This project outlines a research effort aiming to investigate the molecular and cellular mechanisms supporting metastatic spread of prostate cancer and to develop new approaches toward increasing the efficacy of chemotherapy upon prostate cancer metastasis. Prostate carcinoma is the most common cancer among men and the second leading cause of male cancer death in the US, while metastasis is the major cause of prostate cancer-related morbidity and mortality. The molecular and cellular mechanisms of prostate cancer metastasis, however, are still poorly understood. Mounting experimental evidence from this and other groups suggest that interactions mediated by cancer- associated Thomsen-Friedenreich (TF) antigen, a simple mucin-type disaccharide, Gal21-3GalNAc expressed on most human carcinomas including prostate, and 2-galactoside-binding lectin galectin-3 (Gal-3) are likely to play a leading role in initiating and supporting metastatic prostate cancer cell adhesion to microvascular endothelium. In addition, these interactions are also important in promoting cancer cell clonogenic survival and regulating their susceptibility to apoptosis induced by cytotoxic drugs. It has been hypothesized that TF antigen/Gal-3 mediated tumor-endothelial cell adhesive interactions are stabilized by 1321 integrin and induce a crosstalk between major signaling pathways via Src kinase dependent mechanisms promoting cancer metastasis. It has been further hypothesized that inhibiting Gal-3 anti-apoptotic function using synthetic glycoamine Lactulosyl-L-Leucine (LL), will simultaneously target metastasis-associated adhesive events and augment sensitivity of metastatic prostate cancer cells to apoptosis induced by cytotoxic drugs in vitro and in vivo and significantly increase the effectiveness of chemotherapy upon prostate cancer bone metastasis. To test these hypotheses, the following specific aims are proposed: 1. To investigate the molecular mechanisms and temporal dynamics of metastatic cell adhesive interactions with microvascular endothelium; 2. To investigate major signaling pathways triggered by 2-galactoside-mediated adhesive interactions in endothelial and tumor cells; 3. To investigate molecular and cellular mechanisms of LL interactions with cytotoxic drugs to enhance apoptosis in human metastatic prostate carcinoma cells; and 4. To investigate in vivo the ability of LL to increase effectiveness of docetaxel upon established prostate cancer bone metastases. To achieve these goals, an integrated approach is suggested combining in vitro parallel flow chamber techniques and atomic force microscopy in Aim 1; standard cell biology techniques and phosphoproteomic approaches in Aim 2; in vitro experimentation employing comprehensive analysis of the mitochondrial apoptosis pathway in Aim 3; and in vivo nondestructive quantitative bioluminescent imaging in a preclinical model of prostate cancer bone metastasis in Aim 4. Prostate cancer is highly relevant to the veterans' population. The results of this study will ultimately enhance our understanding of cellular and molecular mechanisms underpinning prostate cancer metastasis and provide the rationale for the development of new mechanism-based therapies of this devastating disease. Further, the results of this study may have an immediate profound effect on the development of new therapeutic approaches to treat metastatic prostate cancer, which could be translated into clinical practice in a very short time. If proven successful, these new approaches to prostate cancer chemotherapy could benefit greatly patients with advanced metastatic prostate disease by reducing tumor burden, enhancing quality of life, and reducing morbidity and mortality.
Project Narrative Prostate carcinoma is the most common cancer among men and the second leading cause of male cancer death in the US. It was projected that there will be 186,320 new cases of prostate cancer diagnosed, and 28,660 men will die from the disease in the US in 2008. Currently incurable, metastasis (a spread of cancer to distant organs) is the major cause of prostate cancer-related morbidity and mortality among aging veterans. This project aims to identify new therapeutic targets for preventing and controlling metastatic cancer spread and enhance the efficacy of chemotherapy upon established prostate cancer metastases using non-toxic carbohydrate-based compounds. If successful, the results of this study will be ultimately translated into clinical practice and will benefit veteran patients with prostate cancer by reducing tumor burden, enhancing quality of life, and reducing morbidity and mortality.
