Kenneth D. Aldape, MD PhD - US grants

Animals; Biologic Marker; Biological Markers; Biology; Blood Sample; Blood specimen; Body Tissues; CNS Tumor; CNS neoplasm; Cancer of Brain; Caring; Central Nervous System Neoplasms; Clinical; Collaborations; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Evaluation; Experimental Neoplasms; Experimental Tumor; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Glioma; Histologic; Histologically; Investigation; Investigators; MDACC; Malignant Tumor of the Brain; Malignant neoplasm of brain; Molecular Marker; NRVS-SYS; Neoplasms of Neuroglia; Neoplasms, Experimental; Nervous System; Nervous system structure; Neuroglial Neoplasm; Neuroglial Tumor; Neurologic Body System; Neurologic Organ System; Normal Tissue; Normal tissue morphology; Pathologic; Pathology; Patients; Process; Reproduction spores; Research Personnel; Research Specimen; Researchers; Sampling; Services; Signature Molecule; Specimen; Spores; Tissue Arrays; Tissue Chip; Tissue Microarray; Tissue Procurements; Tissue Sample; Tissues; Translational Research; Translational Research Enterprise; Translational Science; Tumor Tissue; Tumors of Neuroglia; Tumors, Central Nervous System; University of Texas M D Anderson Cancer Center; University of Texas MD Anderson Cancer Center; biomarker; clinical data repository; clinical data warehouse; data repository; design and construction; human tissue; improved; prospective; relational database; repository; tissue resource; translation research enterprise; treatment effect; tumor; tumors in the central nervous system

Glioblastoma (GBM) is the most common primary brain tumor in adults and is highly lethal. A recent phase HI clinical trial demonstrated a benefit for temozolomide-chemoradiation (TMZ-CR) over radiation alone. While these results have changed the standard of care for newly diagnosed GBM patients, it is clear that only a fraction of patients derive significant benefit from this treatment, with overall two-year survival in the TMZ-CR treated patients only 26%. Since diagnosis and treatment decisions in GBM are currently based on histopathology alone, there is a need to: 1) develop sensitive and specific markers to prospectively distinguish those patients who will respond to standard TMZ-CR as initial treatment from those who will not respond;and 2) determine important molecular alterations that define the resistant tumors to design rational trials for patients who will not benefit from TMZ-CR alone. We have mined independent microarray datasets to identify an initial multimarker panel that robustly predicts outcome in GBM. We find that a molecular subtype, defined by overexpression of mesenchymal/angiogenic genes, is predictive of poor outcome. In Aim 1, will refine this panel using 2 independent sets of tumor samples from TMZ-CR treated patients at The University of Texas M. D. Anderson Cancer Center (UTMDACC) and the Mayo Clinic College of Medicine. We will include a larger (-400) set of genes to ensure that an optimal gene panel can be identified that predicts progression-free survival. We will incorporate additional relevant markers, including MGMT and Akt signaling intermediates. Aim 2 will rigorously test and validate this multimarker panel using patient samples from a large phase III clinical trial. The newly opened RTOG 05-25 trial, with a requirement of tissue submission, provides an unprecedented opportunity to study a large (n=834) cohort of uniformily-treated GBM patients using modern molecular techniques to identify a definitive set of predictive markers. Aim 3 will focus on markers of response from novel agents targeted to recurrent GBM patients who have failed TMZ-CR. It is expected that tumors from most of these patients will display the mesenchymal/angiogenic phenotype, and we will therefore identify potential agents which target that phenotype in GBM. The results of this project will set the stage for future trials, in which newly diagnosed GBM patients will undergo a predictive test, and treatment will be individualized according to the molecular profile of the tumor to maximize the chances of benefit.

DESCRIPTION (provided by applicant): Glioblastomas (GBMs) remain among the most devastating of all known human tumors, with median survival times remaining around 12-15 months from initial diagnosis. The introduction of temozolomide chemotherapy, when used concurrently and adjuvantly with radiation, has been shown to significantly improve median survival times and increase the percentage of longer-term GBM survivors. The Radiation Therapy Oncology Group (RTOG), which is one of the largest and most established cooperative groups in oncology, has developed a recursive partitioning analysis (RPA) model for malignant glioma patients, using primarily clinical and demographic variables to stratify malignant glioma patients into one of six distinct prognostic classification groups. The RTOG RPA has long been considered the international "gold standard" as a prognostic model for GBM patients. However, since the original RTOG RPA was developed in the 1990's, two major developments have transpired. First, there has been a rapid advancement in the understanding of the molecular, genetic, and epigenetic mechanisms underlying the pathophysiology and the observed treatment resistance of GBMs, with single institution and limited cooperative group data suggesting that a subset of these biomarkers could serve as useful prognostic markers in GBM. Second, there has been a shift in the adjuvant treatment paradigm of GBMs away from radiation alone (when the original RTOG RPA model was developed) to radiation combined with concurrent and adjuvant temozolomide. Therefore, given these two paradigm shifts, it becomes essential to refine and/or redevelop an RTOG RPA model that is updated along these lines. It is our hypothesis that inclusion of these promising biomarkers will serve to significantly refine the existing RTOG RPA classification model to establish distinct prognostic groups of GBM patients treated in the TMZ era, based on a combination of molecular and clinical variables. The revised RTOG RPA resulting from the proposed effort may be universally used to determine patient eligibility in future clinical trials, as well as to provide guidance with regards to future directions for molecularly-based targeted therapies for GBM patients. The revised RTOG RPA model can be used to establish the "gold standard" expected outcomes for various the prognostic groups of GBM against which the results from clinical trials involving investigational therapies can be compared, much like its decade's old RTOG RPA predecessor model. Therefore, this proposed endeavor is of the utmost importance and relevance for this patient population and will be universally utilized in the international brain tumor community. With regards to methodology, this proposal represents a joint effort between the RTOG and the laboratories of Arnab Chakravarti, MD, Chair and Professor of Radiation Oncology at the Arthur G. James Comprehensive Cancer Center of the Ohio State University and Kenneth Aldape, MD, Professor of Neuropathology at the MD Anderson Cancer Center. Drs. Chakravarti and Aldape are Chair and Co-Chair of the RTOG Brain Tumor Translational Research Group, respectively. Our strategy will be to utilize biorepository specimens from the recently completed RTOG 0525 to accomplish our stated objectives. RTOG 0525 was a Phase III Study conducted in North America, Europe, and Asia comparing dose-dense versus standard dose TMZ when combined with radiation for newly-diagnosed GBM. Tissue blocks were prospectively collected on each and every one of the 1173 GBM patients enrolled on this RTOG study, which have been made available for our NIH challenge grant effort. We will revise the existing RTOG RPA classification model to include not only clinical/demographic variables, but also key molecular, genetic, and epigenetic variables. To this end, we shall validate key signal transduction biomarkers, genetic, and epigenetic markers that have been previously shown to be of prognostic value in smaller GBM studies by our group and others. This data will be combined with the clinical and demographic data previously found to be of importance in the previous RTOG RPA model to generate a revised RPA classification model pertinent to TMZ-treated GBM patients and one that is refined to include molecular, genetic, and epigenetic data of significance.

A fundamental component of the translational research of the The University of Texas 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 objectives of the Pathology and Biorepository Core are these: Objective 1 Maintain and enhance a repository of tumor tissue and matched blood specimens from patients with central.nervous system (CNS) tumors receiving care at MD Anderson Cancer Center Objective 2 Provide comprehensive histologic characterization of tissue samples used in SPORE projects, including specimens from patients and experimental tumors in animals; expeditiously distribute tissue specimens to SPORE investigators for analysis and provide expertise in the interpretation of studies performed on tissue sections within SPORE projects Objective 3 Offer centralized services, including immunohistochemical characterization of biomarkers, tissue array design and construction and primary GSC culture of tumor samples where appropriate. Objective 4 Support a comprehensive, prospective interactive database with detailed clinical and pathologic data for patients with CNS tumors receiving care or evaluation at MD Anderson Cancer Center Objective 5 Facilitate inter-SPORE collaborations through sharing of tissue resources RELEVANCE (See instructions): DO NOT EXCEED THE SPACE PROVIDED. Research into brain cancer depends on the availability of tumor samples obtained from patients. These samples and the DNA, RNA, proteins, and cells derived from them (e.g. GSCs) are the foundation of any translational program. This Core provides the patient samples that are key to understanding and curing brain tumors.

Progress in the treatment of patients with GBM has been limited by the ability to identify those subsets of patients that will respond to a particular therapy. GBM is a heterogeneous disease with a diverse molecular makeup and selecting patients for appropriate novel agents is needed to improve outcomes.. Successful development of the molecular predictors proposed in this project will translate into personalization of treatment and better patient survival.

There is a gap in in the availability of predictive biomarkers that are necessary to personalize treatment for patients with GBM. A challenge has been to separate prognostic makers (those that predict the natural history of the disease) from predictive (those that predict response to a particular treatment). l/Vfe hypothesize that effective biomarkers of treatment response must be decoupled from prognostic influences. Furthermore, to maximize clinical utility, these biomarkers must be developed as high-throughput, validated diagnostics applicable to small quantities of formalin-fixed, paraffin-embedded (FFPE) tissue. The specific aims of Project 3 are: 1) Develop a novel clinical diagnostic to classify patients suitable for FFPE tissue and incorporating the most robust molecular prognostic markers. 2) Develop a predictive marker of response to anti-angiogenic therapy. 3) Develop a predictive marker of response to immunomodulation. In the initial MDACC Brain SPORE funding, we developed a 9-gene FFPE biomarker that distinguished favorable from unfavorable patient prognosis. The assay was validated, commercialized, and incorporated as a prospective stratification factor in a phase III trial evaluating the anti-angiogenesis inhibitor bevacizumab [Radiation Therapy Oncology Group (RTOG) 0825]. To further improve survival discrimination, we expanded the 9-gene signature to a more robust 19-gene. In addition, we identified an additional epigenetic prognostic signature, the glioma CpG-island methlylator phenotype (G-CIMP). Using >300 cases from M.D. Anderson Cancer Center (MDACC) we developed a unified four risk group system called the molecular-clinical, prognosticator (MCP) that combines clinicopathologic factors with gene expression, genetic, and epigenetic factors. The analytic approach in constructing the MCP and its improved prognostic classification will allow us to better develop predictive makers independent of prognostic influences. Based on our success in the initial SPORE funding period and leveraging our expertise in biomarker development and our close involvement with the RTOG we know propose renewal of this project.