Delaying the Hormone Refractory Prostate Cancer by a Dietary Triterpene Lupeol

描述(申请人提供)：癌细胞即使在手术和雄激素消融治疗后仍然存在，它们的增殖、雄激素非依赖性和对远处部位的侵袭是导致人类前列腺癌患者死亡的主要原因。延缓或延缓前列腺癌细胞向高侵袭性激素耐药表型转化的过程，可延长前列腺癌患者的生存期，改善治疗效果，提高患者的生活质量。不幸的是，患有晚期激素难治性肿瘤的患者通常对当前的传统癌症治疗没有反应或反应很差。晚期激素难治性前列腺癌的有效治疗策略的实施所面临的挑战反映了支持生存和促进增殖的信号通路在前列腺癌治疗耐药发生中的多维性质和功能意义。激素非依赖性前列腺癌细胞中雄激素受体的持续激活与PI3K/Akt信号通路的激活有关。激活的PI3K/Akt与2-连环蛋白和核因子：B通路形成一个信号轴，从而汇聚到共同的下游靶点，最终导致激素耐药、化疗耐药和高度侵袭的前列腺癌细胞具有迁移和侵袭人类骨骼和淋巴结等异位组织的能力。虽然对多种信号通路的激素不耐受和促生存特性的全面了解仍在发展中，但Akt/ss-catenin/NF：B信号轴的影响已被广泛接受，并努力利用这些信号通路对其关键信号步骤进行靶向治疗。因此，开发新的治疗药物(具有针对多个分子途径的能力)的强烈需求尚未得到满足，这些药物能够有效地对抗雄激素非依赖性前列腺癌的发展和疾病的复发。我们将提供令人信服的证据，证明羽扇豆醇(一种无营养、无毒的天然制剂，存在于橄榄、草莓、葡萄、芒果、无花果和植物油中)可能是一种理想的多靶点制剂，可以防止或延缓人类前列腺癌从激素依赖向激素非依赖过程的转变。我们推测，羽扇豆醇可能通过破坏Akt/2-catenin/NF：B信号轴来阻止或延缓激素依赖型帽子向激素非依赖型疾病的转化。为了实现我们的目标，我们提出了两个具体目标。在第一个特定目标下，我们建议研究羽扇豆醇(I)在体外条件下是否阻止或延缓人CAP细胞雄激素非依赖性的开始，以及(II)在体外条件下使激素不敏感的CAP细胞对雄激素拮抗剂治疗敏感。在第二个特定目标下，我们建议在原位异种移植小鼠模型中，研究羽扇豆醇(III)单独以及与雄激素消融联合应用是否能够防止或延迟人帽子肿瘤雄激素非依赖性的出现，以及(Iv)使激素不敏感的帽子肿瘤对雄激素拮抗剂治疗敏感。我们相信，这项建议将在提供一种新的水果和蔬菜类药物用于化学预防以及可能用于治疗早期和晚期前列腺癌方面具有极其重要的价值。公共卫生相关性：我们认为，这项提议将非常有价值地提供一种基于水果和蔬菜的新型药物，该药物具有已知的作用机制，可以延缓或防止激素依赖型前列腺癌向激素耐药和化疗耐药表型的转变。这项提案的成功完成将确立鲁普洛尔治疗晚期前列腺癌的潜力。

DESCRIPTION (provided by applicant): Persistence of cancer cells even after surgery and androgen-ablation therapy, their proliferation, androgen- independence and invasion to distant sites is the major cause of deaths in human prostate cancer patients. Delaying or slowing down the process of prostate cancer cells to become highly aggressive hormone refractory phenotype would lead to the prolongation in the survival, better management and in improvement in the quality of life of prostate cancer patients. Unfortunately, patients with advanced hormone refractory tumors most often fail to respond to or very poorly respond to current conventional cancer therapies. The challenges in the implementation of effective therapeutic strategies for the treatment of advanced hormone refractory prostate cancer reflect the multidimensional nature and functional significance of pro-survival and pro-proliferation signaling pathways in the emergence of therapeutic resistance of prostate tumors. The persistent activation of androgen receptor in hormone refractory prostate cancer cells even under non-androgen conditions has been associated with the activation of PI3K/Akt signaling. The activated PI3K/Akt forms a signaling axis with 2- catenin and NF:B pathways, thus converging on common downstream targets, and ultimately leads to the hormone-refractory, chemoresistant and highly aggressive prostate cancer cells with an ability to migrate and invade heterotopic tissues such as bones and lymph nodes in humans. While a full understanding of the hormone-refractory and pro-survival characteristics of multiple signaling pathways is still evolving, the impact that Akt/ss-catenin/NF:B signaling axis has been widely accepted and there are efforts to utilize these pathways for therapeutic targeting of its key signaling steps. Thus, there is a strong unmet need to develop new therapeutic agents (with an ability to target multiple molecular pathways) which are effective against androgen-independent prostate tumor development as well as the recurrence of disease. We will provide compelling evidence that Lupeol, (a non-nutrient and non-toxic natural agent present in olive, strawberry, grapes, mango, figs and vegetable oils) could be an ideal multi-target agent which could prevent or delay the onset of transition of hormone-dependent to hormone-independent process in human prostate cancer. We hypothesize that Lupeol will prevent /or delay the transformation of hormone-dependent CaP to hormone independent disease through the disruption of Akt/2-catenin/NF:B signaling axis. To achieve our goal, we propose two specific aims. Under the first specific aim, we propose to investigate whether Lupeol (i) prevents or delays the onset of androgen-independence in human CaP cells and (ii) sensitizes the hormone refractory CaP cells for androgen-antagonist treatment under in vitro conditions. Under the second specific aim, we propose to investigate whether Lupeol (iii) alone and in combination with androgen ablation prevents or delays the onset of emergence of androgen-independence of human CaP tumors and (iv) sensitizes the hormone refractory CaP tumors for androgen-antagonist therapy, in an orthotopic xenograft mouse model. We believe that this proposal will be extremely valuable in providing a novel fruit and vegetable based agent for chemoprevention and possibly for treating early as well as advanced prostate cancer. PUBLIC HEALTH RELEVANCE: We believe that this proposal will be extremely valuable in providing a novel fruit and vegetable based agent with a known mechanism of action for delaying or preventing the onset of transition of hormone-dependent prostate cancer to hormone refractory and chemoresistant phenotype. Successful completion of this proposal will establish the potential of Lupeol for the treatment of advanced prostate cancer.