HIGHLY INNOVATED TARGETED THERAPY OF MELANOMA

高度创新的黑色素瘤靶向治疗

• 批准号: 9202154
• 负责人: RAYMOND J BUDDE
• 金额: $ 28.12万
• 依托单位: HOUSTON PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9202154
• 关键词: Address; Affinity; Apoptosis; Applications Grants; BRAF gene; Binding; Biological; Biological Sciences; Cancerous; Cell Nucleus; Cells; Cessation of life; Clinical Research; Complex; Cytoplasm; Cytosol; Cytotoxic agent; DNA; DNA Binding Agent; DNA Sequence; Data; Development; Diffusion; Disease; Disease Progression; Endocytic Vesicle; Engineering; Evaluation; Gene Expression Profiling; Goals; Human; Hydrolysis; IL13RA1 gene; Immunohistochemistry; Immunotherapeutic agent; In Vitro; Interleukin-13; Interleukin-4; Legal patent; Life; Ligands; Longevity; Lysosomes; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Modeling; Mutation; Normal Cell; Normal tissue morphology; Nuclear; Oncogenic; Organ; Organelles; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Property; Protein Isoforms; Proto-Oncogene Proteins B-raf; Quality of life; Recruitment Activity; Resected; Resistance development; STAT6 gene; Series; Skin Cancer; Small Business Innovation Research Grant; Solid Neoplasm; Specificity; Staging; Stress; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Tissue Sample; Tissues; Translations; Treatment Efficacy; Tumor Tissue; base; cancer cell; cancer therapy; commercialization; comparative efficacy; curative treatments; cytokine; cytotoxic; design; drug discovery; improved; in vitro testing; in vivo; in vivo Model; innovation; kinase inhibitor; melanoma; mouse model; nanomolar; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; overexpression; pre-clinical; precision medicine; programs; receptor; response; scaffold; subcutaneous; targeted treatment; tool; tumor

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.

尽管最近开发了新的治疗方法，但对于 晚期黑色素瘤，5年生存率低于15%。 靶向治疗是最有前途的 治疗癌症的治疗策略，是精准医学的关键组成部分，其目的是 为特定患者提供个性化癌症治疗。 IL-13 RA 2是普遍存在的IL-13 RA 1受体的致癌同种型，在原发性和继发性肿瘤中过表达。 转移性黑色素瘤，而不是在正常组织中。这种受体在治疗上没有得到充分利用，部分原因是 由于缺乏临床上适用的翻译工具。最近，一种新型的独特配体已经被发现。 开发了不仅选择性结合IL-13 RA 2受体，而且在内化后，达到所需的 包括细胞核在内的细胞区室。 具体而言，我们假设我们的专利DNA结合剂显示纳摩尔效力（IC 50 ~4 nM或更低），但对正常细胞无作用（在1，000 nM时无作用）。 能够将有效载荷递送至黑素瘤肿瘤细胞的细胞核或细胞质的13 RA 2特异性配体， 将产生一类新的高度有效的黑色素瘤选择性治疗剂， 和商业潜力。 我们提出两个具体目标。目的1：研制靶向黑色素瘤的配体-药物偶联物 表达IL-13 RA 2受体。将采用两种缀合策略： 缀合物，所述缀合物含有对于有效载荷的核递送至关重要的结构域或释放有效载荷的pH敏感性接头， 药物从内吞囊泡腔中的内化缀合物转移到胞质溶胶和其他器官。目的 2：评估缀合物在具有可变表达的黑色素瘤模型中的体外和体内功效。 IL13-RA2。我们将测试和比较合成的缀合物在体外和体内模型中的功效， 具有IL-13 RA 2受体的高表达和低表达的细胞/肿瘤。 总之，我们建议开发一种新的，独特的，非常有前途的靶向治疗， 从概念上和实践上来说，对于黑色素瘤患者来说。这一概念具有双重优势，因为它结合了（1） 用（2）黑素瘤特异性、高细胞毒性DNA结合剂选择性结合黑素瘤细胞配体。 这种双重优势的方法将探索不仅与黑色素瘤上的IL-13 RA 2受体结合， 但被内化以将细胞毒性有效载荷递送至所需的细胞区室。这进一步增加 开发具有更高效力和选择性的安全有效的靶向治疗剂的机会。 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2期SBIR资助申请 以及随后经验证的缀合物的商业化。