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比卡鲁胺的组合引起了雄激素非依赖性前列腺癌 (AIPC) 细胞的长期生长抑制和细胞凋亡，尽管两种药物都没有相同的效果作为单一药剂发挥作用。本项目的总体目标是阐明受这种治疗影响的信号转导途径，从而导致细胞周期停滞和细胞凋亡。在初步研究中，我们提供了新的证据，表明单独比卡鲁胺无法抑制 AIPC 细胞的细胞生长并诱导细胞凋亡，因为 mTOR 下游存在强大的不依赖雄激素但对雷帕霉素敏感的生存途径。另一方面，由于雷帕霉素治疗刺激了 AR 依赖性细胞存活途径，雷帕霉素作为单一疗法无法诱导长期生长抑制。因此，我们假设 mTOR 和 AR 途径平行调节前列腺癌细胞的存活，只有当这两种途径同时受到抑制时才会诱导细胞凋亡。设计了以下具体目标来检验这一假设： 1. 检验以下假设：由于存在不依赖雄激素但对雷帕霉素敏感的受体，抗雄激素比卡鲁胺无法诱导不依赖雄激素的前列腺癌细胞凋亡。 ，mTORC1（mTOR 复合物）下游的细胞生存途径。 mTORC1 磷酸化下游靶点 p70S6 激酶和 4E-BP1（一种 eIF4E 结合蛋白）。我们将确定 mTORC1/4E-BP1/eIF4E 通路激活的增加是否会促进雄激素依赖性前列腺癌细胞的雄激素非依赖性细胞增殖和存活。此外，我们将检查 mTOR 通路是否在雄激素非依赖性人类前列腺癌组织中被激活。图 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，从而提高存活率和对雷帕霉素生长抑制的抵抗力。 (i) 我们将检验长期雷帕霉素治疗刺激前列腺癌细胞中 AR 转录活性的假设。 (ii) 我们将检验以下假设：雷帕霉素刺激的 AR 转录活性会导致细胞存活率增加，从而导致对雷帕霉素治疗产生耐药性。 3. 检验雷帕霉素和比卡鲁胺联合治疗诱导前列腺癌细胞凋亡并预防 AIPC 的假设。我们将确定雷帕霉素和比卡鲁胺组合是否可以在体内预防雄激素非依赖性前列腺肿瘤的生长。此外，我们将研究雷帕霉素和比卡鲁胺联合治疗雄激素依赖性肿瘤是否可以在前列腺癌进展模型中预防前列腺肿瘤的复发。公共健康相关性：这是首次将雷帕霉素和比卡鲁胺联合用于治疗雄激素非依赖性前列腺癌的临床前研究。此前尚未证明这些药物的组合可以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。这里提出的研究将证明利用比卡鲁胺和雷帕霉素联合治疗复发性前列腺癌患者的 II/III 期临床试验是合理的。目前，非雄激素依赖性前列腺癌患者的选择有限。因此，这样的研究将为新的治疗选择打开大门。