Novel vitamin D analog for kidney cancer

描述（由申请人提供）：肾癌约占所有成人恶性肿瘤的3%，每年有超过30,000例病例和12,000例死亡。不幸的是，目前缺乏对这一致命疾病的有效干预，迫切需要对这一致命疾病进行有效治疗。许多流行病学研究已经有力地证明了膳食维生素D在预防各种癌症方面的重要性。此外，1,25-二羟基维生素D3 (1,25(OH)2D3)，维生素D的生物活性代谢物及其类似物在癌症中的治疗潜力是有充分证据的。然而，这种激素固有的钙毒性，特别是在治疗剂量下，阻碍了它作为抗癌剂的普遍使用，为开发具有有效抗增殖活性和降低全身毒性的维生素D类似物打开了大门。最近，我们开发了一种新的1,25(OH)2D3衍生物[11,25-二羟基维生素d3 -3-溴乙酸酯，1,25(OH)2D3-3- be]，它将1,25(OH)2D3共价地附着在VDR的配体结合口袋内。我们证明了1,25(OH)2D3-3-BE强烈抑制几种人类癌细胞的生长，包括一组肾癌细胞。我们还证明了1,25(OH)2D3-3-BE在小鼠异种移植模型中以0.1-0.5 g/kg的剂量水平降低激素不敏感前列腺肿瘤而无明显毒性。总的来说，这些结果证明了该化合物在肾癌中的潜在治疗效用。本R21提案的目的是评估1,25(OH)2D3-3- be在肾癌中的潜在治疗价值，并评估这种新型vdr -交联1,25(OH)2D3衍生物的分子机制。这些目标将通过两个特定目标来实现：特定目标1：确定1,25(OH)2D3-3-BE在小鼠异种移植模型中对人肾细胞癌的疗效；特异性目的2：探讨1,25(OH)2D3-3-BE对肾癌细胞生长抑制和凋亡的分子机制。该试点项目的成功完成对于开发1,25(OH)2D3-3-BE和类似的vdr -烷基化维生素D激素类似物治疗肾癌至关重要。公共卫生相关性：1,25-二羟基维生素D3 （1,25(OH)2D3）固有的钙中毒，维生素D的生物活性代谢物阻碍了其作为抗癌剂的普遍使用。最近，我们开发了一种新的125 (OH)2D3衍生物，它能强烈抑制几种人类肾癌细胞的生长，并诱导这些细胞的程序性细胞死亡。该项目的目的是评估该化合物在肾癌中的治疗潜力。

DESCRIPTION (provided by applicant): Kidney cancer comprises approximately 3% of all adult malignancies, and account for over 30,000 cases and 12,000 deaths per year. Unfortunately, efficient intervention of this deadly disease is currently lacking, and effective therapy for this deadly disease is urgently needed. Numerous epidemiological studies have strongly demonstrated the importance of dietary vitamin D in preventing various cancers. In addition, therapeutic potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of vitamin D and its analogs in cancer is well-documented. However, inherent calcemic toxicity of this hormone, particularly at therapeutic doses, has prevented its general use as an anticancer agent, opening the door for the development of vitamin D analogs with potent antiproliferative activity with reduced systemic toxicity. Recently we developed a novel derivative of 1,25(OH)2D3 [11,25- dihydroxyvitamin D3-3-bromoacetate, 1,25(OH)2D3-3-BE] that covalently attaches 1,25(OH)2D3 inside the ligand-binding pocket of VDR. We demonstrated that 1,25(OH)2D3-3-BE strongly inhibits the growth of several human cancer cells, including a set of kidney cancer cells. We also demonstrated that 1,25(OH)2D3-3-BE reduces hormone-insensitive prostate tumor at 0.1-0.5 5g/kg dose level in a mouse xenograft model without significant toxicity. Collectively, these results demonstrate potential therapeutic utility of this compound in kidney cancer. The goal of this R21 proposal is to appraise the potential therapeutic value of 1,25(OH)2D3-3-BE in kidney cancer, and evaluate the molecular mechanism of this novel VDR-cross-linking derivative of 1,25(OH)2D3. These goals will be met by two specific aims: Specific Aim 1: Determine the efficacy of 1,25(OH)2D3-3-BE on human renal cell carcinoma in a mouse xenograft model; and Specific Aim 2: Evaluate the molecular mechanism of growth-inhibition and apoptosis by 1,25(OH)2D3-3-BE in kidney cancer cells. Successful completion of this pilot project will be crucial for the development of 1,25(OH)2D3-3-BE and similar VDR-alkylating analogs of vitamin D hormone for kidney cancer. PUBLIC HEALTH RELEVANCE: Inherent calcemic toxicity of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of vitamin D has prevented its general use as an anticancer agent. Recently we developed a novel derivative of 1,25(OH)2D3 that strongly inhibits the growth of several human kidney cancer cells, and induces programmed cell death in these cells. The goal of this project is to evaluate the therapeutic potential of this compound in kidney cancer.