CA

Immunotherapy

RET or rearranged during transfection

Recurrent

Read more about Immunogenic peptide priming of dendritic cells for RET+ NSCLC

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Comparative Effectiveness of Lung Cancer Screening Strategies

2023

Pierre Massion Young Investigator Award for Early Detection Research

Lawrence Benjamin, MD

University of California Los Angeles

Los Angeles

Dr. Benjamin’s research focuses on improving the rates of lung cancer screening. Currently, there is interest in “centralizing” lung cancer screening into self-contained programs or one-stop shops, with dedicated support staff and clinical personnel to coordinate shared decision-making, scheduling imaging, and arranging appropriate follow-up care. However, it is poorly understood how these centralized programs compare to “decentralized” screening that is coordinated by primary care physicians directly with their patients. Dr. Benjamin seeks to utilize nationwide longitudinal data from multiple lung cancer screening programs from the Veterans Affairs Healthcare System to evaluate and compare the performance of centralized versus decentralized screening programs, with particular focus on highlighting their effectiveness within various racial and income groups.

Research Summary

Lung cancer is the leading cause of cancer-related death. Those at high risk for developing lung cancer from smoking are recommended to undergo screening for lung cancer yearly. However, despite this recommendation for nearly a decade, few who are eligible get screened, and even fewer follow up after their first screening. Lung cancer screening programs should investigate the effectiveness of their organizational structure and how well it serves their patients. The proposed study seeks to study the impact of a lung cancer screening programs organizational structure on its performance amongst various demographic groups using data from the Veterans Affairs Healthcare System.

Technical Abstract

Lung cancer is the leading cause of cancer-related mortality. Lung Cancer Screening (LCS) with an annual low-dose computed tomography (LDCT) scan has been recommended by the United States Preventive Services Task Force (USPSTF) since 2013, but uptake and adherence has been quite poor, estimating less than 20% of those eligible get screened. Additionally, there is a lack of consensus or high quality data to compare implementation strategies for lung cancer screening programs, and how these perform at reaching patients from different demographic backgrounds. Recently, there has been increasing interest in “centralizing” lung cancer screening into self-contained programs, with dedicated support staff and clinical personnel to coordinate shared decision making, scheduling of imaging, and arranging appropriate follow up. It is poorly understood how these centralized programs may compare at scale to “decentralized” screening that is coordinated by Primary Care Physicians directly with their outpatients. The proposed study seeks to utilize nationwide longitudinal data from multiple lung cancer screening programs from the Veterans Affairs Healthcare System to evaluate the comparative performance of centralized versus decentralized screening programs, and specifically highlighting their performance amongst various racial and income groups.

Key words

Early detection

Health equity

Read more about Comparative Effectiveness of Lung Cancer Screening Strategies

Integration of Liquid Biopsy Assays for the Early Detection of Lung Cancer

2023

Early Detection Research Award

Maximilian Diehn, MD, PhD

Stanford University

Stanford

Lung cancer is the number one cause of cancer-related deaths in the US because it is often found only after it has spread to other organs in the body, decreasing the likelihood of surviving at least 5 years after diagnosis. Only 21% of patients are diagnosed then their lung cancer is early stage, when it is most treatable. The goal of this project is to create a new way to screen for lung cancer using a blood sample that can find early stage disease when patients can still be treated and/or cured. In preliminary work, Dr. Diehn has developed a blood test that can identify tiny amounts of DNA from lung cancer cells and in this study he will improve this test and apply it to patients and healthy controls. If successful, Dr. Diehn’s work has the potential to significantly improve early detection of lung cancer and improve outcomes for patients.

Research Summary

Lung cancer is the number one cause of cancer-related deaths in the U.S. and can affect both smokers and non-smokers. Lung cancer is often deadly because it is usually found after it has spread to other organs like the brain, liver, or bones, at which point it is no longer possible to cure the disease in most patients. But if caught early when the cancer cells are still confined to the lung, it can often be cured with surgery or radiation. Screening for lung cancer in current or former smokers using CT scans has been proven to reduce the number of patients who die from lung cancer by catching the disease early. Although insurance covers it in the U.S., only about 15% of those who qualify actually get screened. Some reasons for this low rate of screening include worries about false positives from CT scans and difficulty accessing radiology facilities. Our goal is to create a new way to screen for lung cancer using a blood sample that can find early stage cancers when they can still be cured. Our method looks for tiny amounts of DNA in the blood that comes from lung cancer cells. We have completed initial tests that show our idea could work. Now, we plan to further improve our test and to apply it to several hundred lung cancer patients and healthy controls. If our experiments are successful, our blood test could eventually be used alongside CT scans to cut down on unnecessary follow-up tests or even replace CT scans as the main way to screen for lung cancer. If so, this work could contribute to saving lives of patients with lung cancer.

Technical Abstract

Lung cancer is the leading cause of cancer in the U.S., with over 238,000 new cases and more than 125,000 deaths expected in 2023. Early detection is crucial for improving prognosis, and low-dose computed tomography (LDCT) scans are recommended for high-risk populations. However, LDCT screening has limitations, including a significant false positive rate and low compliance. New approaches are therefore needed to enhance early detection in high-risk individuals. Liquid biopsy assays that can detect circulating tumor DNA (ctDNA) represent a promising alternative early detection approach. Our group has developed three state-of-the-art liquid biopsy techniques that each have the potential to detect lung cancer noninvasively, including a somatic mutation approach (Lung-CLiP), a methylation-based approach (meCAPP-Seq), and a fragmentomic-based approach (EPIC-Seq). We hypothesize that combining mutation-, methylation-, and fragmentomic-based ctDNA analysis will maximize sensitivity for detecting early stage lung cancers. Our proposal includes three specific aims. In the first aim, we will compare the clinical sensitivity and specificity of meCAPP- Seq, EPIC-Seq, and Lung-CLiP for early lung cancer detection. In the second aim, we will determine the analytical limits of detection for the three methods, which is important for future regulatory considerations. In the third aim, we will develop an integrated liquid biopsy assay that combines meCAPP-Seq, EPIC-Seq, and/or Lung-CLiP. We will test if combining two or all three assays can improve performance over the best- performing single assay. The deliverable of this project will be the identification of the combination of liquid biopsy assays that achieves the best performance for early lung cancer detection. If successful, our work has the potential to significantly improve early lung cancer detection which would lead to improved outcomes for lung cancer patients.

Key words

Biomarker or biomarker testing

Early detection

Liquid biopsy

Squamous cell lung cancer

Risk profile

Screening

Stage I

Stage II

Read more about Integration of Liquid Biopsy Assays for the Early Detection of Lung Cancer

Defining and novel therapeutic targeting of ALK fusion protein granules

2022

Partner Awards

Grant title (if any)

ALK Positive/LUNGevity Lung Cancer Research Awards

Trever Bivona, MD, PhD

University of California, San Francisco

San Francisco

Currently available ALK inhibitors are an effective treatment for lung cancer, but tumors can development treatment resistance. In this project, Dr. Bivona will explore a novel way to treat ALK-positive lung cancer by targeting “membraneless cytoplasmic protein granules,” a new mechanism of signaling in ALK-positive lung cancer. His team will use precision medicine approaches that are complementary to current ALK inhibitors and that could improve their efficacy as well as quality of life for patients.

Research Summary

Precision medicines that specifically target anaplastic lymphoma kinase (ALK) gene fusions that drive cancer growth are leading to improved responses and quality of life in many ALK gene fusion positive (i.e., ALK positive) lung cancer patients. While current ALK inhibitors are highly effective, they are not curative in most patients because treatment resistance arises. The studies in this research project focus on the characterization of a new mechanism of oncogenic signaling in cancer that centers on ALK gene fusions in lung cancer. The overall goal we aim to achieve in this project is to create an entirely new approach to treat ALK positive lung cancer by developing a suite of precision therapies that are distinct in their mechanism of action against ALK and that can complement all current conventional ALK inhibitors and even improve their effectiveness, while maintaining safety and quality of life for patients. The work accomplished in this project could yield molecular treatments that better control, or potentially cure, ALK positive lung cancer through improved precision medicine.

Technical Abstract

ALK gene rearrangements (e.g., EML4-ALK fusions) are validated targets in NSCLC and current ALK kinase inhibitors yield impressive responses. Despite this clinical progress drug resistance remains a problem that limits patient survival. Improved therapeutic strategies are critical to identify to improve clinical outcomes. We propose an innovative, multidisciplinary, and collaborative project to hopefully improve the survival of ALK positive NSCLC patients by defining a new mechanism of oncogenic signaling that we uncovered by studying ALK fusion oncoproteins. We aim to capitalize on our discovery of membraneless cytoplasmic protein granules as a distinct mechanism of oncogenic kinase signaling in cancer. Our data suggest a new paradigm in which certain ALK fusion oncoproteins form de novo their own protein-based subcellular compartment devoid of lipid membranes and utilize higher-order protein assembly as distinguishing principles underlying oncogenic output. These properties comprise a mode of oncogenic signaling that is different from that of native receptor tyrosine kinase (RTK) signaling and oncogenic, mutant forms of other RTKs such as EGFR, which both use classical lipid membrane-based signaling. The pathogenic biomolecular condensates formed by ALK fusion oncoproteins locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in cells. We identified a set of protein granule signaling components and established structural rules that define ALK protein granule formation. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling. We propose 3 Specific Aims to further unveil key interacting proteins required for ALK fusion protein condensate formation and signaling, characterize compartmentalized protein-protein interactions (PPIs) that drive condensate formation and/or oncogenic signaling, and identify pharmacologic strategies using existing agents to target the key PPIs required for driving this pathogenic biomolecular condensate formation and relaying the oncogenic signaling underlying the biology of ALK-driven NSCLC. The proposed studies could allow for mechanism-based therapeutic strategies to interfere with ALK protein granule assembly per se and that complement current ALK-inhibitors, which are kinase activity inhibitors. The pharmacologic agents we profile include clinical drugs and could be re-purposed and/or chemically optimized readily for clinical translation. This project will provide insight into ALK fusion biology and potential strategies to better control, or even cure, ALK-driven NSCLC.

Key words

Acquired resistance

Anaplastic lymphoma kinase (ALK)

Targeted therapy

Read more about Defining and novel therapeutic targeting of ALK fusion protein granules

Lung cancer Equity Through Social needs Screening (LETS SCREEN)

2022

Health Equity and Inclusiveness Junior Investigator Award

Ana Velazquez Manana, MD

University of California, San Francisco

San Francisco

Dr. Velasquez Manana will conduct an observational study in a multiethnic group of patients with unresectable lung cancer to determine the association between social needs, care utilization, and quality of life. The goal of this study is to fill a key knowledge gap in the care of patients with NSCLC and inform interventions to support patients at risk of social adversity during treatment to end disparities in lung cancer care.

Research Summary

Social circumstances in which we are born and live are some of the most important factors influencing our health. For people with cancer, these social circumstances (social determinants of health) drive differences in access to cancer screening and diagnostic tests, stage at diagnosis, and the types of treatments they are offered and receive. The treatment options for people living with lung cancer have changed drastically over the last decade with the addition of immunotherapies and targeted drugs. However, these treatments are not accessible to all. The high costs of cancer treatments and time lost from work make people with cancer more vulnerable to financial hardship, that could affect their ability to receive cancer treatments. In this study, we hope to understand how social needs (e.g., food access, ability to pay bills, access to transportation, housing stability, social isolation, and loneliness) relate to the use of healthcare, quality of care patients with lung cancer receive, and quality of life during their treatment. To do this, we will survey 150 patients with unresectable lung cancer within one month of start of systemic treatment and at 3 and 6-months during their treatment. We will measure how social needs change over time and relate to the use of healthcare for acute problems (i.e., emergency room visits, admissions to the hospital, and urgent care visits), quality of life, and quality of care received. To obtain an in-depth understanding of how social needs can affect patient care, we will interview 30 oncology providers. Providers will be asked if and how they consider the social needs of their patients when making treatment and clinical decisions. This study will give us essential information on how to better support patients with lung cancer who face social needs that impact their daily lives and cancer care.

Technical Abstract

Despite significant progress in the development of novel biomarkers and therapies for lung cancer, such progress has not equitably benefitted all population groups in the United States (US). Racial and ethnic minorities, low income, uninsured, and underinsured individuals with non-small cell lung cancer (NSCLC) continue to experience disparate access to diagnostics tests and treatments, and experience inferior outcomes. These disparities are, at least, partially driven by social context (i.e., social determinants of health). Patients with NSCLC experience high rates of financial hardship and unmet supportive needs, making them a population likely to have high rates of health-related social needs. The prevalence of social needs in patients with NSCLC and their impact on healthcare utilization, cancer outcomes, and quality of life (QOL) remains unknown. To fill this important knowledge gap, we propose an observational, prospective cohort study of 150 patients with unresectable lung cancer receiving first-line systemic therapy. Our study has two primary goals (Aims): 1) Prospectively quantify the prevalence of social needs and determine the associations between social needs, acute care utilization, and QOL; 2) investigate how patient’s social needs influence oncology providers’ clinical decisions for outpatient cancer care of adults with unresectable NSCLC. To achieve these goals, we will conduct serial survey assessments of 150 patients with unresectable NSCLC and conduct semi-structured interviews with 30 oncology providers. This study is significant as it is the first study longitudinally evaluating social needs during cancer therapy in patients with NSCLC. This study will fill a key knowledge gap and inform interventions focused on identifying and supporting patients at risk of social adversity during cancer treatment.

Key words

Health equity

Small cell lung cancer (SCLC)

Squamous cell lung cancer

Read more about Lung cancer Equity Through Social needs Screening (LETS SCREEN)

Isotoxic hypofractionation to personalize radiation for NSCLC

2022

Veterans Affairs Research Scholar Award

Lucas Vitzthum, MD

Stanford University/VA Palo Alto

Palo Alto

The purpose of this study is to develop and evaluate a method for personalized radiation therapy in patients with locally advanced NSCLC. Patients will be assessed regarding their expected risk of treatment toxicity, and those at lower risk will be treated in a fewer number of treatments with a more intensified dose of radiation. If successful, this could be used to inform optimal radiation treatment protocols as well as potentially reduce treatment and financial burden for patients, with a major impact on quality of life.

Research Summary

Like all medical interventions, optimal management of lung cancer requires a careful assessment of risks and benefits with treatment. Patients presenting with larger lung tumors or those with cancer that has spread to the lymph nodes are often treated with definitive radiation therapy delivered daily over the course of several weeks. Depending on the location and size of tumors the risk of toxicity can vary greatly between patients. Despite these differences in presentation, patients are generally treated with a "one size fits all" approach to radiation dosing that is unlikely to adequately account for their risk from tumor progression versus treatment toxicity. The purpose of this proposal is to develop and test a method to personalize radiation therapy dosing based on a patient’s expected risk of treatment toxicity. Patients with a lower risk of toxicity will be treated in a fewer number of treatments which results in more time away from the clinic, lower costs, and a more ‘potent’ effective dose of radiation. We will enroll patients in a clinical trial to determine if this approach is safe and without significant toxicity. We will also evaluate how effective this regimen is at treating the cancer. The results of this study may be used to inform optimal radiation treatment for lung cancer or further guide subsequent larger randomized studies.

Technical Abstract

Despite recent advances, locally advanced non-small cell lung cancer (LA-NSCLC) continues to have a high degree of morbidity and mortality related to both disease progression and sequelae from treatment. The purpose of this study is to develop and evaluate a more personalized radiation therapy (RT) approach with the potential to reduce time and financial burden to patients and increase tumor control. Patients undergoing fractionated RT with concurrent systemic therapy for LA-NSCLC will be treated to a total dose of 60 Gy with the number of fractions determined by ability to meet key dose constraints resulting in a shorter treatment course and higher biologic effective dose (BED) among those treated with shorter fractionation. To reduce the iterative time to determine fractionation schedule and standardize the"‘isotoxic hypofractionation" approach, we will employ a previously developed automated RT planning technique after delineation of the tumor and organs at risk. Fifty patients will be enrolled in a prospective non-randomized 2-stage trial to test the primary objective of whether isotoxic hypofractionation results in an acceptable rate of grade 2 or higher toxicity. Secondary endpoints will include G3+ toxicity, local control, progression free survival and overall survival. Finally, to better inform future "isotoxic" dosing strategies we will evaluate additional predictors of radiation toxicity using established retrospective cohorts through the Stanford Cancer Institute and the Veteran’s Affairs Information and Computing Infrastructure (VINCI).

Key words

Immune checkpoint inhibitors

Small cell lung cancer (SCLC)

Radiotherapy

Read more about Isotoxic hypofractionation to personalize radiation for NSCLC

Ensuring precision-medicine delivery for veterans with lung cancer

2021

Veterans Affairs Research Scholar Award

Manali Patel, MD

Stanford University Medical Center/Veterans Affairs Palo Alto Health Care System

Stanford

Research Summary

Veterans suffer from greater rates of lung cancer and lung cancer deaths than non-Veteran populations. Recent clinical advancements have significantly reduced lung cancer death rates, yet, many Veterans do not receive this care due to many factors including chronic and complex medical conditions, limited social support, and psychosocial concerns. In the VA, we developed the Engagement of Patients with Advanced Cancer (EPAC) intervention, which integrates community health workers and Veteran volunteers to assist Veterans with their cancer care at the end-of-life.1 In our randomized pilot study, EPAC improved evidence-based end-of-life care, improved Veteran and caregiver experiences, reduced hospitalizations and emergency department visits and total health care costs.1 In this study, we will refine EPAC to ensure that Veterans receive evidence-based lung cancer care. We established an Advisory Board comprised of Veterans, caregivers, oncology clinicians, and VA facility leaders who will assist in refining EPAC. We will randomly assign 60 Veterans newly diagnosed with lung cancer to either the refined EPAC intervention or to usual care and determine whether the intervention is feasible. Secondarily we will determine whether EPAC improves evidence-based lung cancer care and Veteran activation. This award will support plans to conduct a larger study across other VA facilities.

Technical Abstract

Veterans have significantly greater rates of lung cancer and mortality as compared to civilians. In our prior work, these disparities are partly due to lack of receipt of evidence-based cancer care especially among patients with complex comorbidities, psychosocial concerns, and limited social support, characteristics common among Veteran populations. The overall goal of this research is to overcome structural barriers to ensure delivery of evidence-based lung cancer care among Veterans. In our prior work we identified workforce shortages along with complex psychosocial factors and medical conditions that prevent Veterans from fully engaging in their care. We used community-based participatory research and expert panel methods to develop Engagement of Patients with Advanced Cancer (EPAC) – an intervention that integrates community health workers into care.1 In our randomized trial, EPAC improved evidence-based end-of-life care, Veteran satisfaction and reduced acute care use and total healthcare costs. In this study, with our established Advisory Board comprised of Veterans, caregivers, oncology clinicians, and VA leaders, we will refine EPAC to incorporate evidence-based lung cancer care (Aim 1). We will randomize 60 Veterans newly diagnosed with advanced lung cancer to establish feasibility of the refined EPAC intervention (primary outcome) and secondarily, the effects on evidence-based lung cancer care and Veteran activation (Aim 2). The results will inform a multisite randomized study in the VA.

Key words

Biomarker or biomarker testing

Veterans Affairs

Read more about Ensuring precision-medicine delivery for veterans with lung cancer

Pilot study of SGLT2 in the characterization of early lung adenocarcinoma

2021

Early Detection Research Award

Claudio Scafoglio, MD, PhD

University of California, Los Angeles

Los Angeles

The protein SGL2 seems to be produced in higher quantities on abnormal lung cells than on normal lung cells. Dr. Scafoglio is testing whether SGL2 can be used to image lung cancer cells by using a new imaging technology.

Research Summary

Lung cancer claims around 140,000 lives in the United States every year; there is great need for early diagnosis strategies, and an attractive target is cancer metabolism. Cancer cells require more glucose than normal tissues for their unregulated growth; glucose cannot enter the cells freely, but needs to be transported by specific proteins called glucose transporters.

We have recently discovered that early-stage and pre-cancerous lesions rely on a specific glucose transporter to satisfy their metabolic needs: sodium-dependent glucose transporter 2 (SGLT2). We have introduced a new probe, Me4FDG, which can be used for positron emission tomography (PET) to detect accumulation of glucose in the patient’s tissues through a whole-body scan. We have started a pilot trial of Me4FDG PET in patients diagnosed with lung cancer as proof of principle that this diagnostic technique can be used for early lung cancer diagnosis. We propose to perform more thorough and systematic studies to evaluate the feasibility of Me4FDG PET as a novel diagnostic imaging technique for early stage lung cancer.

Technical Abstract

Lung cancer is the leading cause of cancer-related death in US, and lung adenocarcinoma (LUAD) is the most frequent histology. Early diagnosis is crucial. High-resolution CT has increased the discovery of solitary lung lesions, many of which are benign, whereas some progress to invasive cancer; the identification of novel biomarkers to predict the malignant potential of these lesions is of paramount importance. We found that sodium-dependent glucose transporter 2 (SGLT2) is expressed in human pre-malignant and early-stage LADC, and is required for progression of LUAD. SGLT activity can be measured by PET imaging with methyl-4-[18F] fluorodeoxyglucose (Me4FDG). Importantly, we identified SGLT2 activity in FDG-negative, early-stage lesions in mouse models and in human lung nodules.

Specific aims of the study are: 1. To assess the safety and efficacy of Me4FDG in patients with lung cancer, via a pilot study in 60 patients (30 with pathological diagnosis of LUAD, 30 with a clinical diagnosis of benign nodule); 2. To evaluate the prognostic significance of SGLT2 expression in early lung adenocarcinoma, through SGLT2 staining of 674 samples embedded in tissue microarrays.

The proposed research is likely to introduce a novel diagnostic tool for early diagnosis of lung adenocarcinoma, and further define the prognostic role of SGLT2 in lung cancer. If successful, this pilot trial will open the way for larger clinical studies where we will evaluate the ability of Me4FDG PET to predict the malignant behavior of indeterminate subsolid lung nodules. This will improve the early diagnosis of lung cancer.

Key words

Early detection