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Last Updated: 09/10/21

Emory University Lung Cancer SPORE

Emory University

Principal Investigator(s):

Suresh S. Ramalingam, MD
Suresh S. Ramalingam, MD

Haian Fu, PhD
Haian Fu, PhD

Principal Investigator(s) Contact Information

Suresh S. Ramalingam, MD
Executive Director, Winship Cancer Institute
Roberto C. Goizueta Chair for Cancer Research
Professor of Hematology and Medical Oncology
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
Professor, Department of Hematology & Medical Oncology
Director, Emory Chemical Biology Discovery Center
Associate Dean for Innovation and International Strategies
Winship Partner in Research Endowed Chair
1510 Clifton Road, 5th Floor
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 (Core A) and the Pathology Core (Core B) and will conduct 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)

Our group has identified stem-like T cells that undergo proliferation after immune checkpoint inhibition. We will characterize these cells in lung tumors, draining lymph nodes and peripheral blood, and study their correlation with treatment outcome. In addition, we will study a novel combination regimen of mTOR inhibition and PD1 inhibition in lung cancer patients.

Aim 1: Identify and characterize the phenotype, location, and function of stem-like CD8 T-cells in lung cancer patients. Aim 1a. Characterize the transcriptional, epigenetic, and functional characteristics of tumor-infiltrating stem-like CD8 T cells in NSCLC; Aim 1b. Determine the clonal relationship between T-cell populations in tumor, draining lymph node, and blood using TCR sequencing.

Aim 2: Study the efficacy and immune responses of combined inhibition of PD-1 and mTOR in a neo-adjuvant therapy trial in NSCLC patients. Aim 2a. To examine the clinical efficacy of the combined inhibition of PD-1 and mTOR in a neo-adjuvant therapy trial for patients with early-stage NSCLC. Aim 2b. To examine the correlation between immune responses and clinical efficacy of the combination therapy.

Aim 3: Evaluate T cell dynamics in lung cancer patients using in vivo deuterium labeling. Aim 3a. To measure proliferation in T cell populations in NSCLC patients using in vivo deuterium labeling. Aim 3b. To determine the CD8 T cell populations that proliferate in response to mTOR and PD1 blockade using in vivo deuterium labeling.

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 simertinib in patients with advanced EGFRMT 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 simertinib 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. Development of small molecules that activate Bax may provide a novel approach for the treatment of mutant KRAS or mutant p53 lung cancer or for overcoming 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.

Proposed model of KRAS and p53 mutations or chemo-or radiotherapy-induced signaling networks that contribute to lung cancer treatment resistance.

Proposed model of KRAS and p53 mutations or chemo-or radiotherapy-induced signaling networks that contribute to lung cancer treatment resistance. 

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 2-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