Rapamycin Regulation of the Androgen Receptor: Implications in Prostate Cancer

雷帕霉素对雄激素受体的调节：对前列腺癌的影响

• 批准号: 7786255
• 负责人: PARAMITA M. GHOSH
• 金额: $ 23.53万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-13 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7786255
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Affect; Androgen Antagonists; Androgen Receptor; Androgens; Apoptosis; Apoptotic; Autophagocytosis; Bicalutamide; Binding Proteins; Cell Cycle Arrest; Cell Death Induction; Cell Proliferation; Cell Survival; Cells; Complex; Development; Drug Combinations; Failure; Growth; Hand; Hormones; Human; Inhibition of Apoptosis; Lead; Ligands; Malignant neoplasm of prostate; Mediating; Modeling; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Phosphorylation; Phosphotransferases; Prostatic Neoplasms; Raptors; Recurrence; Refractory; Regulation; Resistance; Role; Signal Transduction Pathway; Sirolimus; Testing; Therapeutic; Time; Tissues; Translation Initiation; Withdrawal; androgen independent prostate cancer; cancer cell; cell growth; deprivation; design; experience; hormone therapy; human FRAP1 protein; in vivo; mTOR Inhibitor; novel; preclinical study; prevent; public health relevance; tumor; tumor progression

DESCRIPTION (provided by applicant): In this application, we show that the combination of the mTOR inhibitor rapamycin and the anti-androgen bicalutamide caused long-term growth inhibition and apoptosis in androgen independent prostate cancer (AIPC) cells despite neither drug having the same effect as single agents. The overall objective of the present project is to elucidate the signal transduction pathways affected by this treatment, which lead to cell cycle arrest and apoptosis. In preliminary studies, we provide novel evidence that bicalutamide alone was unable to inhibit cell growth and induce apoptosis in AIPC cells, due to the presence of a strong androgen-independent, but rapamycin-sensitive, survival pathway downstream of mTOR. On the other hand, rapamycin as monotherapy was unable to induce long-term growth inhibition due to the stimulation of an AR-dependent cell survival pathway by rapamycin treatment. Thus we hypothesize that the mTOR and AR pathways regulate survival in prostate cancer cells in parallel, and apoptosis was induced only when both pathways were simultaneously inhibited. The following specific aims have been designed to test this hypothesis: 1. To test the hypothesis that the anti-androgen bicalutamide is unable to induce apoptosis in androgen-independent prostate cancer cells due to the presence of an androgen-independent, but rapamycin-sensitive, cell survival pathway downstream of mTORC1, a complex of mTOR. mTORC1 phosphorylates downstream targets p70S6 kinase and 4E-BP1, an eIF4E binding protein. We will determine whether increased activation of the mTORC1/4E-BP1/eIF4E pathway promotes androgen-independent cell proliferation and survival in androgen-dependent prostate cancer cells. In addition, we will examine whether the mTOR pathway is activated in androgen-independent human prostate cancer tissues. 2: To test the hypothesis that long-term treatment of prostate cancer cells with the mTOR inhibitor rapamycin stimulates AR transcriptional activity resulting in increased survival and resistance to growth inhibition by rapamycin. (i) We will test the hypothesis that long-term rapamycin treatment stimulates AR transcriptional activity in prostate cancer cells. (ii) We will test the hypothesis that rapamycin-stimulated AR transcriptional activity results in increased cell survival which causes resistance to rapamycin treatment. 3. To test the hypothesis that combination treatment with rapamycin and bicalutamide induce apoptosis in prostate cancer cells and prevent AIPC. We will determine whether rapamycin and bicalutamide in combination prevent the growth of androgen-independent prostate tumors in vivo. Further, we will investigate whether combination treatment with rapamycin and bicalutamide in androgen-dependent tumors prevent the recurrence of prostate tumors in a model of prostate cancer progression. PUBLIC HEALTH RELEVANCE: This is the first time that the combination of rapamycin and bicalutamide will be used in preclinical studies for the treatment of androgen-independent prostate cancer. The combination of these drugs has not been shown before to sensitize hormone-refractory cells to hormone therapy (androgen deprivation or anti-androgens). The studies proposed here would justify a Phase II/Phase III clinical trial utilizing the combination of bicalutamide and rapamycin for the treatment of patients who experience recurrent prostate cancer. Currently, the options for patients with androgen-independent prostate cancer are limited; hence such a study would open the doors for a new treatment option.

描述（由申请人提供）：在本申请中，我们表明MTOR抑制剂雷帕霉素和抗雄激素的生物氨氨酰胺的组合在雄激素独立前列腺癌（AIPC）细胞中导致长期生长抑制和凋亡，尽管没有药物与单剂具有相同的作用。本项目的总体目的是阐明受该处理影响的信号转导途径，从而导致细胞周期停滞和凋亡。在初步研究中，我们提供了新的证据，表明单独的双氨二酰胺无法抑制细胞的生长并诱导AIPC细胞中的凋亡，这是由于MTOR下游的强雄激素敏感但对雷帕霉素敏感的生存途径的强大而导致的。另一方面，雷帕霉素作为单药治疗无法通过雷帕霉素治疗刺激AR依赖性细胞存活途径，无法诱导长期的生长抑制作用。因此，我们假设MTOR和AR途径并行调节前列腺癌细胞中的存活率，并且仅在同时抑制这两种途径时才诱导凋亡。已经设计了以下具体目的来检验这一假设：1。检验以下假设：抗雄激素双学氨酰胺由于存在雄激素独立的前列腺癌细胞中无法诱导凋亡，这是由于存在雄激素独立的，雷他霉素敏感的，但含乳蛋白蛋白敏感性的，但具有雷帕霉素敏感性的，但含乳蛋白敏感性的细胞生存的途径，是mtorc1的Mtorc1，一位Mtorcor的Mtorcor，Mtor的MTOR。 MTORC1磷酸化的下游靶标P70S6激酶和4E-BP1，一种EIF4E结合蛋白。我们将确定MTORC1/4E-BP1/EIF4E途径的激活是否增加了雄激素依赖性前列腺癌细胞中雄激素独立的细胞增殖和存活。此外，我们将检查是否在雄激素独立的人前列腺癌组织中激活MTOR途径。 2：测试以下假设：用MTOR抑制剂雷帕霉素长期治疗前列腺癌细胞会刺激AR转录活性，从而增加生存率和抗雷帕霉素的生长抑制作用。 （i）我们将检验以下假设：长期雷帕霉素治疗刺激前列腺癌细胞中的AR转录活性。 （ii）我们将检验以下假设：雷帕霉素刺激的AR转录活性导致细胞存活增加，从而导致对雷帕霉素治疗的耐药性。 3。检验以下假设：与雷帕霉素和双氨酰胺的联合治疗在前列腺癌细胞中诱导凋亡并预防AIPC。我们将确定雷帕霉素和比酸胺在组合中是否可以防止雄激素独立的前列腺肿瘤在体内的生长。此外，我们将研究在雄激素依赖性肿瘤中与雷帕霉素和双氨酰胺的联合治疗是否可以防止前列腺癌进展模型中前列腺肿瘤的复发。公共卫生相关性：这是雷帕霉素和dicalutamide首次将其用于临床前研究中，以治疗与雄激素独立的前列腺癌。这些药物的组合尚未显示为使激素难治性细胞对激素治疗（雄激素剥夺或抗雄激素）敏感。此处提出的研究将证明，利用Bicalutamide和Rapamycin结合的II/II期临床试验是合理的，用于治疗经历了复发前列腺癌的患者。目前，非雄激素独立前列腺癌患者的选择受到限制。因此，这样的研究将为新的治疗选择打开大门。