This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Leslie J. Kreuger, Phd, FACMG Dominanace of mTOR Inhibitors in Breast Cancer: Broad Antineoplastic Effects In Vitro and In Vivo Of the factors that mediate against therapeutic success in breast cancer, two stand out. First, like all somatic cells, cancer cells are robust. Different growth factors and many unrelated pathways lead to the aggressive and uncontrolled growth that we define as cancer. Once initiated, the complex interactions and patterns of metabolic regulation define distinct subpopulations of cells that become resistant to continued intervention. These paths blunt any internal or external attempts to alter the inherent cancerous growth. In the ?omics (genomics proteomics, pharmacogenomics, etc), the understanding of these pathways is vital to the discovery of anti-cancer targets and the design of new effective drugs. Unfortunately, tumor progression and resistance are fostered by this very same biological redundancy that is so well hard wired. This dynamic nature of the cancer population must be accommodated in any considered approach to therapy. It is because of these concerns that we propose to investigate mTOR inhibitors in breast cancer. These inhibitors are well defined and more importantly act in a dominant manner to """"""""turn-off"""""""" many of these redundant paths. The second major factor is treatment related toxicity. The ability of cancer to escape from single modality therapy led to the discovery of multi-agent chemotherapy. Because tumor progression and resistance occur in the midst of intervention, chemotherapeutic combinations and adjuvant therapies now are currently employed. This leads to toxic effects in the treated patient. Although documented full- and partial-successes are encouraging, problems clearly arise from the added toxic burden that each new drug brings to the patient. While novel multi-drug regimens are clearly required for continued cancer treatment success, we need novel ways of managing the horrific toxicity of these regimens. The mTOR inhibitors are in daily clinical use with minor toxicity. Why mTOR inhibitors? Probability theory tells us that as the number of cancer cells increases so too will the number and severity of adverse events. During growth, the cancer cells will accumulate mutations, thus changing the original clonal population to one both metabolically and genetically diverse. This diversity or genetic heterogeneity of the cancer makes it impossible to foresee all the relevant cancer populations that require intervention ?ultimately leading to treatment failure. One group of pathways, the Akt/PI3K/mTOR growth signaling pathways, has several beneficial properties that are now being exploited in the management of breast cancer. We propose in vitro cell culture and in vivo animal modeling to define the mechanism of action of this novel class of drugs. This project is running in parallel to an identical approach in children with posttransplantation lymphoproliferative disorders (PTLD). The Akt/PI3K/mTOR growth signaling pathways are keys in the functioning of immune modulation using the chemical immunosuppressant, rapamycin. This is similar to the drug that is used in breast cancer. Knowledge gained from either the breast cancer or PTLD protocols will enhance the targeted use of rapamycin (an mTOR inhibitor) in pediatric and adult cancers.
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