Emory University
Principal Investigators
Suresh S. Ramalingam, M.D.
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, Ph.D.
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 remains the leading cause of cancer-related deaths worldwide. It is often diagnosed at an advanced stage and is associated with poor outcomes for most patients. The Emory University Lung Cancer SPORE program aims to address critical gaps to bring new effective treatment options for patients with lung cancer. Our program brings together an outstanding multi-disciplinary team of clinical oncologists, immunologists, computational scientists, drug discovery experts, and translational investigators dedicated to lung cancer research with a track-record of productive collaborations to address critical questions that will improve the outcome for patients with this lethal disease. Through strong teamwork carried out by this highly collaborative team of dedicated investigators, the research projects conducted by our SPORE program will significantly impact three crucial areas of lung cancer treatment:
- Project 1: Examine the novel inhibitory molecules selectively expressed by the stem-like CD8 T cells and how they orchestrate stem-like cell function and interactions with myeloid cells in non-small cell lung cancer (NSCLC) and conduct a clinical trial to evaluate a novel immunotherapy combination approach for advanced NSCLC
- Project 2: Utilize an innovative AI-informed systems biology approach to predict outcomes in stage III NSCLC patients, leveraging a recently completed phase III ECOG-ACRIN clinical trial
- Project 3: Interrogate metabolic enzyme SUCLA2 as a novel therapeutic target for NSCLC
The Emory Lung Cancer SPORE program will be supported by three integrated Cores, the Administrative Core, Pathology Core, and the Biostatistics and Biomedical Informatics Core. The SPORE program will conduct Career Enhancement and Developmental Research Programs (CEP and DRP) to further accelerate translational discoveries for the understanding and treatment of lung cancer. In addition, the SPORE program will receive guidance from highly qualified External and Internal Advisory Board members and input from our patient advocates regarding its progress and direction.
Through team-driven innovative research efforts in immunotherapies, AI-powered biomarker discovery, and targeted therapeutics this SPORE program, in collaboration with other NCI lung cancer SPORE sites, will seek to transform the treatment of lung cancer.
Project 1: Improving the efficacy of immunotherapy for lung cancer
Project Co-Leaders
- Suresh Ramalingam, MD, FACP, FASCO (Clinical Co-Leader)
- Rafi Ahmed, Ph.D. (Basic Co-Leader)
Specific Aims
Immunotherapy, such as therapies blocking the molecule programmed cell death-1 (PD-1), have been some of the most successful options for patients with non-small cell lung cancer (NSCLC). While some impressive results have been generated, not all patients respond to therapy. There is a need to better understand the mechanisms that dictate which patients will or will not respond to this treatment. It is important to understand the immunological factors associated with clinical responses in order to improve current therapies and provide new treatment options to patients with NSCLC.
This Project will build on our previous findings that a novel immune cell population, PD-1+ TCF-1+ stemlike CD8 T cells, plays a critical role in successful PD-1 targeted therapies in NSCLC patients. Given the importance of these stem-like CD8 T cells, there is a need to better understand the molecular and cellular interactions that regulate their function (Aim 1) and to identify therapies that will generate superior CD8 T cell responses from these cells compared to PD-1 monotherapy (Aim 2). We will study the basic mechanisms that regulate the core functions of these T cells and their interactions with other immune cells in lung cancer and conduct a phase II clinical trial to evaluate a novel combination immunotherapy regimen.
- Aim 1: Define novel cellular and molecular interactions between PD-1+ TCF-1+ stem-like CD8 T cells and myeloid cells in NSCLC
- Aim 2: Develop effective PD-1 combination therapies that modify the T cell exhaustion program and generate more potent effector CD8 T cells for controlling NSCLC
Findings from Project 1 will lead to novel discoveries underlying CD8 T cell immunity in NSCLC and potentially provide new treatment options for NSCLC patients and other cancers.
Project 2: Multimodal AI-based outcomes prediction in stage III NSCLC
Project Co-Leaders
- Ticiana Leal, M.D. (Clinical Co-Leader)
- Anant Madabhushi, PhD, FAIMBE, FIEEE, FNAI, FAAAS (Basic Co-Leader)
Specific Aims
Approximately one-third of patients diagnosed with non-small cell lung cancer (NSCLC) are diagnosed at stage III. The standard of care for unresectable stage III NSCLC involves platinum-based chemotherapy combined with concurrent radiotherapy, followed by durvalumab, a PD-L1 inhibitor (except for patients with EGFR mutation). However, despite success of immune therapies across various cancers, over 50% of patients with stage III NSCLC experience disease progression, and approximately 30% suffer from severe adverse reactions, such as pneumonitis. Currently, there are no biomarkers that can predict treatment outcomes and effectively manage pneumonitis risk.
Therefore, this project is taking an innovative approach utilizing artificial intelligence (AI) techniques to study features identified from patient chest CT scans (i.e. radiomics) and pathology H&E images (i.e. pathomics) to develop computational tools for predicting treatment response, survival, and risk for pneumonitis in patients with NSCLC. These “radio-pathomic” tools will examine tumor vasculature and the location of immune cells seen on routine CT and pathology images and integrate them with patient outcomes data and circulating tumor DNA (ctDNA) data.
- Aim 1: Develop and validate radio-pathomic tools for predicting outcomes and survival in NSCLC patients, leveraging in-house data and validating with data from the clinical trial, EA5181
- Aim 2: Develop AI-based radiomic tools to predict pneumonitis and validate the tools using data from the clinical trial, EA5181
- Aim 3: Correlate radiopathomic signatures with ctDNA data over time with imaging-based biomarkers in patients enrolled in EA5181
Successful completion of this Project will result in an inexpensive, non-invasive biomarker to predict outcomes for patients with stage III unresectable NSCLC, that can be used globally, even in resource-constrained settings.
Project 3: Targeting noncanonical mitochondrial signaling in lung cancer
Project Co-Leaders
- Conor Steuer, MD (Clinical Co-Leader)
- Sumin Kang, PhD (Basic Co-Leader)
Specific Aims
Metastasis, rather than the primary tumor, is the leading cause of death in cancer patients, but the mechanisms underlying the development of metastasis remain largely unclear. Lung cancer will often metastasize in patients, therefore it is critical to understand why the cancer spreads in order to develop new therapeutic strategies. Growing evidence suggests that changes in a tumor’s metabolism often occur during the process of metastasis. In particular, mitochondrial metabolism is active and may present as an attractive therapeutic target in NSCLC. Our group identified succinyl-CoA ligase ADP-forming subunit beta (SUCLA2) in the Citric Acid (TCA) cycle of mitochondrial metabolism as a critical factor promoting the survival of NSCLC cells during metastasis and SUCLA2 level positively correlates with metastatic progression in patients with NSCLC. Therefore, SUCLA2 may be a promising anti-metastasis target.
We identified a clinically available compound, proscillaridin A, as a SUCLA2 inhibitor that binds to SUCLA2 and effectively reduces metastasis. Furthermore, combining proscillaridin A with drugs currently used for lung cancer treatment showed that the combination of proscillaridin A and cisplatin most effectively increased cancer cell death. Therefore, this project will further examine how SUCLA2 signaling promotes lung cancer tumor metastasis beyond its typical signaling in the TCA cycle and validate the therapeutic efficacy of targeting the SUCLA2 pathway in NSCLC.
- Aim 1: To decipher the mechanisms by which SUCLA2 promotes metastasis through stress granules and evaluate SUCLA2-mediated metabolic signaling as a predictive biomarker for metastatic lung cancer
- Aim 2: To validate SUCLA2 as a therapeutic target in the treatment of NSCLC using our novel SUCLA2 inhibitors
Results from this Project may identify non-canonical SUCLA2 as a novel therapeutic target and a promising prognostic factor for lung cancer.
Administrative Core
Core Co-Directors
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, Biostatistics and Bioinformatics Core, and pilot projects of the Career Enhancement Program (CEP) and Developmental Research Program (DRP) perform at their best levels. The Administrative Core plays a pivotal role in monitoring progress, 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 patients with lung cancer.
Pathology Core
Core Co-Director
Specific Aims
The Pathology Core provides centralized infrastructure, expertise in lung cancer pathology, and technical knowledge to ensure efficient and highly coordinated procurement, archiving, and storage of fresh and archived lung cancer tissue specimens to support the Emory University Lung Cancer SPORE Projects, Career Enhancement Program (CEP) and Developmental Research Program (DRP). The Pathology Core connects with the Administrative Core and serves as an important link with the Biostatistics and Biomedical Informatics Core for integrated data infrastructure linking human tissue samples with relevant clinical and pathological data. These efforts further advance our understanding of lung cancer biology and help define novel strategies for its treatment. The primary functions of the Pathology Core are:
- Aim 1: Comprehensively acquire, process, store, catalog and disburse tissues, cells and blood with relevant clinico-pathologic data and pathology images
- 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 additional peer-reviewed projects funded by NCI/NIH and various agencies using SPORE-generated tissues
Biostatistics and Biomedical Informatics Core
Core Co-Director:
Specific Aims
The Biostatistics and Biomedical Informatics Core (Core C) integrates with the overall SPORE program to ensure proper data integrity, scientific rigor, and data sharing. The Core provides biostatistical expertise and resources, analytic strategies, data analysis and management platforms, and state-of-the-art methodologies to support each of the projects and the CEP/DRP recipients.
The team of investigators has complementary expertise and extensive experience in biostatistics, bioinformatics, and medical informatics and data management. This expertise and level of experience is critical for rigorous experimental design and streamlined data analysis, interpretation, sharing and management for both basic mechanism-driven examination and clinical studies, including support of the clinical trial. Importantly, Core C will develop and maintain a centralized data acquisition and management system that is customized explicitly for this SPORE.
Overall, the Biostatistics and Biomedical Informatics Core is a critical component of the SPORE program to ensure success of its translational goals and ensure high data integrity and research quality.
Developmental Research Program
Program Co-Director
Specific Aims
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 high risk-high reward projects that might not be funded by other mechanisms. The DRP aims to foster collaborative research between Emory investigators and investigators at other institutions to enhance translational research in lung cancer by increasing the number of meritorious projects and dedicated investigators working on lung cancer.
Career Enhancement Program
Program Co-Director
Specific Aims
The Emory University 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 wish to dedicate their efforts to 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.