Multiple myeloma is an incurable malignancy of the plasma cell characterized by migration and localization to the bone marrow where cells then disseminate and facilitate the formation of bone lesions. Despite initial responses to chemotherapy, myeloma cells ultimately develop drug resistance and become unresponsive to a wide spectrum of anti-cancer agents. Previous work supported by this grant evaluated the role of classical drug resistance genes, including MDR1, MRP, BCRP, and others, in the development of drug resistance. All of these studies used a selection pressure of exposing myeloma cells to drugs grown in routine suspension culture. In the clinic, we reported that the expression of MDR1/Pgp was an acquired event and the proportion of Pgp-positive myeloma cells in patients was related to past chemotherapy administration. This study demonstrated that survival to initial drug exposure was not likely related to Pgp, and that non-Pgp mechanisms conferring low level drug resistance were believed to be important in the survival and expansion of the malignant cell population. Factors that allow for tumor cell survival following initial drug exposure need to be identified because these factors may eventually allow for the expression of genes associated with acquired drug resistance. We recently reported that cell adhesion mediated by Beta 1 integrins may protect malignant hematological cells from drug-induced apoptosis, and that suppression of drug-induced apoptosis may allow for the eventual emergence of other well characterized mediators of drug resistance such as MDR1/Pgp. In this current application, we propose to expand upon our previous observations by examining the contribution of the tumor microenvironment as a determinant of drug response and resistance. Our overall hypothesis is that the bone marrow microenvironment provides a sanctuary for hematopoietic malignant cells by blocking apoptosis thereby allowing for tumor progression and the eventual emergence of acquired drug resistance. The following specific aims will be pursued to evaluate this hypothesis:
Specific aim 1 : To determine if pre-adhesion of myeloma cells to FN alters the frequency and/or phenotype of acquired resistance to doxorubicin.
Specific aim 2 : To examine the role of chromatin structural changes following integrin activation and inhibition of drug-induced apoptosis.
Specific aim 3 : To examine integrin signaling and activation of the caspase cascade following CD95 and cytotoxic drug exposure.
Specific aim 4 : To examine the interaction between cytokines (IL-6 and GM-CSF) and integrin signaling in myeloma and leukemia cells. Understanding the influence of the microenvironment on tumor cell survival and drug response will identify new molecular targets for future therapies of myeloma and other hematologic malignancies.
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