Phase 1 Bioassay-guided Trial of Lycopene and Docetaxel for Prostate Cancer

番茄红素和多西他赛治疗前列腺癌的 1 期生物测定指导试验

• 批准号: 8723134
• 负责人: MICHAEL B LILLY
• 金额: $ 15.94万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723134
• 关键词: Adverse effects; American; Antioxidants; Bayesian Modeling; Benign Prostatic Hypertrophy; Binding; Biochemical; Biological Assay; Biological Markers; Blood; Blood Cells; CYP3A4 gene; Cancer Control; Cancer Patient; Caring; Cell Survival; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Data; Development; Dose; Dose-Limiting; Drug Kinetics; Enzymes; Exercise; Fright; Generations; Goals; Growth; Growth Factor; Hematologic Agents; Human; IGF1 gene; IGF1R gene; IGF2 gene; IGFBP3 gene; IL6 gene; In Vitro; Insulin-Like Growth Factor Receptor; Laboratory Study; Malignant Neoplasms; Malignant neoplasm of prostate; Maximum Tolerated Dose; Measurement; Measures; Methods; Modeling; Molecular Target; Monitor; Mus; Neoplasm Metastasis; Normal Cell; Nutrient; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphorylation; Phytochemical; Pigments; Plants; Plasma; Prostate Cancer therapy; Prostatic Diseases; Publishing; Reactive Oxygen Species; Reporting; Research; Resistance; Sampling; Signal Transduction; Stress; Symptoms; Testing; Therapeutic; Therapeutic Agents; Tomatoes; Toxic effect; Toxicity due to chemotherapy; Uncertainty; advanced disease; base; bench to bedside; cancer cell; cancer therapy; castration resistant prostate cancer; cell growth; cell killing; chemotherapy; clinical effect; cohort; cytokine; cytotoxic; docetaxel; enzyme activity; improved; in vivo; killings; lifetime risk; lycopene; male; novel; phase 1 study; preclinical study; prostate cancer cell; public health relevance; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): While many cases of localized prostate cancer (PCa) can be cured, advanced PCa with metastases is difficult to treat, and is currently incurable. Chemotherapy is an important treatment for patients with advanced PCa, but results are suboptimal. Our overall goal is to determine if plant-derived nutrients will improve the effect of chemotherapy by increasing cell kill or decreasing toxicity from chemotherapy. The specific hypothesis is that lycopene (a red pigment in tomatoes) will increase the effect of docetaxel chemotherapy against PCa, by inhibiting an enzyme called the insulin-like growth factor receptor (IGF-1R). Lycopene is a nutrient commonly taken by patients with prostatic diseases. Lycopene may have the ability to decrease PCa development, or to decrease the symptoms of benign prostatic hypertrophy. However, there are few data on its use to actually treat patients with established PCa. No published reports describe its use to potentiate the effects of docetaxel chemotherapy in patients with advanced disease. Published studies by our group and others demonstrate that lycopene inhibits the growth of PCa cells that express IGF1R but is less active against cells with little of the enzyme. Lycopene appears to bind to, and directly inhibit te activity of the enzyme, blocking its effects in promoting cell growth and survival. Mice treated with a combination of lycopene and docetaxel have better PCa control than mice treated with either agent alone. Thus, lycopene may be an inexpensive, non-toxic, convenient way to improve docetaxel treatment in PCa patients. Our proposal includes three specific aims: Specific Aim 1 is to conduct a Phase I study of lycopene plus docetaxel in PCa patients. The primary goal is to identify doses of these agents that have little toxicity, and that are able to inhibit IGF1R activity in patients. Specific Aim 2 is to determine whether lycopene perturbs the pharmacokinetics of docetaxel when these agents are combined. Serial measurements of docetaxel and lycopene blood levels will be used to model the uptake and disappearance of the drugs from the blood. Specific Aim 3 seeks to identify novel biological markers to monitor effects of lycopene and docetaxel in PCa subjects. We will serially measure levels of IGF1, IGF2, IGFBP3, and IL6 in the blood of the patients, and measure levels of IGF1R on blood cells. We will if changes in any of these measurements predicts who will have the fewest side effects (grade 3-4 dose-limiting toxicity), or are associated with different amounts of treatment. Arguments for or against the use of phytochemicals as safe, inexpensive cancer therapeutics will remain theoretical without mechanism-based clinical studies. This proposal attempts to move lycopene cancer therapy further along the bench-to-bedside continuum by combining lycopene with docetaxel. Our studies will determine if the proposed molecular target is correct, and may point to other enzymes and cytokines as potential targets of lycopene.

描述（由申请人提供）：虽然许多局限性前列腺癌（PCa）病例可以治愈，但具有转移的晚期 PCa 很难治疗，目前无法治愈。化疗是晚期 PCa 患者的重要治疗方法，但结果并不理想。我们的总体目标是确定植物源性营养素是否会通过增加细胞杀伤或降低化疗毒性来改善化疗效果。具体的假设是番茄红素（番茄中的一种红色素）会通过抑制一种称为胰岛素样生长因子受体（IGF-1R）的酶来增强多西紫杉醇化疗对 PCa 的作用。 番茄红素是前列腺疾病患者常用的营养素。番茄红素可能能够减少前列腺癌的发展，或减轻良性前列腺肥大的症状。然而，关于其实际用于治疗患有前列腺癌的患者的数据很少。尚未发表的报告描述其用于增强晚期疾病患者多西他赛化疗的效果。我们小组和其他人发表的研究表明，番茄红素抑制表达 IGF1R 的 PCa 细胞的生长，但对酶含量很少的细胞的活性较低。番茄红素似乎与该酶结合并直接抑制该酶的活性，从而阻断其促进细胞生长和存活的作用。用番茄红素和多西紫杉醇联合治疗的小鼠比单独用任一药物治疗的小鼠具有更好的 PCa 控制。因此，番茄红素可能是一种廉价、无毒、方便的方法来改善 PCa 患者的多西紫杉醇治疗。 我们的提案包括三个具体目标： 具体目标 1 是在 PCa 患者中进行番茄红素加多西紫杉醇的 I 期研究。主要目标是确定这些药物的剂量，毒性很小，并且能够抑制患者的 IGF1R 活性。具体目标 2 是确定当这些药物联合使用时，番茄红素是否会干扰多西紫杉醇的药代动力学。多西紫杉醇和番茄红素血液水平的连续测量将用于模拟药物从血液中的吸收和消失。具体目标 3 旨在寻找新的生物标志物来监测番茄红素和多西紫杉醇对 PCa 受试者的影响。我们将连续测量患者血液中的IGF1、IGF2、IGFBP3和IL6的水平，并测量血细胞上的IGF1R的水平。如果任何这些测量值的变化可以预测谁的副作用（3-4 级剂量限制性毒性）最少，或者与不同的治疗量相关，我们就会这样做。 如果没有基于机制的临床研究，支持或反对使用植物化学物质作为安全、廉价的癌症治疗方法的争论将仍然停留在理论上。该提案试图通过将番茄红素与多西紫杉醇相结合，进一步推动番茄红素癌症治疗从实验室到临床的连续统一。我们的研究将确定所提出的分子靶标是否正确，并可能指出其他酶和细胞因子作为番茄红素的潜在靶标。