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Last Updated: 08/31/20

SPORE in Brain Cancer

The University of Texas/MD Anderson Cancer Center

Principal Investigators:
Frederick F. Lang, MD, FACS, FAANS, FAAAS
Juan Fueyo, MD

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Frederick F. Lang, MD, FACS, FAANS, FAAAS
Professor & Chairman
Beau Biden Chair for Brain Cancer Research
Department of Neurosurgery
University of Texas MD Anderson Cancer Center
1515 Holcombe Boulevard, Unit 442
Houston, TX 77030
Office: 713-792-2400
Fax: 713-794-4950

Juan Fueyo, MD
Professor, Departments of Neuro-Oncology and Neurosurgery
University of Texas MD Anderson Cancer Center
6767 Bertner Ave., Unit 1002
Houston, TX 77030-2603
Office: 713-834-6219
Fax: 713-745-0387

OVERVIEW

Nearly 140,000 people are living in the USA with a primary malignant central nervous system tumor, and about 24,000 people will receive a brain cancer diagnosis every year. Sadly, the median survival for glioblastoma (GBM), the most common primary adult brain tumor is only 14.6 months, despite surgery, radiation, and chemotherapy. Over the past 20 years, treatment advances have been only incremental. Therefore, the overarching goal of this Brain Cancer SPORE is to improve the outcome of patients with GBM and to reverse the nihilism associated with this disease. We achieve this goal through a focused pursuit of our overall hypothesis that advances in GBM therapy will result from a well-organized, multidisciplinary, integrated, flexible, and highly translational (“bench-to-bedside-and-back”) research program that discovers and rapidly translates novel and mechanistically diverse treatment strategies, including bio-immunotherapeutic and targeted therapeutic strategies, while also exploring disease pathogenesis and risk through genetic-based epidemiological studies.

Our SPORE includes three translational research projects:

  • Project 1 — Oncolytic Adenoviruses for Glioma Therapy
  • Project 2 — Targeting Metabolic Vulnerabilities with Molecular Inhibitors of Oxidative Phosphorylation
  • Project 3 — Deciphering Germline and Somatic Genomic Landscape of Gliomas in Black and Hispanic Minority Groups

The three translational projects are supported by four shared resources: Core A. Administrative Core; Core B. Pathology and Biorepository Core; Core C. Biostatistics and Bioinformatics Core; and Core D. Animal Core. This SPORE also supports a Career Enhancement Program to recruit and mentor new investigators in tra nslational Brain cancer research and a Developmental Research Program to support innovative translational projects in Brain cancer.

PROJECT 1: ONCOLYTIC ADENOVIRUSES FOR GLIOMA THERAPY

Project Co-leaders:
Juan Fueyo, MD (Basic)
Frederick Lang, MD, FACS, FAANS, FAAAS (Clinical)

To improve the notoriously poor outcome of patients with malignant gliomas, we developed a novel oncolytic adenovirus, Delta-24-RGD, that selectively replicates in and destroys glioma cells. This virus was tested in a first-in-human Phase I clinical trial in patients with recurrent malignant gliomas (NCT00805376), in which dramatic complete (>95% tumor reduction) and durable (>3 years) responses were observed in 12% of patients. Data from this trial contributed to the groundbreaking paradigm shift demonstrating that the Delta-24-RGD oncolytic virus is a form of immunotherapy. Specifically, analyses of clinical responses and post treatment surgical specimens demonstrated that the oncolytic effect of Delta-24-RGD is followed by an anti-tumor cytotoxic T cell immune response that is capable of resulting in complete tumor regression in a small but significant percentage of patients. These clinical data emphasize the urgent need to amplify the anti-tumor immune response as a means of enhancing the efficacy of Delta-24-RGD. To this end, in this proposal we pursue two convergent approaches whose foundations rest on the concept that immune responses to tumors are mediated by 1) immune checkpoints molecules that attenuate immune responses and against which FDA-approved inhibitors are available, and 2) immune costimulatory molecules which activate immune responses and are ideal to “arm” Delta-24-RGD. In our first approach, we combine Delta-24-RGD with the immune checkpoint inhibitor Pembrolizumab (MERCK), that is directed against the cell surface checkpoint receptor PD-1. We take advantage of the pretreatment biopsy specimens obtained from an ongoing Phase I/II clinical trial of this combination in patients with recurrent gliomas (the CAPTIVE trial, NCT02798406), to not only assess the safety and efficacy of this combination, but also to assess biomarkers for response (Aim 1). In our second approach, we develop and test next-generation Delta-24-RGD viruses that are armed with the cDNA of the ligands of immune co-stimulatory receptors (OX40L, GITRL, 4-1BB). We have already constructed and fully characterized the anti-glioma effects of Delta-24-RGDOX, which carries OX40L, and our data show that Delta-24-RGDOX more efficiently eradicates gliomas compared with Delta-24-RGD in immunocompetent animal models. Therefore, in Aim 2 of this proposal we assess the safety and biological effects of Delta-24-RGDOX on patient tumors in a unique treat-resect-treat clinical trial. Lastly, in Aim 3 we characterize the anti-glioma effects of additional next generation viruses Delta-24-GREAT (which contains GITRL) and Delta-24-ACT (which contains 4-1BBL) alone and in combination with Delta-24-RGD, to define potential synergy of these viruses. If successful, Project 1 will usher in a new age of oncolytic viral therapies for the treatment of malignant gliomas, for which there is currently no effective treatment.

PROJECT 2: OFF-THE-SHELF GENETICALLY ENGINEERED NATURAL KILLER THERAPY FOR GLIOBLASTOMA

Project Co-leaders:
Katy Rezvani, MD, PhD (Basic)
Shiao-Pei Weathers, MD (Clinical)

Despite unprecedented successes in many tumor types, molecular targeted therapeutics focused on targeting activated/amplified oncogenes have not had a meaningful clinical impact on patients with the incurable brain tumor glioblastoma multiforme (GBM). In this proposal we take a radically different approach to targeted therapeutics by exploiting genomic deletions, rather than mutant oncogenes, as points of selective vulnerability. Deletions create attractive therapeutic opportunities as they are usually homogenously distributed, persist during tumor recurrence, and most importantly, can expose pharmacologically targetable vulnerabilities by collaterally deleting nearby redundant metabolic housekeeping genes. We explored this concept by utilizing an unbiased chemical biology approach to identify pharmacologically targetable vulnerabilities exposed by passenger deletions. We found that inhibitors of mitochondrial oxidative phosphorylation (OxPhos) are selectively toxic to glioma cells that contained collateral homozygous deletions in the glycolytic gene ENO1. We hypothesized that the basis for this selective vulnerability is glycolysis-deficiency: ENO1-deleted glioma cells are unable to upregulate glycolysis in the face of OxPhos inhibition, a compensatory response in normal cells (Pasteur effect). A corollary of this hypothesis is that other deletions that cause glycolysis deficiency also sensitize to OxPhos inhibitors. Tool compound OxPhos inhibitors have been extensively used in in vitro studies, but are not drug-like and have poor pharmacology. MD Anderson’s Institute of Applied Cancer Science (IACS) developed a highly potent and specific OxPhos inhibitor, IACS-010759, with nM affinity for mitochondrial complex I, which readily passes the blood brain barrier and is endowed with superb pharmacological properties. In preliminary data we demonstrated that IACS-010759 destroys glycolysis-deficient glioma cells in culture and eradicates intracranial xenografts. Preliminary data indicate that the hypoxia PET probe 18F-fluoroazomycin-arabinoside (18F-FAZA) can be used as a non-invasive in vivo read-out for OxPhos inhibition (target-engagement marker for IACS- 010759), because mitochondrial oxygen consumption is a major driver of tumor-hypoxia. Based on these exceptionally encouraging pre-clinical results, we will conduct a trial of IACS-010759 on GBM patients with 18F- FAZA as a target engagement marker. The goal of this proposal is to support this trial by: 1) pre-clinically validating glycolytic-deficiency as a responder hypothesis and identifying other deletions which confer sensitivity to IACS-010759 by this mechanism, 2) validating 18F-FAZA as a non-invasive read-out for OxPhos inhibition and as a predictor of drug-response in glycolytically deficient tumors, and 3) determining target engagement (OxPhos inhibition) by 18F-FAZA and biochemical response to IACS-010759 in patients with GBMs. This proposal stands to be the first example of precision medicine provides clinical validation of collateral deletions as targetable phenomena.

PROJECT 3: DECIPHERING GERMLINE AND SOMATIC GENOMIC LANDSCAPE OF GLIOMAS IN BLACK AND HISPANIC MINORITY GROUPS

Project Co-leaders:
Melissa Bondy, PhD (Basic)
Christopher Amos, PhD (Basic)
Jason Huse, MD, PhD (Clinical)

Recent genomic profiling, including that of the Cancer Genome Atlas, has greatly clarified the molecular foundations of malignant glioma. However, most of the sample sets employed in these groundbreaking studies were derived from White or East Asian patients. Very little is currently known about the somatic and germline landscapes of gliomas in Black or Hispanic populations. Moreover, significant differences in the annual incidence and clinical performance of gliomas in these minorities relative to those of Whites strongly suggests that fundamental and clinically-relevant genetic distinctions exist between the groups. Consistent with this conjecture, we recently found that patterns of germline single nucleotide polymorphisms (SNPs) differentially associated with glioma by ethnic group and that Blacks and Hispanics with a higher level of White ancestry had a greater risk for glioma development than those with lower levels. We also identified a unique set of SNPs, distinct from glioma-associated SNPs in Whites, that appear to confer glioma susceptibility in Blacks and Hispanics. These findings indicate that a larger study, probing both somatic and germline molecular profiles exclusively in Black and Hispanic patients, would bridge crucial knowledge gaps, setting the stage for more optimized, individualized patient management. The central hypothesis of this proposal is that distinct genetic features, germline and somatic, in Blacks and Hispanics influence risk and clinical prognosis in IDH-mutant and IDH-wild type glioma subgroups. We will combine germline SNP data with extensive genomic profiling in case-matched tumors from the largest, clinically-annotated minority patient cohort assembled to date. Our specific aims will 1) characterize the genomic landscape of glioma in Black and Hispanic patients, 2) determine the extent to which ethnic composition in Blacks and Hispanics correlates with disease-defining molecular alterations, and 3) evaluate the extent to which germline and somatic variation in Blacks and Hispanics impacts clinical outcome. Our work will clarify the somatic and germline genetics of glioma in Black and Hispanic populations and in doing so, address a major knowledge gap in the field. We will also establish robust correlations between ancestry-associated germline genetics, molecularly-specified glioma subclasses, and clinical outcome, providing insights into the mechanisms by which gliomas arise and behave in patient populations of differing ethnicity. These findings should both inform therapeutic development and facilitate the design of optimized patient management.

ADMINISTRATIVE CORE (CORE A)

Core Directors:
Frederick Lang, MD, FACS, FAANS, FAAAS
Juan Fueyo, MD

The Administrative Core provides critical centralized administrative support to ensure the success of the entire SPORE. The specific objectives of the Administrative Core are to:

  • Oversee and administer all SPORE activities.
  • Oversee all SPORE Projects and Core activities.
  • Oversee the Developmental Research and Career Enhancement Programs.
  • Promote integration and communication between the SPORE, the Brain Cancer Program, and the Cancer Center Support Grant.
  • Ensure compliance with institutional, governmental, and NCI regulations.
  • Communicate and consult with the NCI program officer and other staff to ensure timely preparation and submission of reports, publications, and important events that affect management of the SPORE.
  • Oversee and administer all fiscal and budgetary activities of the SPORE.
  • Manage and provide quality assurance, including data quality control, in cooperation with the Biostatistics and Bioinformatics Core.
  • Coordinate meetings of the Executive Committee, Internal and External Advisory Boards, monthly investigator meetings, lectures, and symposia.
  • Ensure compliance with and improvement of policies for recruitment of women and minorities.
  • Coordinate with other Brain Cancer SPORE programs and investigators, as well as other organ site SPORE programs, to promote research communication in meetings, distribution of materials, electronic communications, and evaluation of progress reports.

PATHOLOGY AND BIOREPOSITORY CORE (CORE B)

Core Directors:
Frederick Lang, MD, FACS, FAANS, FAAAS
Jason Huse, MD, PhD
John de Groot, MD

A fundamental component of the translational research of the MD Anderson Cancer Center Brain Cancer SPORE is conduct of focused translational research involving human tissue and blood specimens, allowing investigation of the biology of target and normal tissues, and evaluation of treatment effects on both target and normal tissue and on modulation of specific, relevant biomarkers. The Pathology and Biorepository Core collects, processes and maintains human tissue specimens from patients and will disperse these tissues and tissue-derived primary glioma stem cell (GSC) to SPORE investigators. It has been an effective resource for the existing SPORE projects, which are heavily tissue-dependent and will continue to serve this function in the proposed SPORE Projects going forward.

The specific aims of the Pathology and Biorepository Core are:

Aim 1: Tissue banking. Maintain and enhance the existing repository of glioma tissue, glioma stem cell (GSC) lines, and patient-matched blood specimens, derived from MDACC patients.

Aim 2: Resource distribution. Provide glioma tissue, GSCs, and matched blood to SPORE investigators to facilitate basic, translational, and preclinical investigations.

Aim 3: Pathology expertise and essential services. Provide comprehensive support for the histopathological, immunohistochemical, and molecular characterization of human tissue specimens as well as samples generated from animal models through the course of SPORE investigations.

Aim 4: Integrated data basing. Support a comprehensive, integrated database linking detailed clinical, pathological, and radiographic data with patient-derived tissue resources in the biorepository.

Aim 5: Inter-SPORE collaboration. Facilitate inter-SPORE collaborations through sharing of tissue resources.

BIOSTATISTICS AND BIOINFORMATICS CORE (CORE C)

Core Directors:
Ying Yuan, PhD

The Biostatistics/Bioinformatics Core for MD Anderson Cancer Center SPORE in Brain Cancer is a comprehensive, multilateral resource for the design of basic science experiments and clinical trials, and appropriate statistical analysis of the resulting data. The Biostatistics and Bioinformatics Core incorporates sound experimental design principles that enhance interpretability of study results, performs data analyses using appropriate methodology, and contributes to interpretation of results through written reports and frequent interaction with project investigators. Thus, from inception to reporting, translational experiments benefit from SPORE resources which are used to augment existing M.D. Anderson Cancer Center Biostatistics and Bioinformatics resources. The Biostatistics and Bioinformatics Core collaborates with all project investigators to facilitate the timely publication of all data collected under the Brain Cancer SPORE program.

To serve all proposed SPORE Projects, as well as the Career Enhancement and Developmental Research Programs, the Biostatistics/Bioinformatics Core has the following objectives:

  • Provide biostatistics and bioinformatics expertise in the design and conduct of laboratory experiments and clinical trials arising from the research proposed in this application,
  • Provide biostatistics and bioinformatics analysis and interpretation of all data collected under the SPORE Projects, Developmental Projects, and other Cores, and
  • Collaborate and assist all project investigators with the publication of scientific results.

ANIMAL CORE (CORE D)

Core Director:
Yon Son Betty Kim, MD, PhD
Sherise Ferguson, MD

Investigations into brain tumor biology and therapy are best carried out in orthotopic animal models that mimic the natural milieu of the tumor. The ability to reach meaningful conclusions from these in vivo studies is greatly enhanced when uniform, readily reproducible animal models are used. The purpose of the Animal Core is to provide an animal modeling service that centralizes expertise thereby achieving uniformity and reproducibility that permits accurate comparisons between experiments, research groups, and projects in this Brain Cancer SPORE. The Animal Core also provides support for investigators using genetically engineered mouse models. The specific objectives of the Animal Core are to:

  • Provide support for orthotopic animal experiments using patient-derived glioma stem cell lines (GSCs), which are currently considered the gold standard in vivo model of human gliomas. This Core has developed approximately 100 GSCs, over 40 of which have been fully molecularly characterized;
  • Provide support for flank and orthotopic animal experiments using patient-derived tumor explants from the operating room implanted into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice;
  • Provide support for animal experiments using immunocompetent genetically engineered mouse models (GEMMs), particularly the RCAS/Ntv-a system;
  • Provide support for orthotopic animal experiments testing oncolytic adenoviruses using immunocompetent hamster models that are permissive to viral replication;
  • Provide support for orthotopic animal experiments using traditional profession glioma cell lines from humans (U87, U251, LN229) and mice (GL261);
  • Provide support for in vivo imaging either with bioluminescence imaging (BLI) or magnetic resonance imaging (MRI) to assess efficacy of therapeutic strategies.

DEVELOPMENTAL RESEARCH PROGRAM (DRP)

Directors:
Juan Fueyo, MD
Frederick Lang, MD, FACS, FAANS, FAAAS

Innovative translational research in brain tumors is critically dependent on the availability of funding for pilot projects. The Brain cancer SPORE Developmental Research Program (DRP) has been and will continue to be a source of seed funding for developmental research projects that have the potential to impact the outcome of patients with brain cancer. Our DRP has been an incubator of new concepts as it provided support of highly innovative early stage projects and recruited new investigators to study brain tumors, funding 31 awards over the past 5 years. In our current award period, federal funds will be used to support three DRP awards every year.

CAREER ENHANCEMENT PROGRAM (CEP)

Directors:
Juan Fueyo, MD
Frederick Lang, MD, FACS, FAANS, FAAAS
Krishna Bhat, PhD

Our SPORE Career Enhancement Program (CEP) is designed to provide training and guidance for academic physician- scientists, clinician-investigators, and laboratory-based scientists who wish to dedicate their efforts to improving the diagnosis and treatment of brain tumors through translational research. The SPORE CEP provides a strong mentorship program in which awardees are instructed in the clinical and epidemiological principles of brain cancer, combined with basic science studies of cell biology, molecular genetics, and cancer biology. Established senior faculty who wish to re-direct or extend their ongoing research programs will be eligible for participation in our CEP.