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

描述(申请人提供)：晚期前列腺癌患者有显著的长期发病率。最近，包括番茄红素在内的膳食补充剂的使用在这些患者中越来越受欢迎，尽管缺乏临床数据来证明它们的有效性。由于多西紫杉醇已成为激素难治性前列腺癌患者的一线化疗方案，番茄红素联合以多西紫杉醇为基础的化疗方案的疗效和安全性有待评估。虽然临床前研究表明，番茄红素可以作为一种强大的抗氧化剂来改善许多化疗药物的毒性作用，但番茄红素是否会增强或干扰以多西他赛为基础的化疗的抗肿瘤活性仍不清楚。我们的初步数据表明，生理浓度的番茄红素可以增强多西紫杉醇在体外降低PCa细胞系活力的效果。因此，我们假设番茄红素和多西紫杉醇在体内抑制肿瘤生长方面具有协同或相加作用。我们还证明了番茄红素对PCa细胞生长的抑制作用与其胰岛素生长因子-I受体(IGF-IR)水平密切相关，稳定表达高水平IGF-IR的LNCaP细胞对番茄红素抑制生长的敏感性约为亲本LNCaP细胞的400倍。因此，我们假设IGF-IR在PCa细胞中的表达可以作为番茄红素和多西紫杉醇联合治疗PCa敏感性的指标。我们的具体目标有两个：首先，我们将确定番茄红素、多西紫杉醇或两者联合使用在异种激素难治性前列腺癌模型中抑制肿瘤生长的能力；其次，我们将建立两对过表达或抑制IGF-IR的转基因前列腺癌细胞株，并评估IGF-IR及其主要下游事件AKT和ERK1/2在番茄红素和多西紫杉醇联合作用下的参与情况。我们的长期目标是回答当前临床实践中的一个重要问题：接受多西紫杉醇化疗的前列腺癌患者是否应该服用番茄红素补充剂？如果我们提议的动物实验产生阳性结果，多西紫杉醇和番茄红素联合用于前列腺癌患者的调查性临床试验将被提议应用于R01。这些研究的结果还可能提供证据，证明通过无毒的饮食方法(如番茄红素补充剂)靶向IGF-IR在前列腺癌的治疗中将是有效和安全的，当在临床实践中结合主流疗法时。多西紫杉醇已经成为激素难治性前列腺癌患者的一线化疗药物，而番茄红素补充剂的使用在这些患者中很受欢迎。我们建议在动物模型中研究番茄红素是否可以增强或干扰多西紫杉醇的抗肿瘤效果，以及在前列腺癌的综合治疗中，番茄红素是否可以作为一种无毒的饮食方法来靶向IGF-IR。

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.