Vitamin D Analogs for Chemoprevention of Prostate Cancer

描述(申请人提供)：前列腺癌(CAP)最多 经常被诊断为癌症和导致男性癌症死亡的第二大原因 我们。四种有效的抗癌活性归因于维生素D：1) 抗增殖，2)抗血管生成，3)促凋亡，4) 支持差异化。然而，维生素D也会动员钙库，导致 有毒的高钙血症作用。已经开发出新的类似物，它们保留了 维生素D的抗癌活性但没有相关的全身性 毒性。我们的假设是，维生素D化合物，保持抗癌 但具有降低钙化活性的特性，可用作化学预防 预防/减缓CAP进展和转移扩散的药物。我们建议 4个具体目标： I：确定骨化三醇和两种维生素D类似物是否具有低系统性 毒性(1LX23-7553和QW1624F2-2)可预防/减缓癌症的发生 CAMP(TRAMP)的原地模型及其分子效应特征 这些化合物在前列腺癌进展过程中起作用。 II：确定骨化三醇和钙含量较低的维生素D化合物 ILX23-7553和QW1624F2-2可预防/减缓肿瘤的发生和转移 在去势的流浪汉动物身上发现雄激素非依赖性CAP，并表征 这些化合物在雄激素非依赖性疾病中的分子作用。 III：确定维生素D-S抗癌的关键分子途径 比较初治肿瘤来源细胞分子表型的活性 流行性肿瘤和维生素D抗药性流行性肿瘤。 IV：通过治疗男性来评价人帽子对ILX23-7553的体内反应 ILX23-7553前列腺术前限制帽的临床应用 反应的分子表型。 骨化三醇、ILX23-7553和QWI1624F2-2对细胞增殖的影响 将研究细胞凋亡、血管生成和分化。 雄激素依赖和非雄激素依赖的CAP。对维生素D具有抗药性的肿瘤 TRAMP诱导的分子表型与单纯TRAMP肿瘤的比较。 最后一项检测器官体内分子反应的临床试验 建议将人体帽限制在ILX23-7553。 这些研究将提供有关沙门氏菌预防活动的临床前数据。 可用于设计和启动临床试验的维生素D化合物 使用这些化合物作为人类前列腺癌的化学预防药物。 这些研究将确定维生素D作用的关键分子途径， 可用于识别最有可能/最不可能受益的患者 维生素D疗法。

DESCRIPTION (provided by applicant): Prostate cancer (CaP) is the most frequently diagnosed cancer and the second cause of cancer deaths in men in the US. Four potent anti-cancer activities have been ascribed to Vitamin D: 1) anti-proliferation, 2) anti-angiogenesis, 3) pro-apoptosis and 4) pro-differentiation. However, vitamin D also mobilizes calcium stores causing toxic hypercalcemic effects. New analogs have been developed that retain the anti-cancer activities of vitamin D but without the associated systemic toxicity. Our hypothesis is that vitamin D compounds, that retain anti-cancer properties but have reduced calcemic activity, can be used as a chemopreventive agent to prevent/slow the progression and metastatic spread of CaP. We propose 4 specific aims: I: To determine if calcitriol and two vitamin D analogs with low systemic toxicity (1LX23-7553 & QW1624F2-2) can prevent/slow carcinogenesis in an autochthonous model of CaP (TRAMP) and characterize the molecular effects of these compounds during prostate cancer progression. II: To determine if calcitriol and the less calcemic vitamin D compounds ILX23-7553 & QW1624F2-2 can prevent/slow the development and metastatic spread of androgen-independent CaP in castrated TRAMP animals and characterize the molecular effects of these compounds on androgen-independent disease. III: To identify key molecular pathways involved in vitamin D?s anti-cancer activity by comparing the molecular phenotype of tumor-derived cells from naive TRAMP tumors and vitamin D-resistant TRAMP tumors. IV: To evaluate the in vivo response of human CaP to ILX23-7553 by treating men with localized CaP prior to prostatectomy with ILX23-7553 and characterizing the molecular phenotype of the response. Effects of calcitriol, ILX23-7553 and QWI1624F2-2 treatment on proliferation, apoptosis, angiogenesis and differentiation will be studied in androgen-dependent and -independent CaP. Vitamin D resistant tumors will be induced in TRAMP and the molecular phenotype compared to naive TRAMP tumors. Finally a clinical trial examining the in vivo molecular response of organ confined human CaP to ILX23-7553 is proposed. These studies will provide preclinical data on the preventive activity of vitamin D compounds that can be used to design and initiate clinical trials using these compounds as a chemopreventive agent for human prostate cancer. These studies will identify key molecular pathways for vitamin D action that can be used to identify patients that are most/least likely to benefit from vitamin D therapy.