Vitamin D Analogs for Chemoprevention of Prostate Cancer

描述（由申请人提供）：前列腺癌（CaP）是最常见的 经常被诊断出的癌症和男性癌症死亡的第二大原因， 我们维生素D具有四种有效的抗癌活性：1） 抗增殖，2）抗血管生成，3）促凋亡和4） 亲分化然而，维生素D也动员钙储存， 毒性高钙作用。已经开发了新的类似物， 维生素D的抗癌活性，但没有相关的全身 毒性我们的假设是，维生素D化合物，保留抗癌 但具有降低的钙离子活性，可用作化学预防剂， 预防/减缓CaP的进展和转移扩散的药剂。我们提出 4个具体目标： I：确定骨化三醇和两种维生素D类似物是否具有低全身性 毒性（1 LX 23 -7553和QW 1624 F2 -2）可以预防/减缓致癌作用， CaP（TRAMP）的原位模型，并表征 这些化合物在前列腺癌进展过程中的作用。 II：确定骨化三醇和低钙维生素D化合物 ILX 23 -7553和QW 1624 F2 -2可以预防/减缓肿瘤的发展和转移扩散 雄激素非依赖性钙磷在去势TRAMP动物和表征 这些化合物对雄激素非依赖性疾病的分子作用。 III：确定参与维生素D的关键分子通路？S抗癌 通过比较来自初始肿瘤细胞的肿瘤衍生细胞的分子表型， TRAMP肿瘤和维生素D抗性TRAMP肿瘤。 IV：通过治疗男性CaP，评估人CaP对ILX 23 -7553的体内应答 在用ILX 23 -7553进行前列腺切除术之前， 反应的分子表型。 骨化三醇、ILX 23 -7553和QWI 1624 F2 -2处理对增殖的影响， 细胞凋亡、血管生成和分化将在 雄激素依赖性和非依赖性CaP。抗维生素D肿瘤将是 与初始TRAMP肿瘤相比，在TRAMP和分子表型中诱导的细胞凋亡。 最后，一项临床试验检查了器官移植的体内分子反应。 提出了将人CaP限制于ILX 23 -7553。 这些研究将提供关于以下预防活性的临床前数据： 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前列腺癌的化学预防剂。 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/最不可能受益于 维生素D治疗

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.