Lycopene & Docetaxel in Prostate Cancer: An IGF-I Receptor Targeting Approach

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DESCRIPTION (provided by applicant): Advanced prostate cancer patients have significant long-term morbidity. Uses of dietary supplements including lycopene have recently gained popularity in these patients despite the paucity of clinical data to demonstrate their efficacy. As docetaxel has become the first line chemotherapy for patients with hormonal refractory prostate cancer, the efficacy and safety of lycopene in combination with docetaxel-based chemotherapy needs to be evaluated. While preclinical studies have suggested that lycopene could be used as a strong antioxidant for ameliorating the toxic effects of many chemotherapeutical agents, whether lycopene will enhance or interfere with the anti-tumor activity of docetaxel-based chemotherapy remains unknown. Our preliminary data has demonstrated that lycopene at physiological concentrations can potentiate the efficacy of docetaxel in reducing the viability of PCa cell lines in vitro. Thus, we hypothesize that lycopene and docetaxel have synergy or addition in the inhibition of tumor growth in vivo. We also have demonstrated that the inhibitory effect of lycopene on the growth of PCa cell lines is closely related to their levels of insulin growth factor-I receptor (IGF-IR), and that LNCaP cells stably expressing high level of IGF-IR are about 400 fold more sensitive to the growth inhibitory effect of lycopene than parental LNCaP cells. We therefore hypothesize that the expression of IGF-IR in PCa cells can serve as an indicator for the sensitivity of lycopene and docetaxel combination against PCa. Our specific aims are two folds: First, we will determine the abilities of lycopene, docetaxel or combination of both to inhibit tumor growth in xenograft hormone refractory PCa models; Second, we will generate pairs of genetically modified prostate cancer cell lines with either overexpression or suppression of IGF-IR and evaluate the involvement of IGF-IR and its main down-stream events, AKT and ERK1/2, with the combined effects of lycopene and docetaxel. Our long term goal is to answer an important question in current clinical practices: should prostate cancer patients undergoing docetaxel-base chemotherapy take lycopene supplements? If a positive result is produced in our proposed animal experiments, an investigative clinical trial of docetaxel and lycopene combination in prostate cancer patients will be proposed in an R01 application. The results obtained from these studies may also provide evidence that targeting IGF-IR by a non-toxic, dietary approach (e.g. lycopene supplement) would be effective and safe in treatment of prostate cancer when combined with main-stream therapies in clinical practices. Docetaxel has become the first line chemotherapy for patients with hormonal refractory prostate cancer, and use of lycopene supplements is popular by these patients. We proposed to examine whether lycopene can enhance or interfere with the anti-tumor efficacy of docetaxel in animal models, and whether lycopene can be used as a non-toxic, dietary approach for targeting IGF-IR in combined therapies for prostate cancer.