Delaying the Hormone Refractory Prostate Cancer by a Dietary Triterpene Lupeol

描述（由申请人提供）：即使在手术和雄激素消融治疗后，癌细胞的持续存在，它们的增殖，雄激素不依赖性和向远处的侵袭是人类前列腺癌患者死亡的主要原因。延缓或减缓前列腺癌细胞向高侵袭性激素难治性表型转变的过程，可以延长前列腺癌患者的生存期，改善治疗，提高患者的生活质量。不幸的是，晚期激素难治性肿瘤的患者通常对目前的常规癌症治疗没有反应或反应很差。对晚期激素难治性前列腺癌实施有效治疗策略所面临的挑战，反映了促生存和促增殖信号通路在前列腺肿瘤治疗耐药出现中的多维性和功能意义。即使在非雄激素条件下，激素难治性前列腺癌细胞中雄激素受体的持续激活与PI3K/Akt信号的激活有关。活化的PI3K/Akt与2- catenin和NF:B通路形成信号轴，汇聚到共同的下游靶点，最终导致具有激素难耐、化疗耐药和高侵袭性的前列腺癌细胞，具有迁移和侵袭人类骨骼、淋巴结等异位组织的能力。虽然对多种信号通路的激素耐受性和促生存特性的充分理解仍在不断发展，但Akt/ss-catenin/NF:B信号轴的影响已被广泛接受，并且正在努力利用这些信号通路来治疗其关键信号步骤。因此，迫切需要开发新的治疗药物（具有靶向多种分子途径的能力），以有效对抗雄激素非依赖型前列腺肿瘤的发展以及疾病的复发。我们将提供令人信服的证据，证明Lupeol（一种存在于橄榄、草莓、葡萄、芒果、无花果和植物油中的无营养无毒的天然制剂）可能是一种理想的多靶点制剂，可以预防或延缓人类前列腺癌中激素依赖性向激素非依赖性转变的发生。我们假设Lupeol可以通过破坏Akt/2-catenin/NF:B信号轴来阻止/或延缓激素依赖性CaP向激素非依赖性疾病的转变。为实现这一目标，我们提出了两个具体目标。在第一个特定目的下，我们建议研究Lupeol是否(i)阻止或延迟人类CaP细胞雄激素依赖性的发生，以及（ii）在体外条件下使激素难治性CaP细胞敏化以接受雄激素拮抗剂治疗。在第二个特定目的下，我们建议在一个原位异种移植小鼠模型中研究Lupeol （iii）单独使用和联合雄激素消融是否可以预防或延迟人类CaP肿瘤雄激素依赖性的出现，以及（iv）使激素难治性CaP肿瘤对雄激素拮抗剂治疗增敏。我们相信，这一建议将为化学预防提供一种新的基于水果和蔬菜的药物，并可能用于治疗早期和晚期前列腺癌。公共卫生相关性：我们相信这一建议将非常有价值，因为它提供了一种新的基于水果和蔬菜的药物，具有已知的作用机制，可以延缓或预防激素依赖性前列腺癌向激素难治性和化疗耐药表型的转变。该提案的成功完成将确立Lupeol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.