WP760 for Malignant Melanoma Therapy

描述（由申请人提供）：皮肤癌是美国最常见的癌症，黑色素瘤是皮肤癌中最恶性的。在美国，黑色素瘤的发病率增长速度比其他任何癌症都要快。患有转移性黑色素瘤的患者在5年后的存活率低于5%，而且黑色素瘤最近取代了白血病，成为造成更多工作时间损失的原因。目前还没有批准的治疗转移性黑色素瘤的方法达到20%以上的反应率。德克萨斯大学安德森癌症中心目前管理着美国数量最多的黑色素瘤患者。我们提议与开发小分子抗癌药物的Callisto制药公司一起，探索最近发现的新型抗黑色素瘤药物WP760的潜在开发潜力。根据NCI体外抗肿瘤筛选的初步数据，WP760是一种双插层DNA结合药物，对黑色素瘤细胞具有显著的选择性。使用比较程序（一种比较药物概况的算法），NCI的研究人员发现WP760对黑色素瘤具有高度选择性的活性，这种活性明显独特，不同于与之比较的所有其他8万种癌症药物。在这项I期FLAIR STTR申请中，我们建议进一步评估WP760作为治疗黑色素瘤药物的潜力，目的是进入黑色素瘤的临床试验并最终商业化。我们建议优化WP760的生产化学和配方、药代动力学性能和啮齿动物毒性、人类黑色素瘤与其他肿瘤对WP760体外生长抑制的敏感性，最后通过全身给药WP760在人类黑色素瘤异种移植小鼠模型上的疗效测试，以接近人类的应用。成功完成这些目标之后，将提交II期STTR进行最终的临床前研究，从而导致IND申请和人体临床试验测试。

DESCRIPTION (provided by applicant): Skin cancer is the most prevalent cancer in the USA, and melanoma is the most malignant of skin cancers. The incidence of melanoma in the USA is increasing more rapidly than for any other cancer. Patients with metastatic melanoma have <5% survival after 5 years, and melanoma recently replaced leukemia as responsible for more lost hours in the work place. Currently there are no approved therapies for metastatic melanoma that achieve more than a 20% response rate. The University of Texas, M.D. Anderson Cancer Center currently manages the largest number of melanoma patients in the US. Together with Callisto Pharmaceuticals Inc., which develops small-molecule anticancer drugs, we propose to explore the potential development of a recently discovered novel antimelanoma drug, WP760. WP760, is a bis-intercalating DNA binding drug which has demonstrated remarkable selectivity towards melanoma cells, based on preliminary data from the NCI in vitro anti-tumor screen. Using the Compare Program, an algorithm that compares drug profiles, researchers at the NCI found WP760 to have a highly selective activity against melanoma that was distinctly unique and different from all of the 80,000 other cancer drugs to which it was compared. In this Phase I FLAIR STTR application, we propose to further evaluate WP760's potential as a drug to treat melanoma, with the intent of moving to clinical trials in melanoma and eventual commercialization. We propose optimization of production chemistry and formulation, performance of pharmocokinetics and toxicity in rodents, sensitivity of human melanoma vs. other tumors to growth inhibition by WP760 in vitro, and finally testing of efficacy in a human melanoma xenograft mouse model using systemic administration of WP760 to approach the human use. Successful completion of these objectives will then be followed by a Phase II STTR submission for final preclinical studies, leading to an IND application and clinical trial testing in humans.