Yale University
Principal Investigators
Roy Herbst, M.D., Ph.D.
Ensign Professor of Medicine and Professor of Pharmacology
Chief of Medical Oncology and Hematology
Deputy Director of Yale Cancer Center
Yale University
PO Box 208028
New Haven, CT 06520-8028
203-785-6879
Katerina Politi, Ph.D.
Joseph A. and Lucille K. Madri Professor of Pathology
Scientific Director, Center for Thoracic Cancers
Yale University
25 York Street, Rm 208
PO Box 208028
New Haven, CT 06520-8028
203-737-5921
Overview
The Yale SPORE in Lung Cancer (YSILC) brings together scientists from various cancer research areas to fight lung cancer. The goal of YSILC is to improve survival rates for lung cancer patients by developing new treatments. These treatments are based on understanding the specific biochemical and immune pathways that contribute to cancer growth, resistance to treatment, and metastasis. YSILC seeks to fulfill these goals through the following three projects:
Project 1: Investigate how the increase of the PLA2G10 protein in tumors contributes to resistance to immunotherapies in non-small cell lung cancer (NSCLC).
Project 2: Develop more precise treatment strategies for lung cancers with mutations in the EGFR gene.
Project 3: Targeting the ATM pathway to find treatments for lung cancer that has spread to the brain and resists current therapies.
Three Cores support the projects: the Administrative, Biostatistics and Bioinformatics, and Biospecimen and Biomarker Cores. These cores assist with project goals, detailed studies, and evaluation of biomarkers for clinical use. Additionally, the Developmental Research Program (DRP) and Career Enhancement Program (CEP) focus on developing new innovative projects and new lung cancer researchers. The YSILC projects and cores work together to develop new lung cancer treatments. They use patient samples, lab tests, and preclinical models to design future clinical trials.
The expected outcomes of the program include:
1. Developing a new immune target discovered through our current SPORE research.
2. Gaining knowledge about new vulnerabilities in EGFR mutant lung cancer to help delay drug resistance.
3. Understanding the causes of lung cancer that has spread to the brain and how to treat it.
4. Expanding lung cancer research by developing new researchers and novel cancer treatments through our Career Enhancement Program (CEP) and Developmental Research Program (DRP).
Project 1: Targeting Tumor Phospholipase PLA2G10 for Cancer Immunotherapy
Project Co-Leaders
- Kurt Schalper, M.D., Ph.D. (Applied Co-leader)
- Roy Herbst, M.D., Ph.D. (Clinical Co-leader)
- Patricia LoRusso, D.O. (Clinical Co-leader)
Specific Aims
Only a small fraction of patients with non-small cell lung cancer (NSCLC) benefit from immune checkpoint blockers (ICB), and even those who initially respond often see their disease return. Many NSCLC tumors are "immunologically cold," and exclude T cells which are necessary for ICBs to function (referred to as T cell exclusion, TCE). These tumors show aggressive behavior and are resistant to immunotherapy. The biological reasons behind TCE are not well understood, and there aren’t effective treatments available to counteract TCE in human cancers.
We identified the phospholipase PLA2G10 as a significant T-cell blocker that is increased in NSCLC. This T cell blocker, named PLA2G10, raises the levels of lipid metabolites in the tumor environment, strongly suppresses the movement of activated T-cells, and is only minimally expressed in non-tumor tissues. Based on these findings, we hypothesize that the increase of PLA2G10 in tumors is a dominant factor in causing TCE and resistance to immunotherapy and could be a therapeutic target for TCE tumors.
We have formed a team of experts to address the following three aims:
Aim 1: To determine how PLA2G10 causes T-cell exclusion in NSCLC.
Aim 2: To understand the clinical importance and role in regulating the immune system of PLA2G10 in human NSCLC.
Aim 3: To evaluate the effects of targeting PLA2G10 in cancer patients.
Using advanced methods and various approaches including pre-clinical models, annotated patient samples, and a clinical trial, our proposed studies aim to increase the understanding of TCE mechanisms and test methods for effectively targeting PLA2G10 in cancer patients.
Project 2: Optimizing Precision Medicine Approaches to Treat EGFR-Driven Lung Cancer
Project Co-Leaders
- Katerina Politi, Ph.D. (Applied Co-leader)
- Mark Lemmon, Ph.D., F.R.S. (Basic Co-leader)
- Sarah Goldberg, M.D. (Clinical Co-leader)
Specific Aims
Targeted therapies have changed how we diagnose and treat patients with specific types of lung adenocarcinoma. These therapies have improved many patients' lives, but they are not a cure, and over time, resistance to the drugs can develop. This is seen in EGFR-driven lung adenocarcinoma, where a significant advance was the approval of the third-generation tyrosine kinase inhibitor (TKI), osimertinib, for treating advanced stages of the disease. Osimertinib has been shown to prolong the overall survival of patients with EGFR mutant lung cancer compared to earlier generations of TKIs. However, responses to the drug vary, and resistance is a major challenge.
A key factor in how well tumors respond to TKIs is the type of initial oncogenic mutation. For example, patients with tumors with the EGFR L858R mutation tend to have worse outcomes with EGFR TKI treatment than those with the EGFR EX19DEL mutation. Other gene alterations, like changes in tumor suppressor genes, can also impact how well EGFR-driven tumors respond to TKIs. Therefore, many patients could benefit from treatments that enhance the effectiveness of osimertinib.
Here we will investigate potential approaches to improve the initial response to therapy and more effectively eliminate residual disease to prevent or delay drug resistance. To do this, we propose to study how to optimally use novel approaches to treat EGFR mutant tumors including antibody drug conjugates and to study the potential of the chromatin remodeler SMARCA4 as a therapeutic target in combination with EGFR TKIs. Through this project, we aim to find more effective ways to treat EGFR-driven lung adenocarcinomas from the start, providing long-term benefits for patients.
Project 3: The ATM Kinase as a Therapeutic Target in Drug Resistant NSCLC with Brain Metastasis
Project Co-Leaders
- Don Nguyen, Ph.D. (Applied Co-leader)
- Veronica Chiang, M.D., F.A.A.N.S .(Clinical Co-leader)
- Nikhil Joshi, Ph.D. (Basic Co-leader)
Specific Aims
Patients with non-small cell lung cancer (NSCLC) and metastases in multiple organs have the worst prognosis. NSCLC that spreads to the brain remains difficult to treat, as it can continue to grow even after initially responding to therapies that cross the blood-brain barrier (BBB), such as targeted treatments or immune checkpoint blockers (ICB). The ataxia-telangiectasia mutated (ATM) kinase is a key regulator of the DNA damage response, and it also helps manage oxidative stress and inflammation independently of DNA repair. It is unclear which of ATM's functions are crucial for drug resistance and metastasis in NSCLC.
The central hypothesis of this study is that ATM is activated in late-stage NSCLC as an adaptive response to therapy and stress from the tumor microenvironment (TME). We propose that inhibiting ATM can slow or overcome resistance to standard treatments in certain NSCLC patients with brain and other metastases. This is based on findings showing that ATM is activated in cancer cells from various NSCLC models resistant to therapy, which have spread to the brain, and that ATM inhibition can enhance the effectiveness of these treatments.
To explore this, we will use proteomics to identify the contexts in which ATM is active and responsive to ATM inhibition. In Aim 1, we will use models of EGFR-mutant NSCLC that develop resistance to the kinase inhibitor osimertinib, to test how ATM is activated. In Aim 2, we will investigate how ATM helps tumor cells evade the immune system using models that develop brain and systemic metastases. We will identify if immune cells are necessary for the positive effects of ATM inhibition and ICB, and validate our findings in human samples, including brain metastases and matched extra-cranial tumors. Finally, in Aim 3, we will conduct a clinical trial to test the combination ATM inhibition and osimertinib in patients with TKI-resistant EGFR-mutant NSCLC, including those with progressing brain metastases.
Administrative Core
Core Co-Directors
- Roy Herbst, M.D., Ph.D.
- Katerina Politi, Ph.D.
- Edward Kaftan, Ph.D. (SPORE Administrator)
Specific Aims
The Administrative Core (Core A) is directed by Roy Herbst and Katerina Politi, Principal Investigators of the Yale SPORE in Lung Cancer (YSILC), and co-directed by Edward Kaftan, with support from the program financial management team.
Core A collaborates with the Yale Cancer Center's Research Administration to support and facilitate interdisciplinary research. It acts as the central coordination point for all YSILC researchers, overseeing the progress of all projects and ensuring they move towards clinical applications. The leaders of Core A are responsible for setting research priorities, identifying new research opportunities, monitoring progress, and making necessary adjustments.
Core A helps YSILC researchers work together to quickly turn lab findings into clinical studies. The Core monitors finances, ensures communication among project leaders, and organizes meetings, including monthly SPORE meetings and annual advisory board meetings and coordinates outreach efforts like publications, website development, seminars, advocacy activities, and fundraising programs. Core A is vital to organizing the YSILC program, promoting a strong culture of lung cancer research at Yale, and efficiently achieving program goals to make a significant clinical impact on lung cancer patients.
Biospecimen and Biomarker Core
Core Co-Directors
- Kurt Schalper, M.D., Ph.D. (Core Co-Director)
- David Rimm, M.D., Ph.D. (Core Co-Director)
Specific Aims
The Biospecimen and Biomarker Core C of the Yale SPORE in Lung Cancer (YSILC) focuses on acquiring, processing, and analyzing high-quality blood and tissue samples from lung cancer patients. It supports YSILC projects and the Career Enhancement and Developmental Research Programs. This Core provides access to unique samples, performs quality control procedures, and ensures consistency and reproducibility across YSILC activities. Core C aims to maximize scientific quality by providing top-quality biospecimens with rigorous molecular analysis using both conventional and next-generation technologies.
The biospecimen operations include acquiring, processing, storing, annotating, ensuring quality control, and distributing samples, such as primary specimens and secondary tumor samples like tissue microarray-based cohorts, single-cell suspensions, and primary explants. The biomarker activities provide access to comprehensive biomarker capacities and tissue analysis services, including multidimensional measurements of proteins and nucleic acids from solid and liquid specimens.
Specific aims are:
1. Collect, maintain, and distribute high-quality biospecimens for use in YSILC projects and programs.
2. Develop and distribute advanced secondary biospecimens to support YSILC activities.
3. Conduct or assist in molecular pathology analyses of biospecimens, including quantitative protein analysis and high-plex discovery.
Biostatistics and Bioinformatics Core
Core Co-Directors
Specific Aims
Core B provides support for the Yale SPORE in Lung Cancer (YSILC) investigators regarding their analytical needs. The Core maintains an open-door policy, engages regularly with YSILC researchers and ensures that all studies are well-designed, executed, analyzed, and reported. The Core manages and protects all data, adhering to NIH guidelines for data publication and sharing.
Core B specific aims are to:
1. Provide biostatistical and bioinformatics support: Work with all YSILC projects and investigators, including those funded through the DRP and CEP. Ensure rigorous adherence to plans, monitor progress, adjust designs as needed, and assist in preparing research outputs.
2. Provide effective data management: Offer cost-effective data management services, ensure data is uniformly collected and properly shared according to NIH regulations.
3. Develop innovative methods: Create advanced analysis methods focused on lung cancer data to enhance the YSILC data use and promote lung cancer research.
Developmental Research Program
Program Co-Directors
Specific Aims
The main objective of the Developmental Research Program (DRP) of the Yale SPORE in Lung Cancer (YSILC) is to identify and fund innovative pilot projects with the potential to make a significant impact in lung cancer research. These projects focus on a broad range of areas such as risk assessment, early detection, biomarkers for prognosis and therapy, novel drug targets, and new therapeutic approaches.
Investigators of funded DRP projects are encouraged to collaborate with other researchers both within and outside of Yale, including those in wider SPORE community. The aim is for these pilot projects to evolve into full YSILC projects or studies of equivalent scale. Projects that demonstrate significant progress may be integrated into a full project if there is a programmatic need.
Career Enhancement Program
Program Co-Directors
Specific Aims
Despite the tremendous recent advances in lung cancer research, it remains the leading cause of cancer death worldwide. Ensuring that there is a robust pipeline of talented investigators pursuing lung cancer research is essential to establish future discoveries and further improve lung cancer outcomes. The Career Enhancement Program (CEP) of the Yale SPORE in Lung Cancer (YSILC) is designed to provide funding, mentoring and support for investigators interested in pursuing a career in lung cancer research. The goal of the CEP is to train a new generation of investigators committed to translational research in lung cancer. The CEP has substantial institutional commitment, both in terms of funding and infrastructure. Potential CEP candidates include promising junior faculty who are interested in establishing their careers in translational lung cancer research and/or established investigators whose previous research has been in other areas and who would like to transition into lung cancer focused research. Awardees are paired with mentors who are more established lung cancer investigators with a documented record of successful mentoring. In this way, the YSILC will stimulate the development of the next generation of lung cancer scientists, to tackle the most challenging issues in lung cancer research.