Emory University Lung Cancer SPORE
Emory University
Principal Investigators:
Suresh S. Ramalingam, MD
Haian Fu, PhD
- Principal Investigators Contact Information
- Overview
- Project 1: Evaluating stem-like T cells and improving efficacy of checkpoint inhibitors in NSCLC
- Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC
- Project 3: Targeting BAX signaling to overcome treatment resistant in NSCLC
- Administrative Core
- Pathology Core
- Developmental Research Program
- Career Enhancement Program
- Institutional SPORE Website
Principal Investigators Contact Information
Suresh S. Ramalingam, MD
Professor, Department of Hematology and Medical Oncology
Roberto C. Goizueta Distinguished Chair for Cancer Research
Executive Director, Winship Cancer Institute
Emory University School of Medicine
1365C Clifton Road NE, Suite C4014
Atlanta, GA 30322
(404) 778-5378
Haian Fu, PhD
Professor and Chair, Department of Pharmacology and Chemical Biology
Director, Emory Chemical Biology Discovery Center
Emory University
1510 Clifton Road, 5th Floor
Rollins Rsch Ctr 5111
Atlanta, GA 30322
(404) 727-0368
Overview
Lung cancer is the leading cause of cancer-related deaths worldwide, with an estimated 2.09 million deaths in 2018. It is often diagnosed at an advanced stage and is associated with poor outcomes for the majority of patients. The Emory University Lung Cancer SPORE program brings together an outstanding and multidisciplinary team of oncologists, immunologists, drug discovery experts, and translational researchers dedicated to lung cancer research to address critical questions that will improve the outcome for patients with this lethal disease. Our program will significantly impact two crucial areas of lung cancer management: enhancing the efficacy of immunotherapy and overcoming treatment resistance through the development of novel molecularly targeted agents. Through strong teamwork carried out by this highly collaborative team of dedicated investigators, and building on exciting data published in leading journals by our group, the Emory Lung Cancer SPORE aims to achieve substantial improvements in the management of patients with non-small cell lung cancer (NSCLC) through three overall specific aims:
Aim 1: Evaluate stem-like T cells and improve efficacy of checkpoint inhibitors in NSCLC (Project 1);
Aim 2: Target MERTK to improve outcomes for EGFR-mutated NSCLC (Project 2);
Aim 3: Target Bax signaling to overcome treatment resistance in NSCLC (Project 3).
The Emory Lung Cancer SPORE program will be supported by close interaction with the Administrative Core and Pathology Cores (Cores A & B), and will oversee Career Enhancement and Developmental Research Programs (CEP and DRP) activities. The SPORE program will benefit from regular advice and recommendations from External and Internal Advisory Board members regarding its progress and direction. Our program receives strong institutional support including modern research space, excellent shared resources, and a significant level of matching funds from the Winship Cancer Institute of Emory University (an NCI-designated Comprehensive Cancer Center), Emory University Woodruff Health Sciences Center, Emory Healthcare System, Emory School of Medicine, and the Department of Hematology and Medical Oncology. Through team-driven innovative research efforts in immunotherapies and molecularly targeted therapeutics, we are confident that the Emory Lung Cancer SPORE program, in collaboration with other lung cancer SPORE sites, will have a major positive impact on the management of lung cancer.
Project 1: Evaluating stem-like T cells and improving efficacy of checkpoint inhibitors in NSCLC
Project Co-Leaders:
Suresh Ramalingam, MD (Clinical Co-Leader)
Rafi Ahmed, PhD (Basic Co-Leader)
Programmed cell death-1 (PD-1) targeted therapies have changed the landscape of lung cancer treatment. While some impressive results have been generated, the mechanisms that dictate which patients will or will not respond to this treatment are not well defined. It is important to understand the immunological factors associated with clinical responses not only to improve current therapies but also to identify predictive biomarkers. We have recently identified a novel population of PD-1+TCF-1+ CD28+ CD8 T cells with stemcell like features in a mouse model of T cell exhaustion. Importantly, our preliminary data suggest that stem-like CD8 T cells are present in non-small cell lung cancer (NSCLC) patients. Based on our observations, we hypothesize that the stem- like CD8 T cells play a critical role in successful PD-1 targeted therapies in NSCLC patients.
SARS-CoV-2 has caused severe respiratory illness all over the world making it a global pandemic. More than 5.7 million people have succumbed to SARS-CoV-2 with the highest mortality rate among elderly people. mRNA vaccines BNT162b2 by Pfizer and mRNA-1273 by Moderna have more than 95% efficacy in controlling SARS-CoV-2 disease. However, several variants of concerns (VOC) have emerged resulting in breakthrough infections. Notably, the B.1.1.529 (Omicron) variant carries 37 mutations in its spike protein with 15 of these mutations in the receptor binding domain (RBD), which is an important target of neutralizing antibodies. These mutations enable the Omicron variant to escape both vaccine-induced and therapeutic antibodies. As the median age of lung cancer diagnosis is 70 years and immune dysregulation due to tumor malignancy and immunomodulatory therapies is seen during lung cancer, it is important to evaluate the immune response after SARS-CoV-2 vaccination in these patients.
Aim 1: To identify and characterize the phenotype, location, and function of stem-like CD8 T cells in lung cancer
Aim 2: To characterize COVD-19 immune responses in lung cancer patients
Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC
Project Co-Leaders:
Connor Steuer, MD (Clinical Co-Leader)
Douglas Graham, MD, PhD (Basic Co-Leader)
This project includes a phase 1b clinical trial of MRX-2843 and Osimertinib in patients with advanced EGFR Mutant (MT) Non-Small Cell Lung Cancer (NSCLC) and may lead to the development of more effective and less toxic therapies to improve survival and quality of life for lung cancer patients. Correlative studies are included in the trial to identify potential biomarkers that could be used to monitor target inhibition and/or immune response in patients treated with the combination. Preclinical studies are also being conducted using animal models to expand our understanding of the direct and immune-mediated mechanisms by which MERTK contributes to tumorigenesis and resistance to EGFR inhibition in EGFRMT NSCLC.
Aim 1: Determine the effects of MERTK inhibition alone and in combination with EGFR TKIs in preclinical EGFRMT NSCLC models.
Aim 2: Determine the effects of MERTK inhibition on anti-tumor immunity in syngeneic EGFRMT NSCLC models.
Aim 3: Systematically evaluate the safety, efficacy and biomarkers of activity of the combination of MRX-2843 and Osimertinib in patients with advanced EGFRMT NSCLC.
Project 3: Targeting BAX signaling to overcome treatment resistant in NSCLC
Project Co-Leaders:
Haian Fu, PhD (Basic Co-Leader)
Xingming Deng, PhD (Basic Co-Leader)
Kristin Higgins, MD (Clinical Co-Leader)
Bax functions as an essential gateway to apoptotic cell death. Targeting Bax provides a common pathway to treat NSCLC patients with KRAS or p53 mutations and to overcome resistance to radiotherapy and chemotherapy. The serine (S)184 phosphorylation site of Bax is a critical switch to functionally control Bax’s proapoptotic activity. AKT and PKCz have been identified as physiological Bax kinases that can directly phosphorylate Bax at the S184 site, leading to inactivation of its proapoptotic function. KRAS and p53 mutations activate the PI3K/AKT survival pathway leading to increased resistance to radiotherapy or chemotherapy in various cancers, including lung cancer. Increased levels of phospho-Bax (pBax) were observed in tumor tissues in patients with non-small cell lung cancer (NSCLC). pBax may serve as a new predictive and prognostic biomarker in NSCLC. Expression of KRAS G12D mutant or p53 R273H mutant or treatment with radiation, cisplatin or RAD001 resulted in activation of AKT and/or PKCz leading to increased phosphorylation of Bax, which may contribute to radio-, chemo- or rapalog resistance. We have identified a novel Bax activator, CYD-2-11, that selectively binds the S184 pocket of Bax protein. CYD-2-11 not only reverses radioresistance but also overcomes rapalog resistance. CYD-2-11 potently represses lung cancer xenografts by activating Bax and inducing apoptosis in tumor tissues. CYD-2-11 in combination with BH3 mimetic Bcl2 inhibitor venetoclax synergistically suppressed lung cancer.
This project will demonstrate how KRAS and p53 mutations regulate Bax activity in lung cancer, and characterize and develop novel Bax activator CYD-2-11 for the treatment of resistant lung cancer. By targeting Bax, we expect to develop a new class of anti-cancer agents and combination strategies for lung cancer treatment.
Aim 1: To determine whether and how KRAS and p53 mutations regulate Bax activity and treatment resistance in human lung cancer cells.
Aim 2: To develop novel small molecule Bax activator by targeting the structural pocket around the Bax phosphorylation site for lung cancer therapy.
Administrative Core
Core Directors:
Suresh Ramalingam, MD
Haian Fu, PhD
The Administrative Core executes the administrative, coordination, data sharing, and evaluation functions of the Emory Lung Cancer SPORE to ensure that the research projects, Pathology Core, and pilot projects of the Career Enhancement Program (CEP) and Developmental Research Program (DRP) perform at their best levels with investigators and collaborators of diverse background. The Administrative Core plays a pivotal role in monitoring progress, prioritizing projects with high impact outcomes, and overseeing the change in direction of any under-performing projects and replacing them with new translational projects as needed. This Core is fully dedicated to overseeing the conduct of the Lung Cancer SPORE, and providing organization and resources for the entire program, enabling it to fulfill its objectives to rapidly translate basic science discoveries into clinical applications to benefit lung cancer patients.
Pathology Core
Core Director:
Frank Schneider, MD
The Pathology Core provides expertise in lung cancer pathology to ensure efficient and highly coordinated procurement, archiving, and storage of both fresh and archived lung cancer tissue specimens to support the Winship Lung Cancer SPORE projects. These efforts further advance our understanding of the biology of lung cancer and help define novel strategies for its treatment. The primary functions of the Pathology Core are stated in the following aims:
Aim 1: Comprehensively acquire, process, store, catalog and disburse tissues, cells and blood with relevant clinico-pathologic data;
Aim 2: Provide pathologic and molecular genetic classification of lung tumors and interpretation of immunohistochemical stain results;
Aim 3: Facilitate human tissue-based investigation of the SPORE research projects;
Aim 4: Support Administrative Core-initiated intra-SPORE collaborations, inter-SPORE collaborations, and collaboration between investigators at our own and other institutions, including other peer-reviewed projects funded by NCI/NIH and other agencies using SPORE-generated tissues.
Developmental Research Program
Program Director:
Haian Fu, PhD
The SPORE Developmental Research Program (DRP) provides funding to support new and innovative pilot projects in lung cancer that have the potential to expand into full research projects in the future, including those of high risk-high reward nature. The DRP aims to foster collaborative research between Emory investigators and investigators at other institutions with diverse background and enhance translational research in lung cancer by increasing the number of meritorious projects and dedicated investigators working on lung cancer.
Career Enhancement Program
Program Director:
Adam Marcus, PhD
The Winship Lung Cancer SPORE Career Enhancement Program (CEP) supports pilot projects and the mentoring of early-career academic physician-scientists, clinician-investigators, and laboratory-based scientists who want to develop a career in translational research in the areas of lung cancer diagnosis, imaging, prevention, treatment, and improvement in quality of life. The CEP aims to provide an environment that enables talented early-career investigators to engage in a two-year mentored research program to facilitate their success and academic career development in terms of achieving independent investigator status, and to enhance diversity among the lung cancer research community.
Institutional SPORE Website
https://winshipcancer.emory.edu/research/spore-grants/lung-cancer.html