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Last Updated: 08/31/20

Targeting Lung Cancer Vulnerabilities

University of Texas Southwestern Medical Center (UTSW)
University of Texas MD Anderson Cancer Center (MDACC)

Principal Investigators:
John D. Minna, M.D. (UTSW)
Jack A. Roth, M.D. (MDACC)
John V. Heymach, M.D., Ph.D. (UTSW)
David E. Gerber, M.D. (MDACC)

Principal Investigator Contact Information

John Minna, M.D.
Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research Department of Internal Medicine
Department of Pharmacology
Hamon Center for Therapeutic Oncology Research UT Southwestern Medical Center
6000 Harry Hines Boulevard Dallas, Texas 75390-8593
(Tel) 214-648-4900

Jack A. Roth, M.D., F.A.C.S.
Professor
Thoracic & Cardiovascular Surgery MD Anderson Cancer Center
1515 Holcombe Boulevard
Unit 1489
Houston, Texas 77030
(Tel) 713-792-7664

John Heymach, M.D., Ph.D.
Chair, Dept. of Thoracic/Head and Neck Medical Oncology
UT/MD Anderson Cancer Center
1500 Holcombe Blvd, Unit 432
Houston, TX 77030
(Tel) 713-792-6363

David Gerber, M.D.
Professor of Internal Medicine (Hematology-Oncology) and Population and Data Sciences
Associate Director for Clinical Research, Simmons Comprehensive Cancer Center
5323 Harry Hines Blvd
Dallas, TX 75390-8852
(Tel) 214-648-1653

OVERVIEW

Targeting Lung Cancer Vulnerabilities. The University of Texas SPORE in Lung Cancer represents a unique collaboration between the UT Southwestern and MD Anderson, both of which have outstanding strengths in lung cancer translational and clinical research. The overarching goal of the SPORE is to develop new therapeutic paradigms based on “vulnerabilities” acquired during lung cancer pathogenesis, including a molecular understanding of each patient’s lung cancer, and using this information to “personalize” therapy for patients. Thus, our strategy is to identify lung cancer “therapeutic quartets” which include: 1. a specific vulnerability; 2. the mechanism of action thus defining therapeutic target(s) for the vulnerability; 3. a deliverable treatment for the target(s); and 4. tumor molecular biomarkers for the vulnerability predicting specific therapies for each patient. Our SPORE builds on a 20-year productive history, incorporating recent advances made by our SPORE investigators and the rest of the lung cancer translational research community in the molecular and mechanistic understanding of tumor autonomous and microenvironment changes, acquired vulnerabilities, and important immuno-oncology effects. These advances include novel approaches to identifying and molecularly classifying vulnerabilities in lung cancer metabolomic changes, cancers immunologically “inert” to PD1/PD-L1 checkpoint blockade, the lung cancer fibrotic stroma (microenvironment), and tumorigenesis-induced replication stress. Our contributions also include preclinical human and mouse model systems for testing the different vulnerabilities, as well as large legacy molecular and clinically annotated preclinical model and clinical specimen datasets. The SPORE is composed of 4 projects, all of which have Human Endpoints: 1. Targeting metabolic vulnerabilities in lung cancer; 2. Targeting vulnerabilities in immunologically-inert lung cancer; 3. Targeting vulnerabilities in the fibrotic extracellular matrix (ECM) of lung cancers; and 4. Therapeutic targeting of oncogene-induced replication stress for tumor cell killing and anti-tumor immunity in small cell lung cancer (SCLC) (which includes a clinical trial targeting replication stress combined with immune checkpoint inhibition. There are three cores: A. Administrative (including patient advocates); B. Molecular Pathology and Tissue Resources; and C. Data Sciences, as well as strong Developmental Research and Career Enhancement Programs (DRP, CEP). Our SPORE features leading lung cancer multi-disciplinary clinical and laboratory scientists, a cadre of experienced patient advocates, and an outstanding publication record. Moving forward, this SPORE will provide information on newly identified lung cancer acquired vulnerabilities, biomarkers for personalizing individual patient therapy, and important preclinical and information to facilitate clinical translation that has the possibility of changing the face of lung cancer therapy.

PROJECT 1: Targeting Metabolic Vulnerabilities in Lung Cancer

Project Co-Leaders:
Ralph Deberardinis (Basic Co-Leader)
Kathryn O'Donnell (Basic Co-Leader)
John Minna (Clinical Co-Leader)

We previously used intra-operative infusions with 13C-glucose to observe metabolic phenotypes in human non-small cell lung cancers (NSCLC) and show these tumors exhibit two distinct phenotypes of lactate metabolism, with one subset of tumors displaying prominent import of lactate for use as a fuel, and others primarily producing lactate from glucose and secreting it into the microenvironment. We will greatly expand the number of 13C-infused patients and follow them to identify metabolic activities that correlate with outcomes. Metabolic pathways that portend unfavorable outcomes would be excellent candidates to target with new cancer therapies. This Project will enhance our ability to capitalize on metabolic reprogramming to improve cancer treatment. In Specific Aim 1, tumors infused with 13C will be analyzed by imaging, quantitative histopathology, RNA sequencing and whole exome sequencing to understand relationships between all of these features and cancer metabolism. We focus on finding metabolic features that correlate with reduced progression-free survival. We establish patient-derived xenografts (PDXs) from these tumors to test the importance of predictive metabolic activities for tumor growth and metastasis. We specifically test whether inhibiting lactate import by monocarboxylate transporter protein-1 (MCT1), which predicts disease progression in humans, is required for tumor growth and metastasis in mice. In Specific Aim 2 we follow-up on our observation that lung squamous cell carcinomas (LSCCs) require lactate export for maximal tumor growth. We test whether genetic or pharmacological inhibition of molecular components of MCT4-mediated lactate export suppresses LSCC growth in autochthonous, syngeneic and PDX models. Specific Aim 3 will examine metabolic crosstalk between cancer cells and immune cells in the tumor microenvironment in mice and humans. We test the hypothesis that lactate metabolism impacts these metabolic exchanges and that blocking lactate transport enhances the efficacy of immune checkpoint blockade therapy, (approved for first line therapy of NSCLC). Overall, these efforts will produce the most detailed and clinically-relevant view of NSCLC metabolism to date. The ability to combine our ongoing study assessing metabolic flux in human NSCLC with large legacy clinical datasets ideally positions us to understand the relationship between tumor metabolism and cancer progression, and to advance high-priority therapeutic targets into clinical trials. While studies in the first 2-3 years will be in NSCLC, our work will position us to extend these metabolic findings to SCLC so that we can compare and contrast lactate metabolism and therapeutic targeting in all types of lung cancer.

PROJECT 2: Targeting Immune Vulnerabilities in Lung Cancer Vulnerabilities in Immunologically-Inert Lung Cancer: Replicative Stress and Lactate Metabolism as Targets for LKB1-mutant NSCLC

Project Co-Leaders:
John Heymach (Basic Co-Leader)
Farjana Fattah (Basic Co-Leader)
Ferdinandos Skoulidis (Clinical Co-Leader)
David Gerber (Clinical Co-Leader)

The treatment of metastatic NSCLC has been revolutionized by two recent developments: targeted agents for genomically-defined subgroups, and PD-1/PD-L1 checkpoint blockade (PCB). EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib are now standard first-line treatment for patients with EGFR mutations, while PCB is now part of standard first-line therapy for patients with wild-type EGFR and ALK. This is a major advance, but it is important to note that the majority of NSCLC patients do not have an objective response to PCB. The molecular determinants PCB resistance are not well understood, although low tumor mutation burden (TMB) and PD-L1 levels predict some cases. Recently, we reported that STK11 mutations, and the resulting loss of the LKB1 protein, are associated with an inert immune phenotype and PCB resistance. EGFR mutant, TKI-resistant tumors also have low response rates to PCB, and we and others found that they often upregulate IL-6 and undergo epithelial to mesenchymal transition (EMT), which is associated with changes in the immune microenvironment. Our data suggest STK11/LKB1 mutant (LM) and EGFR mutant tumors are the two largest genomic subgroups associated with a “cold” immune phenotype, accounting for ~40% of the primary resistance to PCB in lung adenocarcinoma (LUAC). We hypothesize that there are distinct mechanisms underlying the immunologically inert phenotypes of LM and EGFR mutant, osimertinib-refractory (OR) tumors, and that by characterizing their immune phenotypes and identifying these mechanism(s) we can develop tailored approaches for enhancing antitumor immunity and overcoming PCB resistance. To test these hypotheses, we will conduct a comprehensive analysis of the immune phenotype in LM and EGFR mutant tumors in early stage and metastatic tumors (Specific Aim 1, SA1), leveraging unique tissue resources developed in part through the Lung SPORE Pathology Core and three innovative investigator initiated-trials, and identify candidate therapeutic targets. In SA2 we will investigate two candidate approaches (inhibitors of DNA Damage Repair and the MCT4 lactate transporter) for enhancing antitumor immunity in LM tumors using preclinical models. In SA3 we will test inhibition of IL-6 and other candidate targets in EGFR mutant, treatment-naïve and OR tumors using our established preclinical models. Significance: This project aims to spearhead a new paradigm of genomically-guided, tailored immunotherapy for the two largest subgroups of PCB-resistant NSCLC tumors and elucidate their underlying mechanisms of immunosuppression, leading to new regimens that can immediately be translated into the clinic via an ongoing and several new potential trials.

PROJECT 3: Targeting Vulnerabilities in the Fibrotic Extracellular Matrix (ECM) of Lung Cancers

Project Co-Leaders:
Don Gibbons (Clinical Co-Leader)
Jonathan Kurie (Basic Co-Leader)

Substantial therapeutic advances have been made in the treatment of NSCLC based upon the incorporation of immune checkpoint inhibitors of the PD-1/PD-L1 axis, producing durable response in 15-20% of patients. Unfortunately, the majority of patients do not benefit from this single-agent approach, either due to primary or acquired resistance mechanisms. There is a knowledge gap about the interplay between the tumor-infiltrating immune cells and the dynamic changes in the extracellular matrix and tumor microenvironment that may drive an immunosuppressive microenvironment, which translates into a major unmet therapeutic need. The members of our multidisciplinary team (Gibbons, Kurie, Cascone, Yamauchi, Dalby, Wistuba, Morris and Wang) have a track record of productivity in studying the tumor matrix dynamics and immune factors in the microenvironment during lung cancer progression and in response to immune therapy. The investigators represent expertise in mouse modeling of human lung cancer, clinical oncology, immunotherapy, molecular pathology of lung cancer, drug development and bioinformatics/biostatistics. We have developed preliminary data from analysis of human lung cancer specimens and preclinical genetically engineered mouse models (GEMMs) of NSCLC that the epithelial-mesenchymal transition (EMT) status of tumors and deposition/crosslinking of the collagen matrix is suppressive of the intratumoral surveillance by immune cells. Based upon preliminary data, we hypothesize that: Extracellular matrix deposition and collagen crosslinking in the tumor microenvironment suppress tumor-infiltrating immune cells, facilitating tumor invasion and metastasis. Using parallel study of pre-clinical models and assessment of patient samples, we will address this hypothesis and explore clinical translational opportunities by: i) evaluating the role of collagen crosslinking enzymes and a fibrotic extracellular matrix on the immune cell profile of murine and human lung tumors, ii) determine how treatment with immune checkpoint inhibitors (ICI, e.g. anti-PD-(L)1 and/or anti-CTLA-4) alters ECM composition and crosslinking in murine and patient tumors, and iii) test the efficacy of agents that block matrix fibrosis or collagen crosslinking with or without immune checkpoint inhibitors to reverse the suppression of a productive intratumoral immune response in preclinical models and in Phase II clinical trials of neoadjuvant treatment.

PROJECT 4: Therapeutic Targeting of Replication Stress Vulnerabilities in Small Cell Lung Cancer Oncogene Induced Replication Stress for Tumor Cell Killing and Anti-Tumor Immunity in Small Cell Lung Cancer (SCLC)

Project Co-Leaders:
Lauren Byers (Clinical Co-Leader)
Jerry Shay (Basic Co-Leader)

The goal of this project is to develop novel synthetic lethal, replication stress related, approaches for lung cancer patients based on their tumor’s molecular profiles. There are two major unmet needs: first, the majority of patients do not have targetable oncogenic drivers; second, the majority of patients will experience primary or acquired resistance to clinically available therapies including immune checkpoint inhibition. Many currently “undruggable” oncogenes promote tumorigenesis through replication stress (RS) and genomic instability, “hallmarks of cancer” that lead to high tumor mutational burden and chromosomal aberrations. In the presence of RS, cancer cells depend on RS responses (RSR), which are a branch of DNA repair response (DDR) mediated by ATR-Chk1 signaling, to resolve DNA damage and stalled replication forks. Several RSR inhibitors are in clinical development, including drugs targeting ATR, Chk1, and Wee1. Our preliminary findings indicate how to exploit oncogene-induced RS (OIRS) as a therapeutic vulnerability in lung cancer. We demonstrated that cancers with OIRS (including KRAS-mutant, STK11(LKB1)-mutant, and MYC-amplified lung cancers) are vulnerable to RSR inhibitors and to drugs that increase RS or genomic instability beyond tolerable levels. The latter group includes 6-thio-dG (incorporated by telomerase positive cells disrupting telomeres and increasing RS) and PARP inhibitors (which deplete nucleotide pools and cause replication fork stalling through PARP-DNA trapping). We have shown that therapeutic targeting of RS increases cytoplasmic DNA, resulting in activation of the innate immune response (via the Stimulator of Interferon Genes [STING] pathway), immune-mediated cytotoxicity, and enhanced response to immune checkpoint blockade. We hypothesize that: 1. RS targeting (through RSR inhibitors, telomere disruption, or PARP inhibition) will lead to synthetic lethality in molecularly-defined subsets of lung cancer with OIRS (e.g., STK11 (LKB1), KRAS, E2F1, MYC) (Aim 1); and 2. that RS targeting will enhance response to immune checkpoint blockade in immunotherapy-refractory subsets of lung cancer via activation of the innate immune system (Aims 2 and 3). Specifically, we expect that RS-targeted therapies (alone or in combination) will lead to replication catastrophe and cell death in oncogene-driven lung cancers and enhance responses to immune checkpoint blockade (e.g., anti-PD-L1, anti-CTLA4). We will test our hypotheses in an extensive panel of molecularly characterized SPORE lung cancer cell lines, patient derived xenografts (PDXs), and animal models (Aims 1 and 2) and in clinical specimens from an investigator-initiated Phase 2 clinical trial (Aim 3) of PARP inhibition with immunotherapy and radiation in extensive-stage small cell lung cancer.

Administrative Core

Co-Directors:
John Minna
Jack Roth
John Heymach

The SPORE Administrative Core has the following Specific Aims: 1. Direct the overall scientific quality and administrative management of the SPORE and ensure effective communication between SPORE investigators and with Patient Advocates, facilitate integration of Research Projects and Cores within and between UTSW and UTMDACC. Encourage and facilitate multidisciplinary collaborations and cooperation and data and resource sharing (including Patient Advocates); 2. Prepare budgets, monitor budget expenditures, and implement corrective actions to stay within budget; 3. Coordinate all meetings of SPORE investigators including monthly SPORE works in progress (WIPs) videoconference/WebEx meetings, and meetings pertaining of the Internal and External Advisory boards; 4. Coordinate access to SPORE Core resources and oversee data quality control and validation determined by review of the Data Sciences Core; 5. Ensure implementation of all federal, state, and institutional regulatory compliances; 6. Oversee the SPORE Developmental Research and Career Enhancement Programs (DRP, CEP) by advertising DRP and CEP grant opportunities, and conducting DRP and CEP grant review processes to ensure identification of the projects with the combination of the best science, innovation, and potential for clinical translation . Work with DRP and CEP applicants to help them use SPORE resources and refine their projects for optimum translational potential, which will include identification of qualified mentors for DRP and CEP awardees. Also, establish and carry out policies for recruiting of women and minorities to be scientifically involved in the SPORE and DRP and CEPs; 7. To enhance recruitment of women and minorities as patients to participate in SPORE related clinical trials; 8. Encourage and facilitate horizontal and vertical collaboration of SPORE discoveries and investigators both within UTSW and MDACC and with other institutions; 9. Coordinate and maintain institutional commitments to the SPORE at UTSW and UTMDACC; 10. Communicate and consult with the NCI program director frequently to ensure adherence to all reporting requirements, including high-quality progress reports; 11. Coordinate and facilitate SPORE interactions with pharmaceutical and biotech industries; 12. Coordinate and facilitate Patient Advocate involvement in the SPORE; 13. Coordinate and facilitate resolution of scientific disputes.

Molecular Pathology and Tissue Resource Core

Co-Directors:
Justin Bishop
Ignacio Wistuba

The Molecular Pathology and Tissue Resources Core will provide routine and innovative tissue resources and materials essential for achieving the aims of the SPORE projects. Routine materials include tumors and non-malignant lung specimens and tumor cell lines. Over 6,000 tumors, 300 lung cancer cell lines, and over 180 tumors PDXs/CDXs are available to investigators, while a large number of samples have been distributed to investigators generating over 380 publications in the last ten years. Our Aim 1 is to collect, process, store, catalog and distribute tissues, cell lines and blood specimens, both malignant and non- malignant, tumor xenografts and relevant clinico-pathologic and molecular data, as requested by the various component projects of the SPORE program. Aim 2 is to develop and utilize innovative and routine tissue and cell line resources that will aid in the successful completion of the SPORE program aims. These include development of new tumor cell lines, additional lung cancer TMA resources, molecular analysis of tumors and liquid biopsy, and comprehensive immune-profiling of tissues. Aim 3 is to perform and interpret tissue- based molecular and immune analysis methodologies in close collaboration with the component projects of the SPORE program to satisfy their approved aims. This Core will play a crucial role on promoting collaboration among our own SPORE investigators, investigators at other Lung Cancer SPORE sites, and investigators at our own and other institutions. All of our SPORE projects will utilize Core B materials and services. Heavy utilization of our routine and innovative materials, and close interactions with the SPORE investigators will greatly aid the successful completion of the aims of our SPORE proposal.

Data Sciences Core

Co-Directors:
Yang Xie
Jing Wang

The research proposed by our SPORE in Lung Cancer encompasses a broad range of activities, including studies in clinically annotated patient tumor samples, tumor cell lines, xenografts, mouse models, and clinical trials. These studies generate many different types of data, including clinical, histologic, genome wide molecular (mutation, expression), proteomic, biochemical, immunohistochemical, drug and immune response phenotype, metabolomic, and tumor environmental. The Data Sciences Core provides comprehensive expertise to ensure the statistical integrity, data integrity, data sharing capability, and data analysis accuracy of the studies performed by the SPORE, which are conducted at UTSW and MDACC. The Core has a Director at each institution (Y. Xie, UTSW, and J. Wang, MDACC) and the flexibility to match personnel to the evolving needs of existing SPORE Projects, and Developmental Research and Career Enhancement Program (DRP, CEP) Projects. The Data Sciences Core: develops and maintain systems for data storage, retrieval, analysis, and sharing; provides an interface for all SPORE investigators to easily and freely exchange data and information; provides analyses to allow others outside the SPORE to have appropriate access to SPORE datasets, and to be able easily to independently reproduce and validate biostatistical and computational analyses. The Core includes innovative approaches to solving data analysis challenges of modern data-centric research. The Core Specific Aims are: Aim 1: To provide valid statistical designs for laboratory research, clinical trials and translational experiments arising for SPORE research; Aim 2: To oversee and conduct the innovative statistical modeling, simulations, data analyses and data integration needed by the Projects, DRP and CEP, and Pathology Core, to achieve their specific aims; Aim 3: To ensure that all complex molecular, biologic, and clinical datasets are protected for confidentiality, analyzed, shared among SPORE investigators and collaborators, and appropriately deposited into publicly accessible databases as required, using valid and innovative bioinformatics methods; Aim 4: To develop and maintain a secure, web-accessible site for SPORE research data integration and storage linked to an extensive tissue repository of clinically and molecularly annotated archived patient samples, tumor grafts, tumor and normal cell lines, and relevant mouse models of lung cancer. To develop and maintain centralized deposits from the literature of lung cancer-relevant datasets in a web site (“Lung Cancer Explorer”) to support SPORE investigators and, more broadly, the research community. To provide data-related analyses and documents for publication (such as “Sweave”) that allow the research community to independently reproduce and validate our analyses.

Developmental Research Program (DRP)

Co-Directors:
John Minna
Jack Roth
John Heymach
David Gerber

The Specific Aims of the DRP are: 1. Provide Funding for Development Research Projects; 2. Use expertise of members of the SPORE External and Internal Scientific Advisory Boards, and Senior Executive Committee to identify high impact projects with potential lung cancer clinical translational utility; 3. Build on the existing well-structured SPORE mentorship platform for Development Research Projects; 4 Build on the existing framework for direct communication between basic and clinical scientists, within and outside UTSW and UTMADCC, across disciplines, and training and guidance of a new generation of translational lung cancer researchers; 5. Facilitate development and transition of these successful projects into competitive applications for extramural peer-reviewed funding; 6. Build on the existing well-structured SPORE DRP to ensure that scientific advances are translated into the clinic to benefit lung cancer patients. The overall DRP goal(s) is to fund UTSW, MDACC personnel, extra-institutional candidates with MD or PhD degrees at all academic levels who want to pursue a career in lung cancer research and who have prepared an application with high potential for significant impact on lung cancer pathogenesis, diagnosis, prevention, prognosis, or therapy. As part of this, awardees will have access to Lung Cancer SPORE Core resources (such as preclinical models, Molecular Pathology, Data Sciences), and access to mentorship by experienced lung cancer investigators and patient advocates. DRP Awardees will bring new and innovative ideas and approaches to lung cancer translational research, and in turn, as appropriate, be trained in identifying major lung cancer problems to attack, as well as new approaches, concepts, technologies, data gathering and analyses for understanding lung cancer biology, pathogenesis, diagnosis and therapy. The DRP is run by the SPORE MPIs from UTSW and MDACC (Minna, Gerber, Roth, Heymach), and applications scored by the SPORE External Advisory Board (EAB) based on the applicant’s ability, significance of project, Innovation, approach, research Environment, and potential of project. Special efforts are made to recruit women and minority applicants. Over the 20 year history of this SPORE, the DRP has been very successful with a large number of awards leading to important publications, providing preliminary data for other grants, assisting with faculty promotions, and progression of the DRP to major roles in SPORE Projects and Cores.

Career Enhancement Program (CEP)

Co-Directors:
Jack Roth
John Minna
John Heymach
David Gerber

The Specific Aims of the CEP are: 1. Maintain lung cancer translational research excellence at UTSW and MDACC by recruitment of highly innovative and talented clinical, applied, and basic scientists at all levels; 2. Promote the development of highly qualified clinical oncologists, applied, and basic scientists with the ability to rapidly translate their findings into clinically applicable utility for lung cancer; 3. Attract candidates with prior experience in cancer at other disease sites who want to acquire expertise in lung cancer translational research; 4. Develop transition of CEP awardees from mentored investigators to successful independent lung cancer translational research scientists including helping them prepare other peer reviewed funding applications. The overall CEP goal(s) is to fund UTSW, MDACC young faculty with MD or PhD degrees (senior post doctoral fellow transitioning to faculty, Instructor, Assistant and Associate Professor level) who want to pursue a career in lung cancer research and who have prepared an application with high potential for significant impact on lung cancer pathogenesis, diagnosis, prevention, prognosis, or therapy. As part of this, awardees will have access to Lung Cancer SPORE Core resources (such as preclinical models, Molecular Pathology, Data Sciences), and access to mentorship by experienced lung cancer investigators and patient advocates. The CEP Awardees will bring new and innovative ideas and approaches to lung cancer translational research, and in turn, be trained in new approaches, concepts, technologies, data gathering and analyses for understanding lung cancer biology, pathogenesis, diagnosis and therapy. The CEP is run by the SPORE MPIs from UTSW and MDACC (Minna, Gerber, Roth, Heymach), and applications scored by the SPORE External Advisory Board (EAB) based on the applicant’s ability, significance of project, Innovation, approach, research Environment, and potential of project. Special efforts are made to recruit women and minority applicants. Over the 19 year history of this SPORE, the CEP has been very successful leading to a large number of awardees whose careers have been enhanced by the awards, including publications, providing preliminary information for obtaining other grants, academic promotion, and progression to playing major roles in SPORE Projects and Cores.

Institutional SPORE Websites

University of Texas Southwestern Medical Center
University of Texas MD Anderson Cancer Center