Enter your search term above.

Current Funded Projects

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.

2020 LCRF Pilot Grant Program

2020 James B. Dougherty, MD Award*

Michael Zimmermann, PhD

European Molecular Biology Laboratory

Watch Dr. Zimmerman accept his award during LCRF’s 15th Anniversary Celebration.

RESEARCH PROJECT:

Identifying risk factors for lung cancer predisposition through systematic evaluation of environmental carcinogens’ activation by the respiratory tract microbiota

* 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.

SUMMARY:

The human body harbors trillions of microbes (known as the human microbiome), which collectively encode many more genes than the human genome. Furthermore, the variation between individuals’ microbial communities drastically exceeds human genome variability. These microbial communities colonizing different body surfaces play an essential role in human health and response to environmental factors. Numerous studies have linked changes in the microbiota composition to different diseases, such as the metabolic syndrome and cancer. Based on these observations and the fact that lung cancer prevalence was linked to altered respiratory tract microbiome compositions, we hypothesize that microbial strains with certain metabolic traits can be identified as predisposition risk factors for lung cancer.

Prominent risk factors for cancer development are environmental carcinogens (e.g., in cigarette smoke), and many of these chemicals require metabolic activation in the human body. While such activation is classically associated with human enzymes, recent studies have demonstrated that human-associated microbes also have the potential to chemically transform carcinogens into their active form. Therefore, we propose to test lung-associated bacterial strains for their capacity to chemically modify environmental carcinogens and to promote lung cancer onset and development. If successful, this project may identify microbial risk factors for lung cancer predisposition.


Hideko Isozaki, PhD

Massachusetts General Hospital

RESEARCH PROJECT:

Targeting APOBEC3A induction as a new therapeutic strategy to prevent acquired drug resistance in non-small cell lung cancer

SUMMARY:

The development of therapies that target oncogenic driver mutations has transformed the treatment of lung cancer. Despite notable progress in the design of successive generations of drugs with more potent activity and improved side-effect profiles, the inevitable development of acquired drug resistance continues to limit the clinical efficacy of these agents. Thus, there remains an urgent need for innovative therapeutic approaches to combat drug resistance. There is increasing evidence that given enough time, cancer cells that initially evade therapy can subsequently evolve new mechanisms of drug resistance. We recently discovered that residual lung cancer cells that have survived targeted therapy treatment exhibit activation of the APOBEC3A cytidine deaminase, a powerful mutator that can cause point mutations as well as DNA damage. Moreover, we found that genetic deletion of APOBEC3A suppresses the emergence of resistant cells during targeted therapy treatment. These results suggest that genomic instability caused by APOBEC3A may accelerate tumor evolution and facilitate drug resistance.

In this project, we will test the hypothesis that preventing APOBEC-driven evolution of cancer cells treated with targeted therapies will prevent the development of acquired drug resistance. Despite many attempts to develop inhibitors of APOBEC proteins, these enzymes remain undruggable. As an alternative approach, we propose to indirectly inhibit APOBEC3A mutagenesis by suppressing its expression. Using patient-derived models of EGFR, ALK and KRAS mutant lung cancer, we will determine the mechanistic basis for APOBEC3A induction and identify potential therapeutic targets for preventing the evolution of drug resistant cells during targeted therapy treatment. Successful completion of this study will provide scientific rationale for a new therapeutic approach designed to alter the evolutionary trajectory of cancer cells and prevent acquired drug resistance.


Chengcheng Jin, PhD

University of Pennsylvania

RESEARCH PROJECT:

Targeting the IL-1beta pathway for lung cancer treatment

SUMMARY:

Chronic inflammation is closely associated with lung cancer and plays a critical role in tumor progression, and metastases. However, the source of such inflammation has not been clearly defined and the contribution of specific cellular and molecular component of the immune system is yet to be elucidated. Interleukin 1β (IL-1beta) has emerged as a key mediator of tumor-associated inflammation. Upregulation of IL-1beta in the tumor microenvironment (TME) has been shown to promote cancer cell proliferation, angiogenesis and tissue remodeling across different types of cancers. Of note, in a recent large, randomized, double-blind clinical trial, blockade of IL-1beta dramatically reduced lung cancer incidence and mortality in high-risk individual. However, the mechanisms underlying the generation of IL-1beta and its action in lung cancer remain poorly understood. As a mucosal organ harboring the largest surface area, the lung is colonized by a diverse bacterial community in both physiological and pathological conditions. Using a genetically engineered mouse model of lung adenocarcinoma, our previous work showed that tumor growth is associated with increased bacterial burden and altered bacterial composition in the lung. This dysregulated microbiota stimulate IL-1beta production from tumor-associated myeloid cells, triggering an inflammatory cascade. Our data pinpointed IL-1beta as a critical mediator of microbiota-immune interaction in lung cancer. Therefore, we hypothesize that selectively targeting the lung microbiota or the responding IL-1beta pathway can rewire the TME to reduce pro-tumorigenic inflammation while boost the anti-tumor immunity both at the baseline and in response to immunotherapies. The overarching goal of this study is to decipher the molecular mechanism by which active IL-1beta is generated in the lung TME, and to understand how IL-1beta shapes the tumor-associated immune response to affect lung cancer progression and response to immunotherapies.


William Lockwood, PhD

British Columbia Cancer Agency

RESEARCH PROJECT:

SNF2 Histone Linker PHD RING Helicase as a novel tumor suppressor gene and risk factor in lung adenocarcinoma development

SUMMARY:

The poor prognosis for lung cancer patients is associated with a late stage of disease at the time of diagnosis, highlighting the need for effective methods for early detection. It has recently been demonstrated that low-dose computed tomographic (LDCT) screening of patients at high-risk of developing lung cancer improves survival outcomes. While a major advancement, LDCT is currently restricted to heavy smokers despite 25% of lung cancers occurring in people who have never smoked. Aside from smoking, a person’s genetics also influences their risk of developing lung cancer, which is highlighted by a history of this disease in certain families. However, very little is known about the underlying genetic causes of lung cancer susceptibility and defining these factors may lead to new screening approaches that catch lung cancer early in more patients, improving diagnosis.

Through genetic analysis of lung tumors, Dr. Lockwood’s group has recently uncovered the mutation of a gene that is located in a region linked to familial risk of lung cancer development. This gene is known to play a role in repairing damaged DNA, and he hypothesizes that its inactivation leads to increased gene mutations over time, increasing the risk of developing cancer. To test this, he will disrupt the gene in normal lung cells to determine if this allows them to transform into lung cancer. He will also do this with the additional exposure to tobacco to see if inactivation of this gene makes cells more prone to developing mutations and subsequently, cancer. Lastly, he will determine whether tumors lacking this gene are vulnerable to cancer drugs that induce DNA damage, potentially offering a strategy to treat patients with this gene mutation in the future. Together, this study will determine whether this gene is associated with lung cancer susceptibility and development, and how this information can be used to improve screening aimed at the early detection of lung cancer in high risk patients.

2020 LCRF Research Grant
on Disparities in Lung Cancer

2020 William C. Rippe Award**

Hilary Robbins, PhD, MPH

International Agency for Research on Cancer

Watch Dr. Robbins accept her award during LCRF’s 15th Anniversary Celebration.

RESEARCH PROJECT:

Development of risk prediction models to ensure equitable eligibility for lung cancer screening in minority populations

* * 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.

SUMMARY:

Lung cancer screening by low-dose CT (LDCT) can reduce lung cancer mortality, but research in the field has largely neglected racial and ethnic minorities. Criteria for defining screening eligibility fail to acknowledge how risk for lung cancer varies across racial and ethnic groups. This implies, for example, that a white individual and an African-American individual might have the same lung cancer risk, but only the white person might meet current guidelines for screening. The most promising solution is to define eligibility based on individual risk calculated using a prediction model; however, this requires that models be properly calibrated to perform just as well in racial/ethnic minorities as among whites. Our proposal aims to develop lung cancer risk prediction tools for African-Americans and Hispanic-Americans, thus allowing screening eligibility to be defined in a way that is fully equitable across racial and ethnic groups.


Joshua Campbell, PhD

Boston University

RESEARCH PROJECT:

Determining differences in immunotherapy outcomes and immunobiology in African American patients with NSCLC

SUMMARY:

Novel classes of cancer therapeutics work by activating the immune system, which in turn targets and kills cancer cells. These “immunotherapies” have had great success in treating some patients with advanced stage lung cancer. However, we do not fully understand why immunotherapy works for some lung cancer patients yet not for others. There is a major need to more fully characterize the immune system in lung cancer patients and determine the clinical and biological factors that are necessary for an immunotherapy to work effectively. For aim 1 of this study, we will determine if there are significant differences in immunotherapy response and toxicity between African American (AA) patients and other populations. Single-cell RNA sequencing is a new approach that can measure the genes which are turned on or off in individual cells. For the second aim of this study, we will perform single-cell RNA-seq on lung biopsies from AA and non-AA patients to determine if molecular pathways associated with response to immunotherapy are similar or different between populations. Identifying molecular features that are associated with response in AA patients can lead to the development of new diagonostic biomarkers and potentially identify novel avenues of therapeutic development.


Marjory Charlot, MD, MPH

University of North Carolina

RESEARCH PROJECT:

Understanding the immune landscape of non-small cell lung cancer in African Americans

SUMMARY:

In the U.S. there are 18% more deaths among Black men with lung cancer compared to White men with lung cancer. Recent advances in the treatment of lung cancer through cancer research have led to significant improvements in survival. However, Black patients are less likely to be invited to participate in cancer research and as a result are less likely to have access to state-of-the art cancer treatments. For example, immune checkpoint inhibitors, also known as immunotherapy, have drastically changed the treatment of lung cancer by using the body’s own immune system to kill cancer cells. Immunotherapy was first studied in clinical trials before its use in the real world, but unfortunately, Black patients were underrepresented in these studies. Having a better understanding of lung cancer that includes the Black population and identifying opportunities to engage Black patients in lung cancer research will likely help to reduce excess lung cancer deaths experienced by Black men. For this project funded by the Lung Cancer Research Foundation, we propose to study (1) the immune landscape in tumor samples obtained from Black patients with lung cancer as well as (2) strategies to enhance participation of Black patients with lung cancer in cancer research.


Chengguo Xing, PhD

University of Florida

RESEARCH PROJECT:

Contributions of tobacco exposure, NNK, and stress to lung cancer risk disparities between AA and CA male smokers

SUMMARY:

In the US, one in every 16 people will be diagnosed with lung cancer in their lifetime with a poor survival. Lung cancer risk disparities are also evident that African American (AA) male smokers have the highest risk. The reasons behind it remain to be determined. Given the limited success in lung cancer early diagnosis and clinical management, understanding why AA male smokers have the highest risk is urgent. The insight will help identify new opportunities for more effective lung cancer management. Specifically, the knowledge would guide the identification of individuals with high risk of lung cancer, the implementation of focused early diagnosis among those high-risk individuals, and the development of personalized precision prevention.

Tobacco exposure is the key risk factor for lung cancer. The survey of cigarette per day (CPD) to estimate tobacco exposure as a risk predictor has limitations, such as no consideration of the depth of tobacco inhalation and second-hand exposure. At the same time, tobacco exposure does not equate to carcinogen bioactivation, one root cause of cancer. NNK is the best-characterized, tobacco-specific, lung carcinogen with plenty of human data to support its causing role in human lung cancer incidence. Its uptake and bioactivation need to be quantified for lung cancer risk prediction. In addition, mental stress, such as anxiety, depression and psychosocial stress, have been reported to increase cancer risk, particularly lung cancer, in epidemiological studies but quantitative analysis is generally lacking. The differences in tobacco exposure, tobacco carcinogen NNK uptake, NNK activation, and mental stress (physiological and psychosocial) likely collectively contribute to the increased lung cancer risk among AA male smokers. This proposal will quantify these risk factors and develop an integrated lung cancer risk factor, which is expected to better predict lung cancer risk and differentiate its disparities in AA male smokers.

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:

Targeting MAST1-BCL2 signaling in small cell lung cancer

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 coordinate cancer cell survival and cell cycle progression in response to platinum treatment. Therefore, it is important to further decipher the downstream signaling of MAST1 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 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.


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.


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.

2017 LCRF Scientific Grant 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.