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。使用膳食补充剂，包括番茄红素最近在这些患者中越来越受欢迎，尽管缺乏临床数据来证明其功效。随着多西他赛成为激素难治性前列腺癌患者的一线化疗方案，番茄红素联合多西他赛化疗的疗效和安全性有待进一步评价。虽然临床前研究表明番茄红素可以作为一种强抗氧化剂用于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多西他赛化疗的抗肿瘤活性尚不清楚。我们的初步数据表明，生理浓度的番茄红素可以增强多西他赛在体外降低前列腺癌细胞系活力的功效。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作用或加法作用。我们还证明了番茄红素对PCa细胞系生长的抑制作用与其胰岛素生长因子- 1受体（IGF-IR）水平密切相关，并且稳定表达高水平IGF-IR的LNCaP细胞对番茄红素生长抑制作用的敏感性比亲本LNCaP细胞高400倍左右。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他赛联合治疗PCa敏感性的一个指标。我们的具体目标有两个方面：首先，我们将确定番茄红素、多西紫杉醇或两者联合抑制异种移植激素难治性PCa模型中肿瘤生长的能力；其次，我们将产生IGF-IR过表达或抑制的转基因前列腺癌细胞对，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：接受多西他赛基础化疗的前列腺癌患者是否应该服用番茄红素补充剂？如果在我们提出的动物实验中产生阳性结果，将在R01申请中提出多西紫杉醇与番茄红素联合应用于前列腺癌患者的研究性临床试验。从这些研究中获得的结果也可能提供证据，证明通过无毒的饮食方法（如番茄红素补充剂）靶向IGF-IR在临床实践中与主流疗法结合治疗前列腺癌时是有效和安全的。多西他赛已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也受到这些患者的欢迎。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功效，以及番茄红素是否可以作为一种无毒的膳食途径，靶向IGF-IR，用于前列腺癌的联合治疗。

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.