Delaying the Hormone Refractory Prostate Cancer by a Dietary Triterpene Lupeol

通过膳食三萜羽扇豆醇延缓激素难治性前列腺癌的发生

• 批准号: 7661136
• 负责人: Mohammad Saleem Bhat
• 金额: $ 16.33万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-07 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661136
• 关键词: Ablation; Adjuvant; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Antiandrogen Therapy; Apoptotic; B-Lymphocytes; Cancer Etiology; Cancer Patient; Carcinoma; Cause of Death; Cells; Cessation of life; Characteristics; Chemoprevention; Choristoma; Clinical; Data; Development; Disease; Distant; ERBB2 gene; Elderberry; Event; Exhibits; Figs - dietary; Foundations; Fruit; Future; Gelatinase A; Genes; Goals; Grapes; Growth; Hormones; Human; In Vitro; Invaded; Lead; Legal patent; Ligands; Malignant neoplasm of prostate; Mango - dietary; Mediating; Medicinal Plants; Metastatic Prostate Cancer; Molecular; Mus; Nature; Nutrient; Olives - dietary; Operative Surgical Procedures; Pathway interactions; Patients; Phenotype; Process; Prostate carcinoma; Prostatic Neoplasms; Publishing; Quality of life; Receptor Signaling; Recurrence; Refractory; Refractory Disease; Resistance; Signal Pathway; Signal Transduction; Site; Somatotropin; Staging; Strawberries; Testing; Therapeutic; Therapeutic Agents; Transgenic Mice; Triterpenes; Tumorigenicity; Vegetable Oils; Xenograft procedure; base; bone; cancer cell; cancer therapy; chemotherapeutic agent; fruits and vegetables; hormone refractory prostate cancer; hormone sensitivity; lupeol; lymph nodes; men; mouse model; novel; novel strategies; novel therapeutics; pre-clinical; prevent; public health relevance; receptor; therapeutic target; treatment strategy; tumor

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.

描述（由申请人提供）：即使在手术和雄激素消融治疗之后，癌细胞仍持续存在，它们的增殖、雄激素非依赖性和远处部位的侵袭是人类前列腺癌患者死亡的主要原因。延迟或减缓前列腺癌细胞变成高度侵袭性激素难治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当前的传统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所面临的挑战反映了前列腺肿瘤出现治疗耐药性时促生存和促增殖信号通路的多维性质和功能意义。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 信号传导的激活有关。激活的 PI3K/Akt 与 2-连环蛋白和 NF:B 通路形成信号轴，从而汇聚到共同的下游靶标上，最终导致激素难治性、化疗耐药性和高度侵袭性的前列腺癌细胞，能够迁移和侵入人体异位组织（例如骨骼和淋巴结）。虽然对多种信号传导途径的激素抵抗和促生存特征的全面了解仍在发展中，但 Akt/ss-catenin/NF:B 信号传导轴的影响已被广泛接受，并且人们正在努力利用这些途径对其关键信号传导步骤进行治疗靶向。因此，迫切需要开发新的治疗剂（能够靶向多种分子途径），以有效对抗雄激素非依赖性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，证明羽扇豆醇（一种存在于橄榄、草莓、葡萄、芒果、无花果和植物油中的非营养且无毒的天然药物）可能是一种理想的多靶点药物，可以预防或延缓人类前列腺癌从激素依赖性向激素非依赖性过程转变的开始。我们假设羽扇豆醇将通过破坏 Akt/2-catenin/NF:B 信号轴来防止/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（i）是否可以预防或延迟人类CaP细胞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）单独使用以及与雄激素消融联合使用是否可以预防或延迟人类CaP肿瘤雄激素非依赖性的出现，以及（iv）是否使激素难治性CaP肿瘤对雄激素拮抗剂治疗敏感。我们相信，该提案对于提供一种新的基于水果和蔬菜的化学预防剂以及可能用于治疗早期和晚期前列腺癌非常有价值。公共健康相关性：我们相信，该提案对于提供一种新型水果和蔬菜制剂非常有价值，该制剂具有已知的作用机制，可以延迟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羽扇豆醇治疗晚期前列腺癌的潜力。