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）：癌细胞的持久性即使在手术和雄激素疗法后，它们的增殖，雄激素独立性和对远处部位的侵袭是人类前列腺癌患者死亡的主要原因。延迟或减慢前列腺癌细胞的过程成为高度侵略性的激素难治性表型将导致生存的延长，更好的管理和改善前列腺癌患者的生活质量。不幸的是，患有晚期激素难治性肿瘤的患者通常无法应对或对当前常规癌症疗法反应。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前生肿瘤抗性抗性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也与PI3K/AKT信号的激活有关。 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.虽然对多个信号通路的激素 - 侵犯和促生物寿命特征的全面了解仍在发展，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途径将这些途径用于其关键信号步骤的治疗靶向。因此，有很强的未满足需要开发新的治疗剂（具有靶向多个分子途径的能力），这些治疗剂有效地抵抗雄激素独立的前列腺肿瘤发展以及疾病的复发。我们将提供令人信服的证据表明，卢佩尔（橄榄，草莓，葡萄，芒果，无花果和植物油中存在的一种非营养和无毒的天然剂）可能是一种理想的多目标剂，可以防止或延迟人类前列腺癌依赖激素与激素依赖于激素依赖激素的过渡。我们假设Lupeol将通过破坏Akt/2-catenin/nf：B信号轴来预防/或延迟激素依赖性帽向激素独立疾病的转化。为了实现我们的目标，我们提出了两个具体目标。在第一个特定目的下，我们建议研究卢佩尔（i）是否阻止或延迟人帽细胞中雄激素独立的发作，（ii）在体外条件下对雄激素抗抗酸剂治疗的激素难治性帽细胞敏感。在第二个具体目的下，我们建议研究卢佩尔（III）并与雄激素消融结合使用，可以防止或延迟人帽肿瘤的雄激素独立的出现，（iv）在腹膜抗流变型Xenogopic小鼠模型中敏感的雄激素 - 抗抗原治疗疗法的激素抑制性帽。我们认为，该提案对于提供一种新型的基于水果和蔬菜的剂来进行化学预防，可能是对早期和晚期前列腺癌的治疗，将非常有价值。公共卫生相关性：我们认为，该提案对于提供一种新型的基于水果和蔬菜的药物具有已知的作用机理，可延迟或防止激素依赖性前列腺癌对激素难治性和化学剂表型的过渡。该提案的成功完成将确定卢在治疗晚期前列腺癌的潜力。