approaches for KRAS-driven cancers.

* This project was awarded the LCRF Scientific Merit Award acknowledging the investigator whose proposal was selected for outstanding overall merit by LCRF’s Scientific Advisory Board.

Stanford University

Principal Investigator:

Amruta Bhate, PhD

Research Project:

Investigating role of ADAR1 in improving cancer immunotherapy efficacy in lung adenocarcinoma

Summary:

Cancer immunotherapy drugs called checkpoint inhibitors are one of the most promising approaches for lung cancer treatment today. These drugs target proteins like PD-1, PD-L1, and CTLA-4, which put the ‘brakes’ on the immune response by repressing the ability of T-cells to recognize and kill cancer cells. Checkpoint inhibitors act against these proteins and enable the patient T-cells to ‘see’ the tumors and attack them. However, these therapies are truly effective only in a handful of lung cancer patients as tumors can develop resistance. Therefore, new strategies are needed to enhance the effectiveness of these checkpoint inhibitors. One such approach could be to activate innate immunity in the cancer cells that is elicited when immune cells detect certain pathogenic molecules and actively recruit T-cells to the tumor.

In this study, Dr. Bhate is investigating one such strategy which uses double-stranded RNAs (dsRNAs) present in the tumor cells itself to act as triggers to provoke a robust innate immune response in cancer cells. However, an RNA editing enzyme called ADAR1 can alter RNAs, so they become invisible to the immune system. ADAR1 expression is high in lung cancers, possibly muffling innate immune response. To that end, Dr. Bhate will develop mouse models to investigate genetic and biochemical details of whether silencing ADAR1 can unmask dsRNA and ‘prime’ tumor cells for an innate immune response. When used in combination with checkpoint inhibitors, this approach will help enhance the anti-tumor activity of immunotherapy drugs. This work will reveal how the presence of dsRNAs affect tumor microenvironment and immune response, and whether inhibition of ADAR1 is a feasible therapeutic avenue for lung cancer treatment.

Dana-Farber Cancer Institute

Principal Investigator:

Israel Cañadas Castillo, PhD

Research Project:

Co-opting endogenous retroviral signaling as a lung cancer vulnerability

Summary:

Both small-cell and non-small cell lung cancers contain different subpopulations of cancer cells, a feature known as tumor heterogeneity. While this cell heterogeneity is a key determinant of cancer progression and drug resistance, how it impacts the immune system in lung cancer patients remains incompletely defined. Dr. Cañadas recently identified a group of genetic elements known as Endogenous Retroviruses (ERVs) that are altered in certain drug-resistant populations of lung cancer cells. He showed that signaling from these ERVs promotes tumorigenesis, but that these retroviruses can also make cancer cells vulnerable to immunotherapy.

This project seeks to study the biology that connects this drug-resistant cancer cell state in lung cancer to the activation of these ERVs, and to use these insights to develop therapeutic strategies that enhance response to immunotherapy. Dr. Cañadas aims to perform genetic screens to identify regulators that control these ERVs in drug-resistant lung cancer cells. Ultimately, the use of a novel 3D culture technology using human lung cancer specimens will allow him to determine the most effective therapeutic combinations that promote responsiveness to immunotherapy. The proposed strategy addresses a key unmet need in the field in an effort to overcome resistance to immunotherapy due to intratumoral heterogeneity.

Rutgers Cancer Institute of New Jersey

Principal Investigator:

Yanxiang Guo, MD, PhD

Research Project:

Elucidating the mechanism of autophagy in supporting Lkb1-deficient lung tumorigenesis

Summary:

Lung cancer remains the leading cause of cancer death worldwide and non-small cell lung cancer (NSCLC) accounts for more than 85% of these cases. Patients harboring mutations in the tumor suppressor liver kinase B1 (LKB1) and the oncogene KRAS, two of the most common mutations in NSCLC, develop more aggressive lung tumors and have limited treatment options. Thus, new therapies for this subtype of lung cancer are urgently needed.

Sufficient energy production is indispensable for tumor growth, and cancer cells have distinct metabolism compared to normal tissues. Thus, targeting cancer metabolism has recently been considered a very important approach to cancer treatment. The catabolic process of autophagy is a protective process that is activated in order to recycle cellular components to maintain energy homeostasis when extracellular nutrients are limited. Using mouse models for LKB1-deficient KRAS-mutant NSCLC, Dr. Guo found that autophagy ablation reduced the frequency of tumor initiation, inhibited tumor growth and extended tumor bearing mouse life span. In this project, Dr. Guo will further elucidate the underlying mechanism by which autophagy maintains energy homeostasis for LKB1-deficient KRAS-mutant lung tumorigenesis using mouse models, metabolomics, lipidomics, quantitative metabolic flux analysis and combination thereof. The overall goal of this project is to find new therapeutic approaches that can be used to effectively treat LKB1-deficient KRAS-mutant NSCLC.

Vanderbilt University

Principal Investigator:

Amanda Kussrow, PhD

Research Project:

High sensitivity assay methodology to improve lung cancer diagnosis

Summary:

Diagnosis of lung cancer presents a significant challenge, resulting in morbidity and management costs of $28 billion/year in the U.S. Current methods to diagnose lung cancer have limitations that result in a high rate of unnecessary procedures, can cause patient anxiety, or even result in missed chances for cure, resulting in death. Here it was possible to significantly improve the diagnostic potential of a blood-based circulating tumor marker, CYFRA 21-1, by using a new assay and detection methodology that provides increased sensitivity over existing techniques. When applied to a 225 patient cohort, the increased performance of the assay allowed discrimination of cancer from non-cancer patient samples that were indistinguishable by current methods. The assay is a mix-and-read approach that is rapid, label-free, and requires only a drop of serum for a determination. The reader is quite simple, having an optical train similar to a CD player, consisting of a diode laser, capillary tube, and camera. This project will further explore the performance of the CYFRA 21-1 biomarker in a larger patient cohort, investigate the diagnostic value of incorporating two additional target biomarker assays (CA-125 and CEA), and refine the assay methodology to make it compatible with the near-patient setting.

The University of Texas MD Anderson Cancer Center

Principal Investigator:

Pawel Mazur, PhD

Research Project:

Mechanisms of protein synthesis regulation in lung cancer

Summary:

A major unmet need for lung cancer treatment is the identification of new therapeutic targets, which requires elucidating the critical genes and signaling pathways driving this disease. Dr. Mazur's research strategy directly addresses these priorities by proposing to identify a new target for which drugs can be rapidly developed. Specifically, this project tests the idea that a class of enzymes named “lysine methyltransferases” (KMTs) plays a key role in promoting cancer. KMTs are enzymes that add methyl groups to lysine residues on other proteins. Methylation of proteins in cancer can modify their activity to promote tumor growth. Importantly, KMTs can be inhibited by small molecules and thus constitute ideal targets for drug development. Surprisingly, however, little to nothing is known about the role of over 100 KMTs in cancer.

Dr. Mazur's study identifies new KMT that regulates the most energy-consuming process in the cell – protein production. Dysregulation of protein production is a hallmark of cancer and is linked to aberrant cell proliferation, survival, and alterations in both immune responses and cancer energetics. While several key molecules involved in protein synthesis were found to be methylated in cancer, the role of lysine methylation in calibrating protein production remains untested. Knowledge into the regulation of protein production by methylation may also uncover a new paradigm for how crosstalk between major signaling systems is integrated to modulate critical cellular behaviors. Thus, identifying reversible molecular mechanisms such as methylation that stimulate protein production in tumors may uncover opportunities to target specific lung cancer vulnerabilities with minimal off-target toxicity.

Wake Forest University Health Sciences

Principal Investigator:

Chandylen Nightingale, PhD, MPH

Research Project:

Caregiver Oncology Needs Evaluation Tool (CONNECT): A technology-based intervention to connect lung cancer caregivers with supportive care resources

Summary:

Lung cancer affects not only the patients who are diagnosed, but also their informal / unpaid family members who provide care. Lung cancer caregivers may face many challenges when tending to patients’ care needs and are at risk for poor mental and physical health. Caregivers who cope well and tend to their own needs may provide better care for patients. Although some supportive care resources are available to address lung cancer caregivers’ needs and challenges (such as depressive symptoms, financial problems, and health behaviors), health care systems often fail to connect caregivers with these resources. Dr. Nightingale's study will test a technology-based intervention (Caregiver Oncology Needs Evaluation Tool; CONNECT) with 40 lung cancer caregivers. CONNECT is designed to empower and educate caregivers about the importance of self-care and benefits of supportive care resource use, identify unmet needs, and connect caregivers with resources, based on each caregiver's specific needs. The study will primarily focus on assessing feasibility of CONNECT and caregivers’ acceptability of CONNECT. Data will also be collected on additional outcomes for caregivers (e.g. use of services, anxiety and depression) as well as the patients they are caring for (e.g. unplanned hospitalizations, physical well-being).

University of Utah

Principal Investigator:

Trudy Oliver, PhD

Research Project:

Arginine deprivation as a novel therapy for MYC-driven small cell lung cancer

Summary:

Small cell lung cancer (SCLC) is a highly aggressive, neuroendocrine type of lung cancer with limited treatment options beyond chemotherapy. Historically, SCLC has been treated as a single disease, but recent work by Dr. Oliver's lab and others suggests that it is comprised of at least two subtypes that each respond differently to therapy. The Oliver Lab recently found in human cell lines and mouse models that depletion of the amino acid arginine is an effective treatment against one subtype of SCLC. Using mouse models, they tested a drug called ADI-PEG20 that is currently in clinical trials and works by depleting arginine from the body. Importantly, ADI-PEG20 treatment was more effective than combination chemotherapy with less toxicity, and it appeared to stimulate the immune system. The goal of this project is to extend these findings by testing ADI-PEG20 in a panel of human tumors using patient-derived xenograft (PDX) models. Second, the Oliver Lab will study how ADI-PEG20 impacts the immune system and whether it combines with immunotherapy for a greater impact on tumor burden and survival.

* * This project was awarded the LCRF William C. Rippe Award for Distinguished Research in Lung Cancer, acknowledging the investigator whose proposal not only demonstrated exceptional scientific merit but also exemplified an enduring commitment to making an impact in the field of lung cancer research.

The University of Texas MD Anderson Cancer Center

Principal Investigator:

Xiaochao Tan, PhD

Research Project:

Targeting chromosome 1q21.3-amplified lung cancer using PI4KB antagonists

Summary:

Lung cancer cells secrete proteins that maintain their survival and enhance their metastatic activity. Clinical trials designed to inhibit secretion by utilizing neutralizing antibodies or decoy receptors against secreted proteins have been largely unsuccessful, which is not surprising given the functional redundancy of secreted protein networks. Addressing this issue will require the identification of actionable targets positioned proximally within the secretory pathway. In work funded by the Lung Cancer Research Foundation, Dr. Tan has shown that secretion is pharmacologically actionable at the level of the Golgi apparatus, an intracellular organelle that sorts, packages, and ships proteins to the cell membrane for secretion into the extracellular space. Her group will test the anti-tumor activity of drugs that inhibit PI4KIIIβ, an enzyme that drives protein packaging in the Golgi. These drugs are currently being developed as anti-viral agents for individuals infected with deadly viruses such as hepatitis and Ebola virus. On the basis of their finding that PI4KIIIβ inhibitors preferentially kill lung cancer cells with a specific genetic mutation, they will test PI4KIIIβ inhibitors in mice bearing lung cancers with that mutation and see whether the drugs are safe to administer and cause tumor regression. If they do, these findings will provide a foundation for clinical trials utilizing PI4KIIIβ inhibitors to inhibit secretion in lung cancer.

Stanford University

Principal Investigator:

Diane Tseng, MD, PhD

Research Project:

Examining tumor-infiltrating T cell functional phenotype, clonality, and antigen specificities in lung adenocarcinoma with single-cell analysis

Summary:

Immunotherapy has revolutionized the treatment of lung cancer. However, not all patients respond to treatment. A deeper understanding of the interaction between the human immune system and lung cancer is critical to improve existing therapies and to discover more effective treatments. To this end, Dr. Tseng aims to comprehensively profile the diversity of tumor-infiltrating T cells from patient lung cancer samples. T cells are immune cells that can mediate an anti-tumor response, a property that can be leveraged therapeutically. First, Dr. Tseng will adapt a novel single-cell methodology to simultaneously examine T cell specificities and functional state at unprecedented resolution. This approach will generate a map reflecting T cell diversity in lung cancer, which she will use to identify novel therapeutic targets expressed on T cells. Second, using T cell receptor sequences derived from lung cancer patients, she will apply novel methods to screen for tumor antigens that are shared across individuals. This approach will allow her to identify novel therapeutic targets displayed by cancer cells. This project will provide important insights into the basic biology of T cells in lung cancers as well as potentially identify novel immunotherapeutic targets for patients with lung cancer.

Fred Hutchinson Cancer Research Center

Principal Investigator:

Athea Vichas, PhD

Research Project:

Targeting oncogenic RIT1 and KRAS in lung adenocarcinoma

Summary:

Today, treatment of lung cancer is evolving from standard cytotoxic to personalized treatment based on the DNA mutations present in the tumor of each patient. Recent DNA sequencing studies of lung cancer patients have identified mutations in the gene RIT1. This gene is very similar to the most commonly mutated gene in lung cancer, KRAS. Mutations in KRAS or RIT1 are found in over 30% of lung cancer patients, accounting for almost 29,000 patients diagnosed per year. Currently, lung cancer patients with mutations in RIT1 or KRAS have few therapeutic options.

In collaboration with the Drug Repurposing Hub at the Broad Institute, Dr. Vichas will use a high-throughput drug screening platform to screen 5,349 drugs, of which 4,045 have been or are currently being tested in human clinical trials for the ability to inhibit RIT1 or KRAS mediated cell growth. Drug repurposing aims to identify new therapeutic uses for existing drugs, providing rapid clinical impact at a much lower cost than new drug development. Dr. Vichas will validate the efficacy of these drugs in RIT1 and KRAS mouse models, which will provide valuable pre-clinical data that could translated into clinical trials. This research has the high potential to discover therapeutic options for patients with lung cancer and radically change disease management for a group of patients urgently in need of effective therapies.

Massachusetts General Hospital

Principal Investigator:

Satoshi Yoda, PhD

Research Project:

Tailoring treatment for ALK-positive lung cancer

Summary:

The development of targeted therapies represents one of the most significant successes of cancer research over the past several decades. For lung cancer patients whose tumors harbor the EML4-ALK fusion gene, ALK-targeted therapies have significantly extended survival and improved quality of life. Unfortunately, the inevitable development of drug resistance limits their benefit and eventually causes disease relapse. Recent results have revealed that lung cancer patients with different variants of the EML4-ALK fusion gene develop different types of resistance mechanisms after treatment with ALK inhibitors. In this project, Dr. Yoda will study cancer cell lines and mouse xenograft tumors established from EML4-ALK lung cancer patients to determine the biological features of different EML4-ALK variants that lead to different resistance mechanisms. These experiments will yield insights that will Dr. Yoda and his team to develop and test new treatments specifically tailored for different EML4-ALK variants. Ultimately, they hope to directly apply these results to optimize cancer treatments in the clinic.