One of the most common genetic alterations found in astrocytic glioma is a mutation in the p53 tumor promoter. Recent evidence from in vitro and preclinical mouse studies suggests that when p53 function is impaired in glioma cells they exhibit an enhanced response to the alkylating chemotherapeutic agent, temozolomide;however, the mechanisms governing the enhanced response are unknown. We recently performed magnetic resonance spectroscopy (MRS) studies on tissue biopsies from astrocytic gliomas and found that tumors with abnormal p53 function consistently had lower creatine+phosphocreatine values than those with normal p53, suggesting that p53 influences the pathway utilized for energy metabolism in gliomas. The purpose of this project is to further explore the relationship between p53 functionality, tumor metabolism, and response to therapy in glioma. Specifically, we will determine the role of p53 in creatine metabolism and determine whether there is a metabolic link between p53 dysfunction and an enhanced response to cytotoxic chemotherapy. Impact: Genomic biomarkers of glioma response to therapy have been discovered over the past decade but the associated physiological mediators of the response are still being determined. This study will attempt to bridge the gap between a common genetic alteration and the resulting enhanced response therapy by determining whether and how the effect is mediated through alterations in tumor metabolism.
In Specific Aim 1, we will compare the metabolic profile and therapeutic responsiveness of glioma cells with functional and non-functional p53 tumor suppressor protein to test the hypothesis that cells with non-functional p53 will have lower creatine+phosphocreatine levels and will be more responsive to temozolomide chemotherapy than cells that have normal p53 function. The concentrations of 13 metabolites will be measured with high resolution magic angle spinning (HRMAS) MRS;however, creatine and phosphocreatine cannot be measured separately with HRMAS. Therefore, in Specific Aim 2 we will further characterize the metabolomic profile of p53 functional and p53 non-functional gliomas in orthotopic xenograft mouse models by adding mass spectrometry to the metabolic assessment.
Aim 2 will test the hypothesis that tumors with non-functional p53 will have lower levels of creatine, higher levels of phosphocreatine, higher levels of metabolites associated with glycolysis and will be more responsive to temozolomide chemotherapy than tumors normal p53 functionality. The proposed studies will explore the metabolic link between p53 functionality and response to chemotherapy to glean more information on the mechanisms by which some cells are more sensitized to chemotherapy while others survive and proliferate in the presence of chemotherapy.
Considerable effort has been made over the last decade toward understanding how cancer presents itself in individual patients so that patient-specific therapies can be developed. As a result, specific genetic mutations are now known to indicate whether a patient will have a positive or negative response to certain therapies;however, the reasons for the differential responses are poorly understood. This project aims to understand how a common genetic mutation that is an indicator of favorable response in brain tumors affects the metabolic processes that govern tumor growth and regression so that therapies targeting those processes can be developed for brain tumor patients that do not have a favorable genetic signature.