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Last Updated: 12/17/24

SPORE in Brain Cancer

The University of Texas MD Anderson Cancer Center

Principal Investigator(s):

Frederick F. Lang, MD, FACS, FAANS, FAAAS
Frederick F. Lang, MD, FACS, FAANS, FAAAS

Juan Fueyo, MD
Juan Fueyo, MD

Principal Investigator(s) Contact Information

Frederick F. Lang, MD, FACS, FAANS, FAAAS
Professor and Chairman
Department of Neurosurgery
The University of Texas MD Anderson Cancer Center
1515 Holcombe Boulevard, Unit 442
Houston, Texas 77030
(713) 792-2400

Juan Fueyo, MD
Professor, Departments of Neuro-Oncology and Neurosurgery
The University of Texas MD Anderson Cancer Center
6767 Bertner Ave, Unit 1002
Houston, TX 77030
(713) 834-6219

Overview

Nearly 25,000 people each year will receive a diagnosis of brain or other central nervous system cancer. Unfortunately, over the past 20 years, advances in the treatment of both adult and pediatric brain cancers have been incremental. The median survival for glioblastoma (GBM), the most common primary adult brain tumor, is only 15 months, and while the 5-year survival for medulloblastoma (MB), the most common pediatric brain tumor, is ~70%, prognosis remains poor in certain subsets of patients. Developing therapeutics for brain cancers is challenging due to tumor complexities and the limitations in standard clinical trial design. Therefore, the overarching goal of this Brain Cancer SPORE renewal application is to improve the outcomes of patients with brain cancer through the rigorous development of novel and mechanistically diverse treatment strategies that are evaluated in window-of-opportunity clinical trials. We will achieve this goal through a focused pursuit of our central hypothesis that a well-organized, multidisciplinary, integrated, flexible, and highly translational (“bench-to-bedside-and-back”) research program, which is designed to discover, develop, deploy and disseminate diverse and complementary therapies, will advance the treatment of brain cancers.

Our SPORE includes three mechanistically diverse projects:

Project 1: Combine Viro-immunotherapy and Natural Killer Cells for the treatment of gliomas

Project 2: Restore Myeloid Phagocytosis in GBM by Targeting the QKI/PPARb/RXRa Complex

Project 3: Exploit Immune Consequences of U1 Mutations in Sonic Hedgehog (Shh) MB

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 translational Brain cancer research and a Developmental Research Program to support innovative translational projects in Brain cancer.

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Project 1: Combine Viro-immunotherapy and Natural Killer Cells for the treatment of gliomas

Project Co-Leaders:
Juan Fueyo, MD (Basic Research)
Katy Rezvani, MD, PhD (Basic Research)
Frederick Lang, MD (Clinical Research)
Shiao-Pei Weathers, MD (Clinical Research)

It is now recognized that oncolytic viruses, including Delta-24-RGD, are potent anti-cancer immunotherapeutic agents, which act through direct oncolysis and by inducing an anti-glioma immune response. This paradigm-shifting concept implies that oncolytic viruses, including Delta-24-RGD, alter the immune tumor microenvironment (TME) and may therefore induce synergistic effects when combined with other immunotherapy strategies. We have recently engineered natural killer (NK) cells (called eCB-NK-TF-/GC- cells) for glioblastoma (GBM) which are resistant to tumor- and corticosteroid-induced immunosuppression by inactivation of TGFb-Receptor 2 and the glucocorticoid receptor 2, respectively, which is being evaluated in a phase 1 clinical trial in patients with recurrent GBM. When combined with NK cells, we found that treatment with Delta-24-RGD increased the recruitment, anti-cancer activity, survival, and memory of endogenous NK cells and extended the survival of glioma-bearing mice compared with controls. To test whether Delta-24-RGD treatment will actively contribute to enhancing the activity and memory of off-the-shelf eCB-NK-TF-/GC- cells resulting in strong anti-tumor activity without undue toxicity in patients with GBM we will:

Aim 1: Leverage the post-treatment biological specimens obtained from the window-of-opportunity arm of our ongoing Phase 1 clinical trial to evaluate the fate of eCB-NK-TF-/GC- cells as a single agent and to determine the associated immune changes in the TME of patients with recurrent GBM;

Aim 2: Explore the combination of Delta-24-RGD and eCB-NK-TF-/GC- cells in a variety of preclinical animal models to evaluate the impact on the TME in GBM (Aim 2);

Aim 3: Execute a phase I clinical trial with a window-of-opportunity arm of intratumorally administered Delta-24-RGD in combination with eCB-NK-TF-/GC- cells in patients with recurrent GBM.

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Project 2: Restore Myeloid Phagocytosis in GBM by Targeting the QKI/PPARb/RXRa Complex

Project Co-Leaders:
Jian Hu, PhD (Basic Research)
Chibawanye Ene, MD, PhD (Clinical Research)
Vinay Puduvalli, MD (Clinical Research)

Immunotherapies have so far not benefited patients with glioblastoma (GBM), largely due to abundant immune-suppressive GBM-associated microglia/macrophages (GAMs). Although heterogeneous, GAMs almost ubiquitously exhibit pro-tumorigenic states with defective phagocytosis. We reasoned that therapeutically reversing the immunosuppressive features of GAMs and restoring phagocytosis would promote anti-tumor activity by enhancing their ability to digest and process glioma cells and present tumor-specific antigens to activate the adaptive immune system. By analyzing human and mouse GBM samples by single cell RNA sequencing, we found that suppression of Quaking (QKI) is a universal feature in human and mouse GAMs and contributes to the impairment of the phagocytic activity of GAMs. QKI forms a complex called QPR, by interacting with peroxisome proliferator-activated receptor b (PPARb) and retinoid X receptor a (RXRa). QPR regulates unsaturated fatty acids (UFAs) synthesis, influences membrane fluidity and driving phagocytosis. Conditional knockout of Qki or PPARb in GAMs greatly impairs the phagocytosis of GAMs and enhances gliomagenesis by decreasing immune cell infiltration. Conversely, activating QPR through small molecule agonists of PPARb (KD3010) or RXRa (bexarotene) greatly enhances the phagocytic ability of GAMs and suppresses GBM growth in syngeneic glioma mouse models, demonstrating the therapeutic potential of these agents. To test whether activating QPR with small molecular agonists will restore GAM phagocytosis, normalize the defective immune microenvironment of GBM and consequently halt GBM progression, we will:

Aim 1: Decipher the molecular mechanisms underlying the effect of QPR activators on phagocytic activity in GAMs in vitro;

Aim 2: Investigate the molecular and cellular effects of KD3010/bexarotene on GAMs in pre-clinical in vivo animal models;

Aim 3: Perform a window-of-opportunity clinical trial to evaluate the therapeutic potential of bexarotene in patients with recurrent GBM.

In all, these studies will define QPR agonists as a new class of immunotherapeutics that can provide new hope for curing GBM by overcoming the immunosuppressive tumor microenvironment that drives this dreaded disease.

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Project 3: Exploit Immune Consequences of U1 Mutations in Sonic Hedgehog (Shh) MB

Project Co-Leaders:
Michael Taylor, MD, PhD (Basic Research)
Nabil Ahmed, MD (Basic Research)
Murali Chintagumpala, MD (Clinical Research)
Nazanin Majd, MD (Clinical Research)

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is responsible for significant morbidity and mortality in the United States. Of the different subtypes of MB, Sonic Hedgehog (Shh) is the most common. Patients with Shh-α (mostly adolescents) who have TP53 mutations have nearly 100% mortality, and those with Shh-δ (mostly adults) experience significant morbidity from standard treatment with craniospinal radiation and have extremely poor outcomes with limited treatment options at recurrence. We recently identified a unique somatic point mutation in a non-coding small nuclear RNA (snRNA) called U1 in 50% of Shh medulloblastomas. This mutation, U1 (r.3A>G), is found in 97% of Shh-δ tumors and >65% of Shh-α tumors with TP53 mutations. The U1 snRNA is an essential component of the spliceosome, and tumors with this mutation exhibit a unique form of post-transcriptional hypermutation which results in the expression of thousands of novel epitopes that are not expressed in normal human tissue. Hypermutant cancers are often responsive to immune checkpoint inhibitors (ICI) therapy, and the thousands of novel epitopes arising from transcriptional hypermutation are likely to be good candidates for CAR T-cell therapy. Therefore, we will:

Aim 1: Conduct a phase II clinical trial of nivolumab and ipilimumab in patients with Shh MB and correlate the clinical outcomes with U1 mutation status;

Aim 2: Identify novel tumor antigenic epitopes, characterize the tumor microenvironment and delineate the molecular biology of cells along the differentiation hierarchy in U1-mutant Shh MBs through state-of-the-art transcriptomic profiling and analysis;

Aim 3: and prioritize U1-mutation driven tumor antigenic epitopes and use these epitopes to design, develop and test CAR T cells in preclinical models of Shh MB.

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Administrative Core

Core Directors:
Juan Fueyo, MD
Frederick Lang, 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.
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Pathology and Biorepository Core

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

The Pathology and Biorepository Core is a key driver of the success of the MD Anderson Brain Cancer SPORE, which seeks to progress home-grown experimental treatment strategies to clinical trials to improve patient management. The Core incorporates an innovative and near-comprehensive tissue procurement and processing pipeline and provides histopathological expertise and the wealth of experience gained over multiple funding cycles. The objectives of the core are:

  • Procure, bank, and supply relevant tissue and biomaterial to SPORE projects and the institutional brain tumor research community
  • Coordinate clinical trial-associated tissue and biomaterial banking, processing, and databasing
  • Support murine sample processing and higher-order human/murine tissue reagent development
  • Provide histopathological, immunohistochemical, and molecular pathology expertise
  • Facilitate collaboration across the SPORE network.
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Biostatistics and Bioinformatics Core

Core Director:
Ying Yuan, PhD
James Long, PhD

The Biostatistics and Bioinformatics Core for the 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 MD 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.
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Animal Core

Core Directors:
Candelaria Gomez-Manzano, MD
Juan Fueyo, MD

The purpose of the Brain SPORE Animal Core is to provide centralized and specialized animal modeling, thereby achieving uniformity and reproducibility that enables accurate comparisons between experiments, research groups, and projects in this Brain Cancer SPORE. To this end, the Core will:

  • Support specialized surgical methods to generate brain tumor models, a keycomponent of which is the intracranial mouse tumor model.
  • Support all animal strains and tumor cell lines.
  • Support specialized treatment delivery methods. Core D can support complex drug delivery regimens including intracranial injection, intra-thecal injections, intravenous and intra-arterial injections, and oral gavage.
  • Support in vivo imaging and sample collection to assess therapeutic efficacy.

The combined expertise of the Animal Core personnel lends itself to productive collaboration with SPORE and non-SPORE investigators in developing new animal models and unique surgical methods for therapeutic delivery and data collection. These services are mission critical and one or more of these services are used by all Projects in this application.

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Developmental Research Program

Program Directors:
Juan Fueyo, MD
Frederick Lang, MD

The Developmental Research Program promotes highly innovative, translational research pilot projects that will ultimately lead to clinically testable hypotheses with the potential to reduce incidence and mortality of brain cancers. The DRP functions as an incubator of new concepts due to strong organization, leadership, planning, and evaluation. The objectives of the Developmental Research Program are to:

  • Fund innovative projects that have significant potential for improving brain tumor therapy and prognosis, including through better understanding the biology of this disease.
  • Foster collaborative efforts among SPORE investigators and with other investigators to encourage the development of new and innovative ideas.
  • Enhance communications between SPORE leaders and outside investigators to encourage the development of innovative translational strategies in brain tumors.
  • Ensure program flexibility so that developmental projects that show promise can be funded for a second or third year; encourage awardees to apply for extramural peer-reviewed funding (i.e., R01) or expanded to become full SPORE projects.
  • Recruit women and underrepresented minorities as a special emphasis of the program.
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Career Enhancement Program

Program Directors:
Juan Fueyo, MD
Frederick Lang, MD

The Career Enhancement Program provides funding for early-stage basic scientist, physician-scientists, and clinical trialists to develop independent careers in brain cancer research, guided by senior mentors with outstanding track-records in translational research. The program also supports established faculty who wish to enhance or refocus their careers on translational brain cancer research. The CEP includes a strong mentorship program, with specific emphasis on translational brain cancer research:

  • Recruit and train early-stage physicians and scientists to become outstanding translational investigators in the field of neuro-oncology.
  • Recruit established faculty who wish to enhance or refocus their careers on translational brain cancer research.
  • Provide funding for projects of early-stage investigators with the goal of obtaining the necessary preliminary data to secure large independent research grants (e.g., R01) or to become full projects in the SPORE.
  • Provide outstanding mentorship to guide recipients to develop the intellectual, communication, organizational and technical skills required to be productive investigators in translational brain cancer research.
  • Teach awardees basic principles of cancer biology that are not commonly included in clinical training or PhD programs.
  • Recruit women and underrepresented groups into the program, as a special emphasis.
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Institutional SPORE Website

https://www.mdanderson.org/research/departments-labs-institutes/spores/brain-cancer-spore.html

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