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、其增殖、雄激素非依赖性和向远处部位的侵袭是人前列腺癌患者死亡的主要原因。延缓或减缓前列腺癌细胞变成高度侵袭性激素难治性表型的过程将导致前列腺癌患者的生存期延长、更好的管理和生活质量的改善。不幸的是，患有晚期激素难治性肿瘤的患者通常对目前的常规癌症疗法没有反应或反应非常差。实施有效的治疗策略来治疗晚期激素难治性前列腺癌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性出现中的多维性质和功能意义。激素难治性前列腺癌细胞中雄激素受体的持续活化，即使在非雄激素条件下，也与PI 3 K/Akt信号传导的活化相关。激活的PI 3 K/Akt与2-连环蛋白和NF：B途径形成信号轴，从而聚集在共同的下游靶点上，最终导致激素难治性、化疗耐药和高度侵袭性的前列腺癌细胞，具有迁移和侵入人类骨骼和淋巴结等异位组织的能力。虽然对多种信号传导途径的难治性和促存活特征的充分理解仍在发展中，但Akt/β-连环蛋白/NF：B信号传导轴的影响已被广泛接受，并且存在利用这些途径用于其关键信号传导步骤的治疗靶向的努力。因此，对于开发有效对抗雄激素非依赖性前列腺肿瘤发展以及疾病复发的新治疗剂（具有靶向多个分子途径的能力）存在强烈的未满足的需求。我们将提供令人信服的证据表明，羽扇豆醇（一种存在于橄榄油、草莓油、葡萄油、芒果油、无花果油和植物油中的无营养和无毒的天然制剂）可能是一种理想的多靶点制剂，可以预防或延迟人类前列腺癌从依赖性前列腺增生向非依赖性前列腺增生转变的过程。我们假设羽扇豆醇将通过破坏Akt/2-catenin/NF：B信号传导轴来预防/或延迟激素依赖性CaP向激素非依赖性疾病的转化。为了实现我们的目标，我们提出了两个具体目标。在第一个具体目标下，我们建议研究羽扇豆醇是否（i）预防或延迟人CaP细胞中雄激素非依赖性的发生，以及（ii）在体外条件下使激素难治性CaP细胞对雄激素拮抗剂治疗敏感。在第二个具体目标下，我们建议在原位异种移植小鼠模型中研究羽扇豆醇（iii）单独和与雄激素消融联合是否预防或延迟人CaP肿瘤雄激素非依赖性的出现，以及（iv）使激素难治性CaP肿瘤对雄激素拮抗剂治疗敏感。我们相信，这一建议将是非常有价值的，在提供一种新的水果和蔬菜为基础的化学预防剂，并可能用于治疗早期以及晚期前列腺癌。公共卫生相关性：我们相信，这一建议将是非常有价值的，在提供一种新的水果和蔬菜为基础的代理与已知的作用机制，以延迟或防止发病的激素依赖性前列腺癌的激素难治性和耐药性表型的转变。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.