Exploiting The Heterogeneous Composition Of Tumor Tissue And The Altered Metabolism Of Tumor Cells For Cancer Therapy Design

Texas A&M Engineering Experiment Station, College Station TX

Investigators

Abstract

Title: Exploiting the heterogeneous composition of tumor tissue and the altered metabolism of tumor cells for cancer therapy design The number of cells in an adult multicellular organism such as a human being is under very tight control and, under normal circumstances; there is some kind of a balance between new cell production and cell death. Roughly speaking, cancer results when there is excessive cell division or reduced cell death due to some malfunctioning in the cell number control system. What makes cancer therapy so difficult is that this malfunctioning can happen in many different ways and at many different locations and would, therefore, require different tailored treatments. Furthermore, cancer tissue is usually heterogeneous in the sense that it is a mixture of cells with different malfunctions. As a result, directing treatment at one type of malfunctioning cells may lead to the dominant emergence of other types of malfunctioning cells, manifesting itself in the phenomenon of acquired drug resistance usually observed in cancer therapy. Thus, to achieve better therapeutic outcome, the dominant cell subpopulation needs to be identified so that the therapy can be targeted towards it. The first goal of this project is to experimentally demonstrate the feasibility of such an approach using a heterogeneous mixture of cancer cell lines. The second goal of this project is to exploit metabolic alteration in cancer cells to design therapies that differentially target cancer cells. More specifically, the project seeks to experimentally validate via cancer cell lines the benefits of including the anti-diabetic (metabolism targeting) drug Metformin as part of a combination cocktail therapy for cancer. Since both the goals are directed towards improving cancer treatment, the potential societal benefits of this project could be enormous. In addition, the project will be carried out at the newly formed Center for Bioinformatics and Genomic Systems Engineering (CBGSE) at Texas A & M University, where widespread dissemination of the research results, imparting truly interdisciplinary hands-on education to graduate students, and beneficially targeting minorities and minority institutions, are top priorities. Cancer is an umbrella term for a large number of diseases that are associated with loss of cell-cycle control, leading to uncontrolled cell proliferation and/or reduced apoptosis (programmed cell death). This loss of cell-cycle control usually results from different malfunction(s) in the cellular signaling pathways. Since cancer tissue is usually heterogeneous, it is appropriate to first identify the dominant subpopulation and then accordingly tailor the targeted treatment, hopefully achieving a better therapeutic outcome. The first goal of this project is to utilize such an approach, developed using hierarchical Bayesian methods, and experimentally validate it using a mixture of cancer cell lines, harboring known mutations. To introduce the second goal, we note that the traditional approach to cancer therapy is to induce cancer cell death by using therapeutic drugs, radiation, etc. Most of these treatments are toxic to normal cells and carry significant side effects. On the other hand, cancer cells are known to be addicted to glucose while normal adult cells are not. This brings up the natural question as to whether the preferential killing of cancer cells could be achieved by targeting the supply of glucose. Indeed, epidemiological studies have shown that the commonly used anti-diabetic drug Metformin has beneficial effects in preventing or slowing the onset of breast and certain other cancers. Motivated by this, the second goal of this project is to experimentally study the role of Metformin in cancer therapy when used as part of a combination therapy design. Since most chemotherapeutic drugs have toxic side effects while Metformin does not, including the latter as part of a combination therapy for cancer certainly has the potential to enhance the quality of life for cancer patients.