The most common question asked in the pediatric cancer arena by parents, patients, caregivers is: How can we find a cure?   The Ready or Not Foundation believes that scientific research will lead to the answer.  The Texas Children's Cancer Center (TCCC) is searching for the answer; that is, TCCC has laid out a plan to search for a cure for the most deadly of pediatric brain cancers.  In the process, better treatments will be revealed, greater knowledge will be gained as to genetic predispositions, and methods to avoid and/or minimize debilitating long term adverse effects will be achieved.  TCCC, a joint program between Baylor College of Medicine and the Texas Children's Hospital, has embarked on such an endeavor.  As a part of the effort, the following proposal was presented to the Ready or Not Foundation.  The TCCC proposal outlines with specificity the research that TCCC will pursue in their quest for a major breakthrough with this disease.  The Ready or Not Foundation has accepted TCCC's proposal, and is thus raising funds in support of these efforts.  With our financial help, the seed is planted. Watching these efforts grow into maturity might take some time, but let us begin.

Baylor College of Medicine

A proposal to support the

GLIOMA RESEARCH PROGRAM

at

Texas Children's Cancer Center

Submitted to the

Jackie Black Brain Cancer Foundation

Executive Summary

Baylor College of Medicine respectfully submits this request for a gift of $1.5 million, payable over three years, to enable the Texas Children's Cancer Center to support a comprehensive Glioma Research Program. These funds would allow us to pursue new strategies of drug development for gliomas, the most devastating of all human brain tumors.  The requested funds would support and expand the center's current glioma research efforts, establish a formal Glioma Research Program, and create a named Jackie Black Brain Cancer Foundation Glioma Research Laboratory.  Your support is needed to match a gift we hope to receive soon from a large local foundation that has been supportive of the Cancer Center's brain tumor research. The total impact, therefore, of the Jackie Black Brain Cancer Foundation's gift would be $3 million.

This proposal is specifically aimed at expediting the development of more effective and innovative therapies for glioma, a commonly occurring brain tumor that strikes both children and adults.

Background

Glioma is the most common type of brain tumor in both adults and children.  Despite decades of basic science and clinical research, there have been few substantial improvements in treatment success and overall patient survival.  The prognosis for patients with malignant glioma remains dismal, with the majority of individuals dying within one year of initial diagnosis.  Long-term survival is particularly poor in the large subset of patients with gliomas that are not amenable to surgical removal.  With conventional therapeutic approaches, approximately half of these patients will suffer from progressive disease and many will suffer significant adverse sequelae.  Thus, there is an urgent need for the development of effective new therapies for gliomas. Among the major obstacles to the development of effective therapies is an incomplete understanding of the biology of these tumors that defines their clinical behavior, and a lack of systematic and efficient strategies for drug development.

This proposal focuses on overcoming these obstacles by implementing an integrated approach aimed at streamlining the process of identifying new therapeutic targets in gliomas and translating them into new therapies. In addition, it seeks to exploit recent promising findings emanating from Texas Children's Cancer Center investigations that suggest a promising role for innovative nanotechnology and immunotherapeutic approaches to treat gliomas. Texas Children's Cancer Center has assembled a multi-disciplinary team of investigators focused on better understanding the biology of gliomas and identifying novel therapies for them.

The Glioma Research Program

The proposed Glioma Research Program will focus its efforts on the scientific initiatives outlined below.

Developing a Comprehensive Genomic Database:

We plan to develop a comprehensive genomic database containing all types of pediatric gliomas that will be used not only by TCCC investigators but also by external collaborators from various institutions in the United States and other parts of the world.  This genomic database will help us identify novel therapeutic targets based on the genetic changes unique to pediatric gliomas.  Previously this type of effort has been hampered by the lack of a sufficient number of samples in each institution.  We have overcome this obstacle by forming an international consortium of research centers that have agreed to pool all of our cases and work together to develop such a resource. This approach has been endorsed by the Children's Oncology Group (COG). The TCCC has become the genomic reference laboratory for a number of COG-sponsored brain tumor clinical trials.

Improving Understanding of Glioma Biology: Identification of the Key Growth Regulatory Pathways that Represent Molecular Targets for Therapeutic Drug Design:

One of the major problems in the development of an effective therapy for glial tumors is an inadequate understanding of the underlying biology of these tumors. To more completely identify the genetic changes associated with glioma formation, we plan to employ a combination of approaches, including genomic, gene expression, and DNA methylation profiling.  We propose to perform comprehensive high-throughput genome-wide profiling, incorporating state-of-the-art approaches that include using Affymetrix U133 Plus 2 or "all exon" arrays for gene expression profiling, CpG methylation arrays and BAC arrays for methylation profiling, microRNA arrays for microRNA profiling, and Affymetrix 500K SNP arrays for both allelotyping and comparative genomic hybridization (CGH). In addition to identifying novel targets, these genomic studies will also help identify key regulatory pathways and specific molecular targets critically important for glioma formation.  In addition to these studies on human glioma tissues, we will also use clinically relevant mouse models to perform cross-comparisons between human and mouse tumors.  These studies are likely to help uncover molecular signature changes that are critical for tumor formation and progression. 

Using Unique Animal Models for Preclinical Drug Screening:

An additional obstacle in developing novel therapies for gliomas has been the lack of preclinical glioma models that accurately predict clinical response.  Many of the compounds entered into clinical brain tumor trials were originally identified by screens using subcutaneous xenografts, which do not develop in the context of the central nervous system (CNS) microenvironment.  We plan to integrate three in vivo models as part of a thorough preclinical evaluation of lead drug compounds: an orthotopic glioma xenograft model, a genetically-engineered mouse model, and a nonhuman primate CNS pharmacokinetic model. The orthotopic intracerebral and intracerebellar xenograft models, developed by Dr. Xiao-Nan Li in our center, has been demonstrated to better recapitulate the biological behavior of clinical glial tumors.  In addition, this orthotopic xenograft model has been shown to retain the unique subpopulation of tumor stem cells, which have been implicated to be a major reason for glioma resistance to conventional therapy and to relapse after initial response. This is the most clinically relevant model available to date for preclinical evaluation of potential therapies against gliomas.  In addition, another Texas Children's Cancer Center investigator, Dr. Susan Blaney, has developed a nonhuman primate model for CNS pharmacokinetic studies that can be used to evaluate the CNS penetration of promising new compounds.

Implementing High-Throughput Therapeutic Drug Validation Strategies:

Another major obstacle in the application of a genomic approach to drug development has been the lack of high-throughput validation strategies in the discovery phase.   Once our preliminary gene profiling studies performed on glioma tissues have identified potential drug targets, we will perform high-throughput studies to validate these possible targets using highly sophisticated technologies now available to us through the recent establishment of the John S. Dunn Gulf Coast Consortium for Chemical Genomics.  Using this state-of-the-art facility, we propose to use RNA interference approaches to independently validate the function of the candidate genes and pathways by either targeted inactivation or using whole genome siRNA libraries. We will also use the chemical genomics approach as part of the target validation process.  This will involve the use of either small chemical libraries that target specific pathways/molecules or large-scale combinatorial chemical libraries. The compounds identified at this stage could be used both as chemical probes to further dissect the pathways and as potential lead compounds in our subsequent drug development phase of this project. We currently have access to a library of 35,000 discreet compounds for routine screening and are in the process of expanding the library to 85,000 compounds.  In addition, because of our ongoing collaborations with several pharmaceutical companies, we will have access to more specialized chemical libraries to study for possible therapeutic efficacy against gliomas.

Developing Novel Nanotechnology and Immune-Based Therapies:

We are already developing methodologies to use novel technologies, such as nanotechnology for drug delivery and tumor vaccines, that can utilize the patient's own immune system to seek out brain tumor cells that carry the unique targets identified through genomic analysis and high-throughput validation. TCCC investigators are already successfully pursuing these novel therapeutic approaches and have generated significant interest within the scientific community regarding these approaches.

A number of the TCCC investigators hold leadership positions in the Phase I Consortium of  the COG and the Pediatric Brain Tumor Consortium (PBTC), both of which are charged to develop novel therapies for pediatric cancers and, in the case of the PBTC, specifically for pediatric brain tumors.  Thus, any novel therapies discovered through our Glioma Research Program can be quickly translated into national clinical trials.

Request for Funding

Physician-scientists involved in brain tumor research at Texas Children's Cancer Center seek to expand their current glioma research efforts and develop a coordinated research program that is focused on identifying improved therapies for human gliomas, the most devastating of all brain tumors.

Establishment and implementation of the Glioma Research Program described above holds a high likelihood for success.  This program will improve our understanding of the biology of gliomas and facilitate the identification of new molecular targets.  The program is highly likely to lead to the discovery of novel drug therapies for  brain tumors.  Moreover, current research exploring nanotechnology and immunotherapy approaches holds significant promise.

Texas Children's Cancer Center's expertise in cancer genomics and brain tumor research is well recognized nationally and was instrumental in our Center becoming one of 10 select institutions in the country, chosen competitively by the National Cancer Institute, to become a member of the national Pediatric Brain Tumor Consortium.

Gliomas are the most difficult brain tumors to treat and the ones with the poorest prognosis.  A more robust research effort is needed to more rapidly achieve our goal of developing innovative, tumor-specific therapies for both children and adults with glioma.  

Your gift would allow Texas Children's Cancer Center (1) to support the research efforts of our most promising glioma researchers and their technical staff (including a postdoctoral fellow), (2) to recruit an additional Assistant/Associate Professor with expertise in glioma research, (3) to hire a postdoctoral computational biologist who would participate in overseeing the complex data derived from these high-throughput studies and (4), to provide necessary supplies and equipment for this highly sophisticated research program.

We believe that we are well poised to successfully pursue our Glioma Research Program.  We respectfully request a gift of $1.5 million, payable over three years, from the Jackie Black Brain Cancer Foundation to provide the resources necessary to expand our current glioma research efforts and to develop a formalized Glioma Research Program that will pursue the scientific initiatives described in this proposal. As noted above, your gift would help encourage support from the local foundation mentioned earlier, such that the total impact of this gift would be $3 million.  In appreciation of this gift, Baylor College of Medicine would establish the named Jackie Black Brain Cancer Foundation Glioma Research Laboratory at Texas Children's Cancer Center.