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Last Updated: 1/3/19

University of Texas Southwestern Medical Center SPORE in Lung Cancer

Principal Investigators:

John D. Minna, M.D. Principal Investigator (UTSW) University of Texas Southwestern Medical Center, Dallas, TX
Jack A. Roth, M.D. Co-Principal Investigator (M.D. Anderson CC) University of Texas M.D. Anderson Cancer Center, Houston, TX

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
Tel: (214) 648-4900
Email: john.minna@utsouthwestern.edu

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
Email: jroth@mdanderson.org

Overall

The University of Texas (UT) SPORE in Lung Cancer represents a unique collaboration between the University of Texas Southwestern Medical Center (UTSW) and the University of Texas MD Anderson Cancer Center (MDACC) both of which have outstanding strengths in lung cancer translational research. This SPORE has some of the leading lung cancer translational investigators in the world, includes a multidisciplinary group of clinical and laboratory scientists, and experienced Patient Advocates, and has developed a series of academic and Pharma/Biotech collaborations to facilitate the translation of our objectives horizontally and vertically.

Specific Objectives and Goals of the SPORE

The unifying goal of the SPORE is to develop new paradigms leading to personalized medicine based on a molecular understanding of lung cancers in individual patients and using this information to select the therapy (“personalize”) each NSCLC patient’s treatment. The focus is on non-small cell lung cancer (NSCLC) with inclusion of NSCLC cancers with neuroendocrine features to provide a path for developing similar approaches for small cell lung cancer (SCLC). The SPORE builds on a 16-year productive history, incorporates recent advances made by SPORE investigators and others in lung cancer genomics, as well as important new advances in identifying and understanding lung cancer “acquired vulnerabilities” (synthetic lethalities). Together this will provide a more complete and mechanistic understanding that will permit the integration of the molecular findings into deliverable personalized therapies. The advances include innovative approaches to functionally classify lung cancer by precisely determining the acquired vulnerabilities of each tumor, studying NSCLC mRNA expression and DNA mutational “clades” and integrating their functional characteristics, developing tools for CLIA certifiable classification tests, preclinical model systems for testing the new classification schemes, and a large legacy of molecular and clinical annotated datasets of lung cancers for retrospective analyses.

Project 1: Molecular Signatures for Individualizing Lung Cancer Therapy

Project Leaders:
John D. Minna, M.D. UT Southwestern Medical Center (Clinical and Basic Scientist),
John Heymach, M.D., Ph.D. UT MD Anderson Cancer Center (Clinical and Basic Scientist)

Translational Objective(s): The long term goal of this Project is to be able to sample a patient’s non-small cell lung cancer (NSCLC) before therapy, perform molecular analyses and determine the best therapy (chemotherapy or targeted therapy) for that individual patient (develop “personalized medicine” for that patient). The translational goals are to develop a molecular classification system for NSCLCs that provides CLIA certified “enrollment biomarkers” for such personalization and that provides a direct relationship between patient tumor samples with preclinical models (tumor cell lines and xenografts) to allow testing and personalization of new therapies first in preclinical models and then in patients. We will do this in a manner that integrates recent knowledge of lung cancer genome wide molecular characterizations, such as our own classification (NSCLC “clades”), and our genome wide functional definition of lung cancer acquired vulnerabilities (“synthetic lethality’s”) as therapeutic targets. Success in this project would have a major impact on overcoming the current large barrier in correct selection of therapy for individual NSCLC patients, provide a rapid and efficient integration of new targeted therapy into clinical trials, and ultimately lead to significantly better therapy results for NSCLC patients.

Project 2: Epidemiologic Studies of Germline Polymorphisms in miRNA Pathways to Determine Their Role in Risk of Lung Cancer Development and Recurrence

Xifeng Wu, M.D., Ph.D. MDACC (Epidemiologist/Basic Co-Leader)
Lin Ji, Ph.D, MDACC (Basic Co-Leader)
Jack A. Roth, M.D., MDACC (Clinical/Basic Co-Leader)

Translational Objective(s): For new early detection and prevention efforts, especially those stimulated by the large CT scan lung cancer (LC) screening efforts generated following the positive results of the National Lung Cancer Screening Trial (NLST), we urgently need new ways to identify people at the highest risk of developing lung cancer. miRNAs are a class of small non-coding endogenous RNAs capable of regulating one third of human genes. Specific miRNAs are already known to be functionally important in lung cancer pathogenesis acting as oncogenes and tumor suppressor genes. Genetic polymorphisms in miRNA regulatory pathways may have significant effect on gene expression and cellular processes by disrupting miRNA biogenesis and modulating miRNA-target interaction. We propose to conduct a systematic study of miRNA pathway SNPs (using our custom designed arrays) as susceptibility factors for the risk and clinical outcome of non-small cell lung cancer (NSCLC).

Project 3: Preclinical Development and Clinical Testing of MEK and PI3K Targeted Therapy for KRAS mutant NSCLC as a Method of Radiosensitization and Metastasis Inhibition

Jonathan Kurie, M.D. MDACC (Project Co-Leader)
Steven Lin, M.D., Ph.D. (Project Co-Leader)
Neda Kalhor, M.D. (Project Co-Leader)

Translational Objective(s): In patients with locally advanced non-small cell lung cancer (NSCLC), the survival benefit conferred by concomitant chemoradiation might be improved by integrating targeted therapies against genetic mutations that maintain tumor cell survival. On the basis of preliminary data in a KRAS-mutant human orthotopic lung adenocarcinoma model and in Kras/Tp53-mutant (KP) mice, which develop metastatic Kras/Tp53-mutant lung adenocarcinoma owing to down-regulation of the microRNA-200 (miR-200) family, we propose that (a) downstream signaling pathways activated by KRAS mutations and miR-200 down-regulation, namely those regulated by MAPK/ERK kinase (MEK) and/or phosphatidylinositol 3-kinase (PI3K), are key mediators of radiation resistance and metastasis in KRAS-mutant lung adenocarcinoma; and (b) KRAS codon 12 substitutions (G12D, G12V, and G12C) and microRNA-200 (miR-200) family expression levels predict tumor cell sensitivity to PI3K targeted therapeutics. We propose to test these hypotheses using a small molecule inhibitor of MEK1/2 (GSK1120212 or Trametinib) and a dual PI3K/mT0R inhibitor (BEZ235) that are both under clinical development.

Project 4: Therapeutic targeting of telomerase in lung cancer stem cells

Jerry Shay, Ph.D. UTSW Medical Center (Basic Co-Leader)
James Kim, M.D., Ph.D. (Clinical Co-Leader)

Translational Objective(s): Because constitutive expression of telomerase represents a “Hallmark of Cancer” (limitless replicative potential) in NSCLCs and it plays a critical role in the subpopulation of NSCLC cells that act as “cancer stem cells” (CSCs, also called “cancer initiating cells”, CICs) we focus on telomerase and our new discoveries of 6-thio- 2'deoxyguanosine (6-thio-dG) and WNT inhibitor, IWR-1 that targets tankyrase (PARP5A) as novel telomerase function inhibitors, and specific ALDH isozymes (ALDH1A1 and ALDH1A3) as important NSCLC therapeutic targets. Our long-term goal is to develop strategies to combine these telomerase inhibitors to enhance telomerase blockade in lung cancer treatment and to determine the most effective way to use telomerase inhibitors clinically to prolong progression free and overall survival of NSCLC patients. Toward this goal we have developed a large amount of preclinical model information on the effect of telomerase inhibition on lung cancer growth, lung cancer stem cells, and the development of new ways to inhibit telomerase in lung cancer. During the previous review period we conducted two clinical trials targeting telomerase as part of this SPORE project One was a Phase lb trial that enrolled 27 patients and the other is an ongoing Phase II that has completed enrollment (116 patients). We propose to advance a new telomerase inhibitor from (6-thio-dG) to clinical trials as well as to develop our own UTSW telomerase inhibitors (specifically a WNT inhibitor that targets tankyrase, a telomere associated protein). We also initiated collaborative effort with Novartis and Genentech to investigate their tankyrase inhibitors in a preclinical setting.

Administrative Core

Core Directors:
John Minna, M.D. and
Jack Roth,M.D.

Core Directors, Drs. Minna and Roth, will provide the administrative leadership for Core A. They will facilitate the interactions of the project and core leaders and direct their SPORE activities to accomplish the following aims:

  1. To direct the overall scientific quality of the SPORE and ensure communication, cooperation, and integration between The University of Texas Southwestern (UTSW) and The University of Texas MD Anderson Cancer Center (UTMDACC).
  2. To monitor the overall compliance of the SPORE in conjunction with all general Governmental and specific NCI regulations and requirements.
  3. Communicate and confer with the NCI Project Officer and other staff, and ensure all necessary reporting requirements.
  4. Coordinate data quality control and quality assurance issues in conjunction with the Internal Review and Monitoring Committees of UTSW and MDACC and the Biostatistics and Bioinformatics (Core C).
  5. Oversee expenditures and maintain budget information.
  6. Organize all necessary meetings, including the Executive Committee, External and Internal Advisory Committees, monthly scientific videoconference meetings, lectures, symposia, and attendance at the Lung Cancer SPORE meetings.
  7. Oversee the Developmental Research and Career Development Programs including obtaining mentors, biostatistical, and bioinformatics support and assist in selection of projects for funding. Specifically establish and monitor policies for recruitment of women and minorities to this program.
  8. Coordinate and maintain Institutional commitment to the SPORE at UTSW and MDACC.
  9. Encourage and facilitate inter SPORE communication, collaborations, cooperation, data and resource sharing.
  10. Coordinate and facilitate SPORE interactions with the PHARMA and Biotech industry
  11. Coordinate and facilitate Patient Advocate involvement in the SPORE.

Pathology and Tissue Resources Core

Core Directors:
Ignacio I. Wistuba, M.D. and
Adi Gazdar, M.D.

The 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 3,000 tumors and 300 lung cancer cell lines have been banked, and over 50,000 aliquots of tumor or cell line pellets, RNA or DNA or paraffin sections have been distributed to investigators. Our Aim 1 is to collect, process, store, catalog and distribute tissues, cell lines and blood specimens, both malignant and nonmalignant, 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 line resources to complement recent genome wide mutation data on lung cancer oncogenotypes. Aim 3 is to perform and interpret tissue-based molecular methodologies in close collaboration with the component projects of the SPORE program to satisfy their approved aims. This will involve developing molecular assays that eventually can be deployed as CLIA certified lab tests to facilitate the planned translational science clinical trials in most of the SPORE projects. 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 including other peer-reviewed projects funded by NCI/NIH and other agencies. 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.

Biostatistics and Bioinformatics Core

Core Director:
Yang Xie, Ph.D.

The research proposed by The University of Texas SPORE in Lung Cancer encompasses a broad range of lung cancer translational research activities, including studies in cell lines, xenografts and transgenic animal models, clinically and molecularly annotated tumor and other biospecimens, germline polymorphisms, and clinical trials. These studies will generate many different types of data, including clinical, epidemiological, biochemical, immunohistochemical, dose response, gene expression microarrays, sequencing, and more. The Core provides comprehensive expertise to ensure the statistical integrity, data integrity, data sharing, and data analysis of the studies performed by the SPORE, which are conducted at the University of Texas Southwestern Medical Center (UTSW), the M.D. Anderson Cancer Center (MDACC) and Ohio State University (OSU). The Core has a director at each institution (Xie at UTSW, Baladandayuthapani at MDACC, and Coombes at OSU) and has the flexibility to match personnel to the evolving needs of existing and developmental SPORE Projects. Members of the Core participate in monthly SPORE video conferences linking researchers at UTSW in Dallas, TX, MDACC in Houston, TX and OSU in Columbus, Ohio, ensuring that proper consideration is taken of biostatistics and data management issues during all phases of SPORE experiments. The Core will develop and maintain systems for data storage, retrieval, analysis, and sharing. It will provide an interface for all SPORE investigators. The Core services are made possible by the accumulated experience, accumulated computer codes and resources and by innovative, unique, sometimes customized approaches to solving the data analysis and interpretation challenges in the modern data centric research laboratory. To carry out its responsibilities, the Core has the following Specific Aims: Aim 1: To provide valid statistical designs of laboratory research, clinical trials and translational experiments arising from the ongoing research of the SPORE. Aim 2: To oversee and conduct the innovative statistical modeling, simulations, data analyses and data integration needed by the Projects, Developmental and Career Projects, and the other Cores to achieve their specific aims. Aim 3: To ensure that the results of all Projects are based on well-designed experiments, appropriately interpreted, and to assist in the preparation of manuscripts describing these results. Aim 4: To provide an integrated site for data storage and distribution for the SPORE Projects, particularly those with genome-wide and other data-dense Projects.

Developmental Research Program (DRP)

Directors:
Jack Roth, M.D. and
John Minna, M.D.

DRP is an integral part of the overall Lung Cancer SPORE research. This Program provides, after selection by external review and applicant discussion with senior SPORE investigators, a flexible and nimble platform for seed funding of novel research that have potential to significantly impact lung cancer translational research. It is designed to fund promising early stage projects that address important translational objectives in early detection, prevention, and therapy of lung cancer. Through institutional commitments at both UTSW and UTMDACC there are $300,000 in funds (that can be used for DRP or CDP Projects) matched to the $50,000 DRP funds provided by the grant. The DRP program has evolved into a highly structured process for solicitation, evaluation and collaboration with skilled scientists inside and outside UTSW and UTMDACC institutions. We want to attract new investigators to lung cancer translational research who have novel approaches and techniques that address significant barriers in lung cancer and which could benefit from SPORE Core Resources, interaction and mentorship, and that have potential to synergize with our existing Projects. The DRP has resulted in a large number of publications, new lung cancer translational scientists, and new peer reviewed grants. We have the following Specific Aims: 1. Provide Development Project funding to projects focused on lung cancer translational research. 2. Use the expertise of UTSW and MDACC scientific and clinical leaders and SPORE investigators and Core leaders to identify high impact lung cancer translational projects in the UTSW, UTMDACC and related environments. 3. Build on well-established SPORE mechanisms for mentorship of and integration with SPORE investigators, Projects, and Cores. 4. Build on the existing SPORE framework to promote communication between basic and clinical scientists, within and outside UTSW and UTMADCC, across disciplines, and guide the training of a new generation of translational researchers. 5. Facilitate development and transition of these successful projects into competitive applications for peer-reviewed funding. 6. Build on existing SPORE mechanisms to translate the findings into the clinic.

Career Enhancement Program (CEP)

Directors:
Jack Roth, M.D. and
John Minna, M.D.

CEP is an integral part of the overall Lung Cancer SPORE research. This Program provides, after selection by external review and applicant discussion with senior SPORE investigators, a flexible and nimble platform for seed funding to stimulate the careers of young investigators in lung cancer translational research. It is designed to fund promising young investigators that address important translational objectives in early detection, prevention, and therapy of lung cancer. Through institutional commitments at both UTSW and UTMDACC there are $300,000 in funds (that can be used for CEP or DRP Projects) matched to the $50,000 provided by the grant for the CEP. The CEP program has evolved into a highly structured process for solicitation, evaluation and mentorship, to attract new investigators to lung cancer translational research who have novel approaches and techniques that address significant barriers in lung cancer and who could benefit from SPORE Core Resources, interaction and mentorship, and that have potential to synergize with our existing Projects. The CEP has resulted in a large number of publications, new lung cancer translational scientists, and new peer reviewed grants. The Specific Aims of this competing renewal Lung Cancer SPORE CEP application are to build on the current and past exemplary SPORE progress of training the next generation of lung cancer leaders to fuel discovery and innovation. They are summarized as follows: 1 .To enhance the translational lung cancer research capability at UTSW and MDACC via recruitment of highly innovative and talented entry-level and junior scientists; 2. To attract candidates with prior experience in cancer at other disease sites who want to acquire expertise in Lung cancer translational research; 3. To transition CDP awardees from mentored to successful independent lung cancer translational research scientists; 4. To promote the development of clinical oncologists and basic scientists who can rapidly translate basic observations in cell and molecular biology/genetics into clinically applicable utility. We are particularly interested in recruiting applied and basic clinicians, scientists, and physician-scientist candidates who: 1. Have the potential to bring new and innovative ideas and approaches to lung cancer research. 2. Are trained in biomedical concepts and technologies, data gathering, evaluation and interpretation. 3. Are expert or can be trained to use new approaches and techniques to detect and resolve weaknesses and gaps in our understanding of lung cancer biology, pathogenesis, and treatment.