Three important goals of clinical research pertinent to glioma are to choose the best treatment available for each glioma patient, to enhance patient stratification so that new treatments can be more quickly and accurately evaluated, and to provide better information to patients and their families on what they can expect as a result of their disease.
Unambiguous diagnosis is a cornerstone for each of these goals. Currently, however, glioma diagnosis is primarily based on assessments of tumor morphology, which are inherently subjective. There is an urgent need to identify tumor and patient characteristics that better define glioma subtype and patient prognosis. This project is addressing this need by examining survival in relationship to several tumor markers which define genetic subtypes of gliomas, and which are thought to be potentially important in prognosis. In addition to consideration of known prognostic indicators such as age, the study also is considering survival as a function of patient characteristics, including a variety of polymorphisms in DNA repair and carcinogen metabolizing genes, personal and family medical histories, diet, smoking, and alcohol consumption prior to diagnosis, as well as other demographic factors such as education.
The survival information derived from this study is expected to be useful to clinicians in planning and refining treatments while information from other factors will be useful in providing patients with a clearer picture of their probable outcomes based on individual characteristics.
This study aims to determine whether quantitative parameters derived from magnetic resonance spectroscopy imaging (MRSI) data are predictive of response to therapy for patients with gliomas. This is an important clinical question because gliomas are heterogeneous, infiltrative tumors with poorly defined margins. Although histological grade has been shown to be predictive of outcome in large-scale clinical trials, there is considerable variability between tumors of the same grade in terms of response to therapy and time to progression. The identification of new factors that predict treatment response are critical for tailoring therapy to individual patient characteristics and are expected to have a significant impact upon the criteria used to select patients for future clinical trials.
UCSF laboratory studies have used MRSI to derive a number of different quantitative parameters that are valuable for defining the metabolic activity and spatial extent of tumor. These include a choline to N-acetylaspartate index (CNI), a choline to creatine index (CCrI), a creatine to N-acetylaspartate index (CrNI), and a lactate plus lipid index (LLI). The present study will determine if these indices provide information that is clinically relevant for the management of gliomas and will determine, using patients on clinical trial protocols at UCSF, if there is a basis for integrating the technology into the design of future clinical trials.
High-grade gliomas remain a surgically incurable disease, largely because of infiltratative growth into surrounding normal brain. Radiotherapy and chemotherapy are limited by inadequate tumor specificity, inherent and/or acquired resistance, and the inability to achieve effective exposure within the brain without causing excessive systemic toxicity. Better therapies must achieve efficient delivery of agents not only to the brain but via selective and efficient targeting to the tumor cells themselves.
A research project of the UCSF Breast Cancer SPORE has resulted in development of an immunoliposome technology for receptor-targeted, intracellular drug delivery. This technology will now be applied to brain tumor treatment. Liposomes will be designed to contain a variety of toxic small molcules and nucleic acids. These liposomes will then be targeted to glioma cells by linkage to single-chain antibodies specific for tumor cells expressing EGFR or mutant EGFR. These immunoliposomes will then be targeted to the brain.
Following optimization and evaluation, the most promising constructs will be moved into clinical trials. This approach is expected to selectively increase drug delivery to brain tumors and to have a significant impact on the therapy of otherwise untreatable gliomas.
Dysregulation of the phosphoinositide 3-kinase (PI3-kinase) signaling pathway plays a key role in the development of gliomas. Novel agents that inhibit elements within the PI3-kinase pathway have entered clinical trials, although to date there is no way to predict which tumor will respond to which kinase pathway inhibitor. This project’s long-term objective is to utilize the molecular profile of individual tumors to guide therapy with effective, molecularly targeted treatments that will improve survival for glioma patients. To achieve this goal, investigators must identify the most promising target for therapeutic inhibition, define the patient population likely to benefit from treatment with signaling inhibitors, and validate the ability of molecular features to guide the choice of signaling inhibitor in the treatment of individual patients.
To identify the signaling molecule whose inhibition is most likely to affect patient survival, elements within the PI3-kinase cascade will be analyzed in diffuse gliomas of all grades. Molecules such as EGFR and PDGFR, which function upstream of PI3-kinase, and molecules such as mTOR and PKB, which function downstream of PI3-kinase, will be characterized for each tumor and correlated with each other and with patient survival. In addition, a subset of patients will be defined who are likely to benefit from inhibition of the PI3-kinase pathway.
To validate the ability of molecular features to guide the choice of signaling inhibitor, investigators will analyze tumors from patients who are enrolled in currently open Phase I clinical trials employing signaling inhibitors. The status of elements within the PI3-kinase pathway will be retrospectively correlated with tumor response to the novel agent. Furthermore, a Phase II trial is being proposed, which will prospectively examine the value of molecular profiling in selecting appropriate treatment for individual glioma patients. The choice of signaling inhibitor to be tested in this protocol will rest on the prevalence of the targeted aberration, the strength of its association with patient survival, and any clinical response data that may arise from the completed phase I trials.
In order to enhance the specificity of agents that inhibit the PI3-kinase pathway, glioma therapy agents that target central elements of this signaling cascade will be incorporated. To this end investigators have developed approaches to specifically inhibit PI3-kinase or its immediate downstream effector PDK1. The delivery and efficacy of these agents will be tested in xenograft models of human gliomas with the goal of incorporating them into the multimodality treatment of glioma patients.
Several clinical trials have shown the feasibility, safety, and anecdotal efficacy of glioma vaccines, although an effective clinical glioma immunotherapy regimen has yet to be developed. The goal of this project is to develop effective vaccine therapy for the treatment of glioma.
Vaccine therapies designed to provoke a cellular immune response depend on activation of both CD8-positive, tumor-specific T-cells and natural killer cells. The investigators in this project have found that two proteins, B7-homologue 1 (B7-H1) and FLIPs, are overexpressed by glioma cells and interfere with the therapeutic immune response by inducing CD8-positive T cell apoptosis and by blocking NK cells activation. Furthermore, both B7-H1 and FLIPs appear to be positively regulated by the same PI(3)K/Akt/mTOR pathway that contributes to the formation and maintenance of gliomas. This project therefore will test the hypothesis that activation of the PI(3)K/Akt/mTOR pathway in human glioma suppresses the T- and NK-cell-mediated anti-glioma immune response, and that modulation of this pathway may improve vaccine efficacy. This hypothesis will be tested within the context of an ongoing phase I/II clinical trial of a newly developed heat shock protein vaccine (HSPPC-96). If successful, this work may lead to the implementation of the first effective vaccine for the treatment of human brain tumors.