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Last Updated: 08/15/19

Emory University Lung Cancer SPORE

Emory University

Principal Investigators
Principal Investigator: Suresh S. Ramalingam, MD
Multi-Principal Investigator: Haian Fu, MD

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Suresh S. Ramalingam, MD
Professor of Hematology and Medical Oncology
Roberto C. Goizueta Chair for Cancer Research
Director, Division of Medical Oncology
Deputy Director, Winship Cancer Institute
Emory University School of Medicine
1365C Clifton Road NE, Suite C4014
Atlanta, GA 30322
Phone: 404-778-5378
Email: ssramal@emory.edu

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
Phone: 404-727-0368
Email: hfu@emory.edu

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-Leads:
Suresh Ramalingam, MD (Clinical)
Rafi Ahmed, PhD (Basic)

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 stem cell-like features in a mouse model of T cell exhaustion. The proliferative burst of CD8 T cells after PD-1 blockade comes from this stem-like CD8 T cell population and is dependent on signals from costimulatory molecule CD28. 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. One of the major goals of this project is to identify and characterize these stem-like CD8 T cells in NSCLC patients. Another important point to be addressed is if the presence of these stem-like CD8 T cells correlates with proliferative responses of CD8 T cells as well as clinical efficacy of the immunotherapies. The following specific aims are proposed to achieve our goals:

Aim 1: Identify and characterize the phenotype, location, and function of stem-like CD8 T-cells in lung cancer patients.

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 3: Evaluate T cell dynamics in lung cancer patients using in vivo deuterium labeling.

PROJECT 2: TARGETING MERTK TO IMPROVE OUTCOMES FOR EGFR-MUTATED NSCLC

Project Co-Leads:
Taofeek Owonikoko, MD, PhD (Clinical)
Douglas Graham, MD, PhD (Basic)

Lung cancer is the most common cancer worldwide and the leading cause of cancer-related death in the US.

EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes for patients who have non-small cell lung cancer (NSCLC) with an activating EGFR mutation (EGFRMT), but many tumors do not respond and most that do will become resistant in 9-12 months. Osimertinib, a 3rd generation EGFR TKI, has recently advanced to frontline therapy for EGFRMT NSCLC, irrespective of T790M mutation, but treatment options remain limited for patients who develop resistant tumors. This project describes preclinical studies to evaluate inhibition of the MERTK receptor tyrosine kinase in combination with EGFR TKIs for treatment of EGFRMT NSCLC and includes a phase 1b clinical trial to test the combination in these patients. 70% of NSCLCs have abnormally high levels of MERTK and inhibition in tumor cells decreases tumor growth in mice. MERTK is also present in immune cells in the tumor microenvironment, where it suppresses the anti-tumor innate immune response. Our data suggest that inhibition of MERTK reprograms the immune system to attack the tumor. MERTK can also mediate resistance to EGFR TKIs, including osimertinib, suggesting that MERTK inhibition will sensitize EGFRMT tumors to treatment with EGFR TKIs and may decrease development of resistance. These data identify MERTK as a new target in NSCLC and implicate MERTK-targeted inhibitors as an unprecedented opportunity to provide a three-pronged therapeutic approach in a single drug, leading to (1) direct tumor cell killing, (2) activation of anti-tumor innate immunity, and (3) increased sensitivity to EGFR TKI therapy. To test this idea and generate drugs that can be used in humans, we developed MERTK-selective TKIs, including MRX-2843. MRX-2843 is effective as monotherapy in mice and increases sensitivity to EGFR TKIs in EGFRMT NSCLC cells. The proposed studies use MRX-2843 and other MERTK inhibitors to investigate the effects of combined MERTK and EGFR inhibition in cell culture and mouse models of EGFRMT NSCLC, including models with tumor cells implanted directly in the lung, models derived from fresh patient samples, and models of tumor cell metastasis. Mice with MERTK knockout will also be used to determine the effects of MERTK inhibition in the tumor microenvironment and its impact on anti-tumor immunity. Additional studies will determine how MERTK inhibition in the immune system leads to tumor rejection. Finally, a highlight of this project is the dedicated clinical trial of MRX-2843 and osimertinib in patients with advanced EGFRMT NSCLC, a study that includes two expansion cohorts with paired collection of pre and post-treatment tumor biopsies and blood samples to evaluate biomarkers of MERTK inhibition, including changes in immune function, following treatment with MRX-2843. The results from the clinical trial and associated studies will provide more effective and less toxic treatment options leading to optimized care and improved survival for patients with 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 RESISTANCE IN NSCLC

Project Co-Leads:
Walter Curran, MD (Clinical)
Xingming Deng, PhD (Basic)
Haian Fu, PhD (Basic)

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. We previously discovered that the serine (S)184 phosphorylation site of Bax is a critical switch to functionally control Bax’s proapoptotic activity. AKT and PKC have been identified as physiological Bax kinases that can directly phosphorylate Bax at the S184 site, leading to inactivation of its proapoptotic function. It is known that KRAS and p53 mutations can activate the PI3K/AKT survival pathway leading to increased resistance to radiotherapy or chemotherapy in various cancers, including lung cancer. Increased levels of phosphor-Bax (pBax) were observed in tumor tissues in patients with non-small cell lung cancer (NSCLC). We hypothesize that 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 PKC 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 but does not bind other Bcl2 family members. CYD-2-11 not only reverses radio-resistance but also overcomes rapalog resistance in vitro. CYD-2-11 potently represses lung cancer xenografts by activating Bax and inducing apoptosis in tumor tissues. To characterize and develop this novel Bax activator for the treatment of resistant lung cancer, we propose two specific aims:

Aim 1: Determine whether and how KRAS and p53 mutations regulate Bax activity and treatment resistance in human lung cancer cells. Studies will determine whether pBax is a novel prognostic biomarker or therapeutic target in patients with NSCLC.

Aim 2: Develop novel small molecule Bax activator (CYD-2-11) by targeting the structural pocket around the Bax phosphorylation site for lung cancer therapy. Studies will test the antitumor efficacy of CYD-2-11 alone or in combination with ionizing radiation, chemotherapy, and/or mTOR inhibitor in patient-derived xenograft (PDX), radioresistant, and genetically engineered mutant KRAS-driven lung cancer animal models.

By targeting Bax, we expect to develop a new class of anti-cancer agents and combination strategies for lung cancer treatment.

ADMINISTRATIVE CORE A

Core Directors:
Suresh Ramalingam, MD
Haian Fu, PhD

The Administrative Core will execute 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. The Administrative Core will play 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.

To achieve its goals, the Administrative Core will perform the following administrative functions:

  • Provide necessary resources and fiscal oversight/accounting;
  • Acquire and allocate institutional matching funds to facilitate clinical trials and pilot projects;
  • Administer the CEP and DRP programs;
  • Prepare yearly non-competing progress reports;
  • Ensure the ethical design and conduct of the proposed clinical trials in Projects 1 and 2 and the ethics companion study associated with Project 1.

The Administrative Core will also undertake the following coordination functions:

  • Arrange and coordinate monthly SPORE investigators meetings, and the annual retreat;
  • Arrange travel to SPORE-related investigator workshops & NCI Translational Science meeting;
  • Plan and facilitate annual meetings of the Internal and External Advisory Boards;
  • Plan and facilitate monthly Executive Committee Meetings;
  • Provide and coordinate SPORE-SPORE and SPORE-NCI interfaces;
  • Coordinate to assure the compliance of all research projects with NCI, FDA and other federal, local and institutional regulations;
  • Engage patient advocates to integrate a patient perspective.

Lastly, the Administrative Core will perform the following planning and evaluation functions:

  • Regular monitoring and assessment of research progress;
  • Remediation or replacement of under-performing projects;
  • Identification of new translational opportunities.

The Administrative Core is fully dedicated to overseeing the conduct of the Lung Cancer SPORE program, 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 B

Core Director:
Gabriel Sica, MD, PhD

The objective of the Pathology Core is to serve as a centralized infrastructure to provide the materials and technical expertise necessary to accomplish the translational studies conducted by the Emory University Lung Cancer SPORE research projects and Developmental Research and Career Enhancement programs. With experience and expertise specifically in lung cancer pathology, the Pathology Core will interact directly with each research project to ensure efficient and highly coordinated procurement, archiving, and storage of both fresh and archived lung cancer tissue specimens. Continuous communication between clinicians, scientists, research nurses, biostatisticians and pathologists, together with established standardized operating procedures for all core activities, will provide optimal tissue collection and accurate processing, analysis and storage of each sample. The Pathology Core will function as the main repository of patient specimens; it will utilize and expand the well-established tissue banking efforts at the Winship Cancer Institute of Emory University for translational research, including annotating human tissue samples with relevant clinical and pathologic data that is collected and stored from the patient history, and maintaining patient confidentiality. Histopathologic analysis by the core pathologist will confirm the quality of study tissue in research specimens. Selected cellular biomarkers utilizing immunohistochemistry (IHC) will be interpreted by the core pathologist. In addition, animal study specimen processing, histopathology, IHC, and pathologic interpretive support will be provided. Collectively, 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.

CAREER ENHANCEMENT PROGRAM (CEP)

Program Directors:
Adam Marcus, PhD
Taofeek Owonikoko, MD, PhD

Emory University’s Lung Cancer SPORE aims to promote the advancement of early career lung cancer investigators through the conduct of a Career Enhancement Program (CEP). The goals of the proposed Lung Cancer SPORE CEP are to provide training and guidance for academic physician-scientists, clinician investigators, and laboratory-based scientists who wish to dedicate their efforts to translational research in the areas of diagnosis, imaging, prevention, treatment, and improvement in quality of life in lung cancer, and to enhance diversity among the lung cancer research community. The SPORE CEP will build on the strong commitment of the Emory Winship Cancer Institute and associated School of Medicine departments to the career development of junior investigators, which has included 18 career development program awardees as part of Emory’s previous Head and Neck Cancer SPORE and T32 physician-scientist training program in molecular oncology. The CEP aims to provide an environment that enables talented early career investigators to engage in a 2-year mentored research program and to facilitate their success and academic career development in terms of achieving independent investigator status. Specific aims for the CEP are as follows:

Aim 1: Attract and mentor a talented group of early career investigators towards a career in translational lung cancer research;

Aim 2: Engage biologists, scientists and physicians currently at Emory University and local partner research institutions in the state of Georgia in translational lung cancer research;

Aim 3: Enhance diversity among the lung cancer research community by encouraging minority individuals, women, and individuals with disabilities to apply for CEP support;

Aim 4: Foster and guide emerging strategies for the study of the biology, prevention and long-term treatment of lung cancer.

On average, two to four research projects will be funded annually. Additional support for the CEP has been secured from matching funds from Winship Cancer Institute, Emory University School of Medicine and the Woodruff Health Sciences Center.

DEVELOPMENTAL RESEARCH PROGRAM (DRP)

Program Director:
Haian Fu, PhD

Emory University’s Lung Cancer SPORE aims to pursue new and innovative research opportunities in the lung cancer field through the implementation of the Developmental Research Program (DRP). The DRP will solicit, evaluate, and fund the most outstanding pilot projects, monitor progress twice annually, and promote the most successful pilot projects into full projects funded by the SPORE and/or other sources. The goals of the DRP are to identify and support meritorious proposals that might expand into full research projects focused on lung cancer in the future, including those of high risk-high reward projects that might otherwise not be funded; to foster collaborative research between Emory investigators and investigators at other institutions; and to enhance translational research in lung cancer by increasing the number of investigators working in this field. Winship Cancer Institute of Emory University has a strong track record in conducting successful pilot project programs. Through the Winship Invest$ program, Winship has awarded 230 pilot grants, with a total of over $10M in funding, since 2012. Our track record is illustrated by the DRP in Emory’s Head and Neck Cancer SPORE (funded from 2006-2013) that awarded 17 pilot projects, which evolved into 15 full projects funded by NIH or foundations such as the American Cancer Society and the publication of 34 research articles and four review articles. Winship is also a recipient of the ‘Institutional Research Grant’ funded by the American Cancer Society that supports pilot research projects. Specific aims for the DRP are as follows:

Aim 1: Solicit research proposals by sending request for proposals (RFP) to all possible applicants at Emory University and other research and medical institutions throughout the state of Georgia;

Aim 2: Identify the most outstanding and novel proposals to fund through a clearly defined and well-established review process. Led by a DRP Committee, applications will be reviewed by a panel of leaders of all projects, cores/programs, and other researchers in relevant fields, following NIH review criteria;

Aim 3: Monitor the progress of funded peer-reviewed pilot projects using a series of return-on-investment metrics, including the evolution of projects into major projects (e.g., R01s, full SPORE projects), publications, investigator career development etc.

On average, two to four novel research projects in basic, translational and clinical studies will be funded annually. Additional support for the DRP has been secured from matching funds from Winship Cancer Institute, Emory University School of Medicine, and the Woodruff Health Sciences Center. Completion of these high-risk but innovative studies will result in strong publications, additional peer-reviewed grants, and the development of a larger and stronger group of investigators focusing on the translational study of lung cancer.