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Last Updated: 10/10/18

SPORE in Brain Cancer

University of Texas M.D. Anderson Cancer Center

Principal Investigator:
Frederick F. Lang, M.D.

Principal Investigator Contact Information

Frederick F. Lang, Jr., M.D., F.A.C.S., F.A.A.N.S.
Professor
Department of Neurosurgery
1400 Holcombe Blvd, Unit 442
Houston, TX 77030
Phone: (713) 792-2400
Fax: (713) 794-4950
Email: flang@mdanderson.org

OVERVIEW

Almost 70,000 people will be diagnosed with a primary brain tumor in 2013, and of these, 11,900 will be diagnosed with glioblastoma, the most common and the most aggressive malignant brain tumor. Sadly, the median survival for glioblastoma is 14.6 months, despite standard surgery, radiation, and chemotherapy treatments, with only incremental improvement over the past 20 years. This Brain Cancer SPORE builds upon exciting advances, including the development of new biological (oncolytic virus, stem cell delivery), targeted (PI3K inhibitors), and immunomodulatory (p-STAT-3 inhibitor) therapeutic strategies. In the last 5 years, the MD Anderson SPORE in Brain Cancer supported the completion of a Phase I clinical trial of the oncolytic virus Delta-24-RGD, a Phase II clinical trial of the PI3K inhibitor BKM120, and an Investigative New Drug (IND) designation for a new immunological agent, WP-1066. This grant also advanced the potential for personalized treatment for glioblastoma with a prognostic biomarker profile (9-Gene Signature), which was incorporated into two large Phase III trials (RTOG-0525; RTOG-0825). In the next 5 years, our goal is to capitalize on our prior successes in order to improve the outcome of patients with malignant gliomas through a continued multidisciplinary, integrated, flexible, and highly translational (bench to bedside and back) research program that aims to discover and rationally test new biologic, targeted, and immunological therapies, and to develop prognostic and predictive biomarkers that inform "personalized" approaches to glioblastoma treatment. To achieve these goals, we propose four fully translational research projects (3 therapeutic; 1 population-based), which incorporate tissue-based clinical trials, and are supported by five Cores (Administrative, Pathology/Biorepository, Biostatics/Bioinformatics, Clinical, and Animal).

PROJECT 1: A Tropism Enhanced Oncolytic Adenovirus for the Treatment of Brain Tumors

Project Co-Leaders:
Juan Fueyo, M.D.
Frederick F. Lang, M.D.

The oncolytic virus, Delta-24-RGD, was developed in MD Anderson laboratory to target a cellular mutation seen only in cancer cells. Work in the SPORE led to the successful testing of the virus in a Phase I trial. Investigators will now enhance the ability of the virus to infect cancer cells by using bone marrow stem cells (proven to ‘home’ to cancer cells and improve tumor cell kill by combining Delta-24-RGD and temozolomide. Clinical trials of these strategies are planned.

PROJECT 2: Targeting Altered Signaling Pathways in Glioblastoma with PI3K Inhibitors and Rational Combinations

Project Co-Leaders:
W.K. Alfred Yung, M.D.
Guilio Draetta, M.D., Ph.D.

The phosphoinositide-3 kinase (PI3K) signaling pathway plays an important role in tumor initiation and growth. Project 2 investigators are leaders in identifying molecular targets in glioblastoma, testing inhibitors of these targets in the laboratory, and successfully translating these drugs into clinic trials. Targeting the PI3K signal transduction pathway is part of this broader approach of combining specific inhibitors of signal transduction pathways critical to glioma development and growth. Rational combination therapies will be developed and tested, based on analysis of molecular ‘escape’ mechanisms found in tumor tissue and the glioma stem cell model, leading to strategies to block cancer cell resistance.

PROJECT 3: Prognostic and Predictive Markers to Personalize Medicine for Malignant Glioma

Project Co-Leaders:
Erik P. Sulman, M.D., Ph.D.
Jason Huse, M.D., Ph.D.

Project 3 SPORE investigators have been pioneers in the field of glioblastoma biomarkers. They described the first glioblastoma molecular classification (proneural, proliferative, mesenchymal) based on expression profiling, and developed the first genetic test (the 9-gene prognostic signature) for stratifying patients into outcome groups based on gene expression. Project 3 investigators have now combined clinical, mutational, and expression analyses into a novel unified (clinical and molecular) classification system, and propose to take the important next step of transforming the MCP into a clinical diagnostic test that will identify patients whose prognosis after standard therapy is particularly poor and allow those patients to be funneled early into appropriate clinical trials.

PROJECT 4: Overcoming Immunosuppression with a Novel Inhibitor of the STAT-3 pathway

Project Co-Leaders:
Amy B. Heimberger, M.D.
Suyun Huang, M.D., Ph.D.
Waldemar Priebe, Ph.D.

Tumor-mediated immunosuppression is a significant hurdle preventing the success of immunotherapy in glioblastoma. Work funded in part by a SPORE Developmental Research Project identified p-STAT3 as a driver of tumorigenesis and immune suppression in glioblastomas and spurred the testing of a new p-STAT3-inhibitor, WP1066. Investigators will use GSCs, immune-competent animal models, and ultimately a Phase I/II clinical trial to decipher the direct cytotoxic effects from the immunomodulatory effects of WP1066.