HIGHLY INNOVATED TARGETED THERAPY OF MELANOMA

尽管最近开发了新的治疗方法，但目前还没有治愈的方法。 晚期黑色素瘤，5年生存率低于15%。 靶向治疗是最有希望的治疗方法之一 癌症治疗策略，是精准医学的关键组成部分，其目的是 针对特定患者进行个体化癌症治疗。 IL-13RA2是无处不在的IL-13RA1受体的致癌亚型，在原发性和非小细胞肺癌中过表达。 转移性黑色素瘤，但不在正常组织中。这种受体在治疗上一直未得到充分利用，部分原因是 由于缺乏临床适用的翻译工具。最近，一类新的独特的配体被发现 不仅选择性地结合IL-13RA2受体，而且在内化后达到所需的 包括细胞核在内的细胞室。 具体地说，我们假设我们的专利DNA结合剂显示出纳摩尔效力(IC50~4 NM或更低)与IL-1结合时，对黑色素瘤细胞有抑制作用，但对正常细胞无作用(1,000 nM无作用) 能够将有效载荷运送到黑色素瘤细胞核或细胞质的13RA2特异性配体， 将产生一类新的高效黑色素瘤选择性治疗剂，具有很好的翻译能力 和商业潜力。 我们提出了两个具体目标。目的1：研制针对黑色素瘤的配体-药物结合物 表达IL-13RA2受体。将采用两种结合策略：要么提供稳定的药物 含有对核传递有效载荷或pH敏感连接体至关重要的结构域的结合物，它可以释放 从内吞泡腔内的内化结合物到胞浆和其他器官的药物。目标 2：评价结合物对不同基因表达的黑色素瘤模型的体内外疗效。 IL13-RA2。我们将在体外和体内模型中测试和比较合成的偶联物的效果 IL-13RA2受体高表达和低表达的细胞/肿瘤。 综上所述，我们建议开发一种新的、独特的、非常有前景的靶向疗法，两者都 从概念上和实践上讲，都是针对黑色素瘤患者的。这一概念具有双重优势，因为它结合了(1) 选择性地将黑色素瘤细胞配体与(2)黑色素瘤特异的、高度细胞毒性的DNA结合剂结合。 这种双重优势的方法将探索不仅与黑色素瘤上的IL-13RA2受体结合的配体， 但被内化以将细胞毒性有效载荷递送到所需的细胞室。这进一步增加了 开发具有更高效力和选择性的安全有效的靶向治疗药物的机会。 这些创新研究的结果将提供所需的原则证明，并将支持 旨在启动临床研究的高级临床前开发的第二阶段SBIR赠款申请 以及随后验证的偶联物的商业化。

Despite the recent development of novel therapeutic approaches, no curative treatment is available for advanced stage melanoma, with 5-year survival below 15%. Targeted therapy is one of the most promising therapeutic strategies to the treatment of cancer and is a key component of precision medicine, which aims to individualize cancer treatment for a given patient. IL-13RA2, an oncogenic isoform of the ubiquitous IL-13RA1 receptor, is overexpressed in primary and metastatic melanomas, but not in normal tissue. This receptor has been underutilized therapeutically, partly due to the lack of clinically applicable translational tools. Recently, a novel class of unique ligands has been developed that not only selectively bind the IL-13RA2 receptor but also, after internalization, reach the desired cellular compartment including the nucleus. Specifically, we hypothesize that our patented DNA binding agent showing nanomolar potency (IC50~4 nM or lower) against melanoma cells but not normal cells (no effect at 1,000 nM), when conjugated to IL- 13RA2-specific ligands capable of delivering a payload to the nucleus or cytoplasm of melanoma tumor cells, will generate a new class of highly efficacious melanoma selective therapeutic agents with great translational and commercial potential. We propose two specific aims. Aim 1: To develop ligand-drug conjugates targeting melanoma tumors expressing the IL-13RA2 receptor. Two conjugation strategies will be employed: delivering either a stable drug conjugate containing domains critical for nuclear delivery of the payload or a pH sensitive linker that liberates drug from the internalized conjugates in the lumen of endocytic vesicles to the cytosol and other organs. Aim 2: To assess in vitro and in vivo efficacy of the conjugates in melanoma models with variable expression of IL13-RA2. We will test and compare the efficacy of synthesized conjugates in vitro and in vivo models using cells/tumors with both high and low expression of the IL-13RA2 receptor. In summary, we propose to develop a new, unique, and highly promising targeted therapy, both conceptually and practically, for melanoma patients. This concept has a double advantage as it combines (1) selectively binding melanoma cells ligands with (2) a melanoma-specific, highly cytotoxic DNA binding agent. This double-advantage approach will explore ligands that not only bind to the IL-13RA2 receptor on melanoma, but are internalized to deliver a cytotoxic payload to the desired cellular compartment. This further increases the chances of developing safe and efficacious targeted therapeutics with increased potency and selectivity. The results of these innovative studies will deliver the required proof of principle and will support the Phase 2 SBIR grant application for advanced preclinical development aimed at the initiation of clinical studies in humans and the subsequent commercialization of validated conjugate.