Enter your search term above.

Our Investigators

Each year, LCRF awards research grants to around the world that demonstrate promise and ingenuity in their work. These investigators, selected from hundreds of applicants, represent some of the brightest minds committed to improving outcomes for lung cancer patients. Coming from various career paths including scientists, physicians, students, and fellows, and working on a variety of innovative research projects related to lung cancer, we are proud to include them in our portfolio of currently funded projects, which you can learn more about below. View our full portfolio of previously funded research here.

2019 LCRF Pilot Grant Program

Alice Berger

Alice Berger, PhD

Fred Hutchinson Cancer Research Center

RESEARCH PROJECT:

Novel strategies for therapeutic target discovery in lung cancer

SUMMARY:

Recent advances in understanding the human genome have led to successful new “precision oncology” for the treatment of lung cancer, such as the use of EGFR-targeted therapies in EGFR-mutant lung cancer. The discovery and application of these therapies has motivated a continued search for novel drug targets in these and other lung cancers. The foundation of these searches are high-throughput methods for genetic screening. However, traditional target discovery experiments can only query a single gene’s involvement in cancer. Some genes with redundant functions would not be identified in these traditional studies. The goal of this project is to identify genetically redundant genes in the human genome and to identify gene pairs that are required for resistance to EGFR-targeted therapies.

This work will directly help the tens of thousands of patients with EGFR-mutant non-small cell lung cancer. Increasingly, genomic information leads to “repurposing” of drugs developed for other diseases. If drugs already exist for some of the targets that are identified in our study, they can be repurposed for lung cancer therapy, and our work could positively impact lung cancer patients in less than five years. If therapies do not already exist, our work will provide the preliminary evidence that these genes/proteins would be worth investment from pharmaceutical companies, thereby serving a vital role of academic research and promoting the development of new lung cancer therapies.

Lingtao Jin, PhD

University of Florida

RESEARCH PROJECT:

The role of protein kinase signaling in cisplatin-resistant ASCL1-high subtype SCLC

SUMMARY:

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Due to very limited improvements in SCLC therapy or survival over the past 30 years, SCLC has been categorized as a recalcitrant cancer. Platinum-based chemotherapies, which are the standard of care for SCLC patients, usually lead to a robust initial clinical response, but the majority of patients quickly become resistant to therapy. Therefore, identification of critical factors responsible for the emergence of resistance to chemotherapy will not only provide personalized treatment options, but also help to identify cancer patients who may or may not benefit platinum-based chemotherapies. Dr. Jin’s lab recently found that a protein called MAST1 promotes the development of resistance to platinum treatment in SCLC. They found that MAST1 abundance correlates with platinum resistance in SCLC cell lines and patient tumors. Initial studies suggest that MAST1 may regulate cancer cell cycle progression and increase cancer cell survival ability in response to platinum treatment. Therefore, it is important to further decipher the role of MAST1 signaling in driving platinum resistance. In addition, Dr. Jin’s group will validate MAST1 as a therapeutic target to overcome platinum resistance. They found that a drug called CEP-701, which inhibits MAST1 activity, is effective in killing small cell lung cancer cells when combined with platinum. They will further evaluate the efficacy of CEP-701/platinum combination therapy in small cell lung cancer cell lines and animal models, and develop next generation of MAST1 inhibitors that may be used to treat platinum-resistant small cell lung cancer.

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

Benjamin Lok, MD

Princess Margaret Cancer Centre / University of Toronto

RESEARCH PROJECT:

Investigating a resistance mechanism mediated by a Skp, Cullin, F-box containing E3 ubiquitin ligase complex in small cell lung cancer

SUMMARY:

Small cell lung cancer (SCLC) is a particularly aggressive subtype that represents approximately 15% of all lung cancers. Despite an initial response of SCLC to therapy, disease recurrence often occurs, and cure is rare, with dismal 5-year overall survival rates of about 7%. There is a critical need to understand the mechanisms of therapeutic resistance to develop more effective treatments for this disease. We have found that loss of a key component of a protein recycling complex leads to resistance to chemotherapy and a newer therapy, known as a PARP inhibitor, in SCLC. Here, we propose to understand more about how this protein recycling complex regulates DNA repair through experiments to precisely determine its impact on DNA damage and repair. Through these efforts, we seek to further our understanding of how cancer cells repair, tolerate and become resistant to our current treatments while designing newer treatment approaches to improve outcomes for our patients.

* * This project was awarded the 2019 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.

Zhan Yao, PhD

Memorial Sloan Kettering Cancer Center

RESEARCH PROJECT:

Studies on the oncogenic function and mediation of drug resistance by ARAF in lung cancer

SUMMARY:

Despite the significant clinical benefit of epidermal growth factor receptor (EGFR, a receptor tyrosine kinase) inhibitors, primary and acquired resistance are commonly seen in lung cancer patients with EGFR activating mutations. Among those patients, ~20% tumors progress upon treatments by unknown mechanisms. By analyzing the genome sequencing data of the lung cancer patients with acquired resistance to EGFR inhibitors, Dr. Yao and his colleagues at MSKCC identified ARAF amplification as a new genetic event that may be responsible for the drug resistance. They observed that ARAF could activate RAS, a major effector of EGFR, through disrupting the binding of NF1 (a negative regulator of RAS) to it. Thus, the elevation of ARAF protein in cells could promote the RTK-mediated RAS activation and the downstream pathways that are required for cell proliferation or differentiation. Current data suggest, in EGFR mutant lung tumors, ARAF amplification likely causes the drug resistance by activating RAS signaling. Dr. Yao seeks to explore the detail functional consequences of ARAF activation of RAS in lung cancers and determine its role in the regulation of drug sensitivity. In addition, patient-derived xenograft models will be used to investigate therapeutic strategies for treating the ARAF-dependent drug resistance.

2019 LCRF Research Grant on Disparities in Lung Cancer

Melinda Aldrich, PhD, MPH

Vanderbilt University Medical Center

RESEARCH PROJECT:

Identifying determinants of racial disparities in lung cancer stage

SUMMARY:

Racial disparities in lung cancer stage of diagnosis are well-documented. Fewer African Americans than whites are diagnosed at early-stage lung cancer, when better treatment options are available. Studies in patients seeking care at community health centers are limited and as a result, the causes of disparities in stage among the most vulnerable patients are poorly understood. This project will provide a deeper understanding of which factors influence lung cancer stage of diagnosis among community health center patients and provide outreach to the community about the importance of early detection for lung cancer.

Manali Patel, MD, MPH

Stanford University

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.

Betsy C. Risendal, PhD

University of Colorado Denver AMC

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.

Rajwanth Veluswamy

Rajwanth Veluswamy, MD, MSCR

Icahn School of Medicine at Mount Sinai

RESEARCH PROJECT:

Assessing the mechanisms underlying the association between sex and immunotherapy response

SUMMARY:

Recently, immune checkpoint inhibitors have become a mainstay in the treatment of advanced non-small cell lung cancer (NSCLC) after demonstrating unprecedented clinical activity in several large clinical trials. However, data from a systematic analysis of these trials suggest that females may have less response to immune checkpoint inhibitors than experienced by males. If validated, this finding will highlight the need to explore new immunotherapy regimens specific for women. Furthermore, understanding differences in immunotherapy efficacy amongst females vs. males may also reveal important underlying mechanisms of therapeutic immunity and potentially even provide targets for future synergistic immunotherapy combinations. This proposal intends to use advanced statistical modeling and cutting-edge laboratory techniques to 1) determine if female sex is independently associated with decreased immunotherapy efficacy in patients with advanced lung cancer, 2) determine if differences in the pre-treatment composition of the tumor immune microenvironment (TIME) is responsible for the association of sex and immunotherapy, and 3) study the role of hormones such as estrogen as a mediator in the relationship between sex and immunotherapy response. Elucidating these potential important mediators of immunotherapy response will have significant implications in guiding the treatment and future study of immunotherapy in lung cancer.

2019 Lung Cancer Treatment Focused Research Grant Program

Ryan Gentzler, MD

University of Virginia

RESEARCH PROJECT:

Real-time monitoring and modeling of symptoms and adverse events in lung cancer patients receiving oral targeted therapies for tumors with oncogenic driver mutations

SUMMARY:

Over the past few years there have been many new oral treatments that have become standard of care for patients with lung cancers that have certain genetic mutations or gene rearrangements, such as EGFR or ALK. Although these treatments are usually better tolerated than traditional chemotherapy, management of the adverse events (AEs), or side effects, has become more complex for treatment providers. Unrecognized side effects can progress to severe symptoms and drug discontinuation, which could affect quality of life and other cancer outcomes. Real time and accurate symptom monitoring may allow for earlier interventions to reduce severity of symptoms, improve quality of life, and avoid drug discontinuations or dose reductions. This project proposes to address this problem by developing a technology-enabled mechanism to both aid patients in self-reporting of symptoms and clinicians in optimizing therapeutics for patients with molecularly-driven lung cancers on oral targeted therapies. We will gather data to test the feasibility of a mobile health system for remote monitoring of patients on oral targeted therapies for EGFR and ALK lung cancers.  The system will use software on smart phones and smart watches with the goal of estimating the frequency of side effects in a real-world, non-trial setting. In the future, we hope this system could improve monitoring and may reduce the severity of side effects, promote long-term treatment adherence, and improve patient reported quality of life (QoL) measures.

Nisha Mohindra, MD

Northwestern University Feinberg School of Medicine

RESEARCH PROJECT:

Development and implementation of 4R care sequences in patients with NSCLC receiving targeted therapies

SUMMARY:

This project’s overall goal is to implement the systematic and innovative approach for care planning and delivery to improve side effect management, treatment adherence and supportive care for patients with non-small cell lung cancer (NSCLC) receiving targeted therapies. The improvement will be achieved via the 4R Care Sequence plans that will be used by patients, their caregivers and their care team. The 4R (Right Information and Right Treatment to the Right Patient at the Right Time) model is an innovative approach to personalized cancer care planning, team-based care delivery and patient / caregiver self-management. 4R uses project management principles to create a personalized, comprehensive, patient-specific “care project plan” called 4R Care Sequence. The 4R Care Sequence plan outlines the order and timing of treatment, side effect management, supportive services, chronic disease / comorbidity management, nutrition services, and quality of life, while incorporating the patient’s goals and preferences. The 4R Care Sequence plan is used by patient / caregiver and multi-disciplinary care teams as a comprehensive care pathway, with the purpose to optimize care delivery, outcomes of treatment and patient’s quality of life, while minimizing treatment side effects and comorbidities.

Katharine Rendle, PhD, MSW, MPH

University of Pennsylvania

RESEARCH PROJECT:

Implementation strategies for monitoring adherence in real-time (iSMART)

SUMMARY:

(Awarded with Samuel U. Takvorian, MD, MSHP) The objective of this project is to identify effective strategies to help patients with lung cancer manage side effects and achieve optimal adherence to oral targeted therapies. To achieve this goal, we will evaluate the impact of a novel digital intervention (“chatbot”), compared to usual care, on adherence to oral targeted therapies using a two-arm randomized controlled trial, and explore how multilevel factors impact the acceptability and effectiveness of this strategy by collecting qualitative and quantitative data from clinicians and patients. The intervention is a conversational agent or chatbot that engages patients in real time via text messaging and feeds data back into clinical systems, allowing for two-way communication between clinicians and patients, longitudinal symptom monitoring with self-management support, and motivational cues to promote adherence. Guided by established theory of behavior change, we hypothesize the chatbot will improve adherence to oral targeted therapies by improving patient-level symptom management and other determinants of behavior change. Primary outcomes (adherence and persistence) will be measured using electronic pill caps. Secondary outcomes will be assessed using longitudinal surveys and electronic medical record data. Semi-structured interview data will also be collected from a subsample of 60 patients and clinicians following the intervention period. By combining innovations from behavioral economics and machine learning with a highly accessible digital platform, our project has the potential not only to identify scalable, patient-targeted strategies for improving symptom management and increasing adherence to targeted therapies, but also to transform the way cancer care is delivered and implemented.

Christian Rolfo, MD, PhD, MBA

University of Maryland, Baltimore

RESEARCH PROJECT:

Proactive monitoring of treatment-related adverse events through a mobile application in NSCLC patients treated with tyrosine kinase inhibitors: the “Empower Me” Digital Therapeutic Study

SUMMARY:

Targeted therapies have dramatically changed the therapeutic landscape of non-small cell lung cancer (NSCLC) over the past two decades leading to unprecedented results in selected patient populations. This novel therapeutic option is associated with a distinct toxicity profile that is, in many ways, different from toxicities commonly observed with conventional anticancer therapies. In selected cases, these toxicities can be severe and might affect compliance of the patients to the treatment regimen, including discontinuation of definitive therapy. In this study we will evaluate the potential impact of a proactive monitoring of treatment-related adverse events through a mobile application in NSCLC patients treated with tyrosine kinase inhibitors (TKIs). The APP will provide a simple, user-friendly interface to foster easy and efficient patient-provider communication. The implementation of an easy to use app and web-based communication will minimize dose limiting side effects with the use of TKIs in lung cancer.  This will enable the patient to receive the anticancer therapy in the correct dose, frequency and without breaks in treatment.

2018 LCRF Scientific Grant Program

Jalal Ahmed, MD, PhD

Icahn School of Medicine at Mount Sinai

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.

Chiara Ambrogio, PhD

Dana-Farber Cancer Institute

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.

Amruta Bhate, PhD

Stanford University

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.

Israel Cañadas Castillo, PhD

Dana-Farber Cancer Institute

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.

Amanda Kussrow, PhD

Vanderbilt University

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.

Pawel Mazur, PhD

The University of Texas MD Anderson Cancer Center

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.

Chandylen Nightingale, PhD, MPH

Wake Forest University Health Sciences

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).

Trudy Oliver, PhD

University of Utah

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 2018 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.

Xiaochao Tan, PhD

The University of Texas MD Anderson Cancer Center

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.

Diane Tseng, MD, PhD

Stanford University

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.

Athea Vichas, PhD

Fred Hutchinson Cancer Research Center

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.

Satoshi Yoda, PhD

Massachusetts General Hospital

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.

2017 LCRF Scientific Grant Program

Ashley Bakhoum, PhD

Weill Cornell Medicine

RESEARCH PROJECT:

Targeting metastasis-initiating cells in lung adenocarcinoma

SUMMARY:

Most cancer deaths are caused by metastasis – the recurrence of disease in organs distant from the primary tumor site. Cancer cells may leave the primary tumor and spread throughout the body very early in disease progression, even before a patient’s initial diagnosis and treatment. A subset of cells that survive the stress of spreading to a new environment may lie dormant for months to years before initiating a metastatic outgrowth. They are stem-like and often resist anti-cancer therapies, which primarily target dividing cells. The biology underlying these metastasis-initiating cells in lung cancer is poorly understood. This proposal utilizes single-cell sequencing and multiplexed imaging approaches to identify where these metastasis-initiating cells reside and how they survive, evolve, and continuously evade detection by our innate immune defense system. A major problem facing the treatment of lung cancer is the emergence of metastasis or drug resistance arising from tumor cell heterogeneity. By tackling single cell heterogeneity head-on, this proposal aims to transform how we define, think about, and treat lung cancer – ultimately, to develop therapies that may eradicate or control metastasis from its earliest stages of inception. 

Amy Davidoff, PhD

Yale University

RESEARCH PROJECT:

Patterns of palliative care and concurrent therapy for lung cancer at end-of-life: implications for quality

SUMMARY:

This study will examine patterns of care during the final six months of life for Medicare beneficiaries who died from lung cancer. We will focus on the types of palliative care services received during this period, and the relationship to ongoing cancer-directed treatment, such as chemotherapy or radiation therapy. Palliative care is designed to manage symptoms of cancer and the side effects of treatment, and to reduce emotional distress for patients and families. While hospice has been a key provider of palliative care services, we will assess the extent to which palliative care is provided outside of the hospice setting. Several studies have suggested that early palliative care is associated with more patient-centered and less aggressive treatment at the end-of-life. Our study will examine this issue using a large, population-based dataset that includes almost 30% of Medicare beneficiaries. The results of this study will provide critical information on the current landscape of palliative care receipt and Medicare spending outside of hospice, and receipt of concurrent cancer-directed therapy. This research will allow refinement of quality measures related to end-of-life care. In addition, this research will help to guide development of new approaches to pay for palliative care within the Medicare program.

Khinh Ranh Voong, MD, MPH

Johns Hopkins University

RESEARCH PROJECT:

SPARC: Studying the Pathologic and Immunologic Response after Ablative Radiation in Stage I Non-Small Cell Lung Cancer

SUMMARY:

Stereotactic ablative radiation (SABR) is a non-invasive treatment option for patients with early stage lung cancer where surgery is either not wanted or not possible. An alarming 30-40% of early stage lung cancer patients treated with SABR may have their cancer come back in other areas of the body in their lifetime. This is in part why lung cancer is the leading cause of cancer death in the United States. This study aims to clarify how ablative radiation may spark the body’s own immune system to better recognize and attack cancer cells. This study will look at immune changes that happen within the treated cancer and in the blood after having received ablative radiation.  Next, it will see if killed pieces of cancer that are released after SABR may be seen by the immune cells found elsewhere in the blood. Lastly, the study will test a new way to see the cancer treatment response using a special CT scan. The study hopes to allow doctors to better understand the immune changes that happen after ablative radiation, so that better treatments that uses the body’s own immune system to fight cancer may be given with ablative radiation to improve cancer kill.

2016 LCRF Scientific Grant Program

Yasir Elamin, MD, MAS

The University of Texas MD Anderson Cancer Center

RESEARCH PROJECT:

Identification and targeting primary resistance mechanisms in lung cancer patients with EGFR mutations

SUMMARY:

Mutations in the EGFR gene can drive lung cancer cells growth, survival and spread. Patients whose tumors contain these mutations can benefit substantially from targeted therapy with an EGFR inhibitor. Unfortunately, a subset of these patients do not respond to EGFR inhibitors. Dr Elamin’s study will focus on this group of lung cancer patients with primary resistance to currently available EGFR inhibitors. Specifically, he will study a novel EGFR inhibitor with promising activity in lung cancer patients. Working with a group of clinicians and scientists, they will analyze DNA, RNA and protein obtained from patients treated within a clinical study of this novel EGFR inhibitor. The team will then determine the mechanisms by which lung cancer cells evade treatment. They will also study potential resistance mechanisms and treatment strategies that may overcome resistance in mouse models. The overall goal of this study is provide EGFR mutant lung cancer patients with a new effective treatment option.

Dan Raz, MD, MAS

City of Hope Cancer Center

RESEARCH PROJECT:

Incorporating lung cancer screening education into tobacco cessation counseling

SUMMARY:

As lung cancer develops, it has to escape detection and elimination by the immune system. New drugs that reverse this, and allow the immune system to better attack a growing cancer, are under intense investigation. Early data shows that such treatment, termed immunotherapy, is very effective in many lung cancers.

Lung cancer screening (LCS) with low dose radiation computed tomography (LDCT) substantially reduces lung cancer mortality and is recommended by the US Preventive Services Task Force (USPSTF) and many other medical organizations. Despite this, few eligible patients are being screened for lung cancer. Although the number of patients screened for lung cancer is low, hundreds of thousands of smokers seek tobacco cessation services nationwide annually. Tobacco cessation counseling may be an important opportunity to educate and counsel eligible patients on LCS with LDCT. We seek to understand the perceptions of lung cancer screening among patients in a large regional tobacco cessation program, and to study the effect of LCS education on tobacco cessation rates and LDCT utilization in a tobacco cessation group-class setting. To accomplish these objectives, we will first administer a brief survey on lung cancer risk perception, knowledge of lung cancer screening, and barriers to LCS in patients who meet eligibility criteria for LCS who have recently enrolled in tobacco cessation counseling in Southern California Kaiser Permanente. Next, we will incorporate LCS information into tobacco cessation group-classes in selected Southern California Kaiser Permanente sites and study the effects of this educational intervention on tobacco cessation and utilization of LDCT for LCS at 6 months. These data are important so that we can determine if education on LCS during tobacco cessation impacts tobacco cessation and whether there is an effect on LCS utilization.

2016 Metastatis Research Grant

Chad Pecot

Chad Pecot, MD

The University of North Carolina at Chapel Hill

RESEARCH PROJECT:

Targeting lung squamous metastasis with CCR2 inhibitors

SUMMARY:

While targeted therapies of lung adenocarcinoma have improved patient survival, similar advances in lung squamous carcinoma (LUSC) have been stagnant. Recent analyses of the genes that characterize LUSC have revealed they are highly idiosyncratic tumors with no clear “smoking gun” drug target. Recently, however, the use of new therapies that activate the immune system has demonstrated remarkable promise in LUSC.

We have uncovered a previously unrecognized group of LUSC patients whose tumors manipulate the immune system for its own advantage. Remarkably, this group accounts for nearly half of all LUSC patients. Through extensive analysis of the Cancer Genome Atlas (TCGA), as well as through novel cancer models we have developed, we found that LUSC metastasis are driven by immune cells called monocytes.

Here, we hypothesize that (i) blocking monocytes in LUSC will stop its spread and will be synergistic with already proven immune therapies, (ii) a gene signature we have developed will determine who will benefit from immune therapies, and (iii) that proteins in LUSC tumors will establish a biomarker of patients likely to respond to drugs blocking monocytes. The objectives of this proposal are 1) to determine the therapeutic role of targeting monocytes in LUSC, alone or in combination with a proven immune therapy, and 2) to develop predictive biomarkers of response to these novel immune therapies, which will be useful for design of an already planned Phase II clinical trial.

2015 Metastasis Research Grant

Brendon Stiles, MD

Weill Cornell Medical College

RESEARCH PROJECT:

ART1: a novel therapeutic target for the prevention of metastases from non-small cell lung cancer

SUMMARY:

ART1 is a protein expressed on the surface of lung cancer cells. Although it has not been previously described to play a role in lung cancer, similar proteins provide the mechanism for pathogenic bacteria to invade and take over normal cells.  We believe cancer cells utilize ART1 in a similar fashion to activate or inactivate proteins made by other cells in the local microenvironment, in particular to avoid death induced by cells of the immune system.  In this project, we hope to determine what types of lung cancers express ART1 and to understand how ART1 facilitates the metastatic spread of cancer. We will demonstrate how cells with and without ART1 interact with other cells in the immune microenvironment and determine what proteins expressed by those cells are functionally altered by ART1 expression on the cancer cells.  In patients, we believe that blocking ART1 expression will allow for destruction of the cancer cells by the patient’s own immune system.  Several drugs that inhibit ART1 are already in use clinically, although they have never before been specifically targeted to ART1 over-expressing tumors.  We plan to evaluate those and other drugs in laboratory studies and in mouse models for their ability to overcome ART1-mediated metastasis formation.  Because many of the drugs are already used safely in patients, we anticipate a quick turn-around time to begin clinical trials in human patients with ART1 over-expressing tumors.