An IGF-1R-targeting peptide drug conjugate for targeted treatment of atypical teratoid/rhabdoid tumors

项目摘要 非典型畸胎样/横纹肌样肿瘤（AT/RT）是一种罕见的胚胎性中枢神经系统恶性肿瘤， 是致命的目前诊断为AT/RT的儿童的治疗策略仅限于 手术、放疗和化疗，但迄今为止，这些方法都没有成功地提高生存率， 18个月，并且鉴于患者的年轻年龄，大多数与显著毒性相关。遗传 SWI/SNF染色质重塑复合物的失活是AT/RT肿瘤发生的基础;因此，靶向 可以纠正AT/RT中的表观遗传失调的疗法提供了令人信服的治疗策略， 这些药剂可以选择性地递送到脑中的肿瘤细胞。肽-药物缀合物（PDC）是一种 可以通过将靶特异性肽与强细胞毒性药物连接来实现这一点的治疗方式， 增强位点特异性递送和肿瘤特异性治疗效果，同时限制药物暴露于 健康的周围组织。为了利用AT/RT的这种方法，NightHawk Biosciences，Inc.发展 结合针对胰岛素样生长因子1受体的新型结合肽（“429”）的PDC策略 在AT/RT细胞表面高度表达的IGF-1 R与强效细胞毒药物靶向 在第一阶段STTR中，NightHawk将与Nadia Dahmane博士在威尔的实验室合作。 康奈尔医学测试两种研究性抗IGF-1 R PDC，一种与抗有丝分裂毒素结合 一种是单甲基澳瑞他汀E（MMAE），另一种是与泛HDAC抑制剂帕比司他缀合， 在初步研究中，抗IGF-1 R PDCs对表达IGF-1 R的AT/RT动物模型有效。 和AT/RT细胞系。此外，单次瘤内注射429-MMAE显著降低了肿瘤生长。 在侧腹植入A431（一种IGF-1 R表达上皮癌）后的体积。验证 潜力的这种方法的AT/RT和定义的最佳药物将用于最终的PDC格式，我们建议 为了检查抗IGF-1 R PDC对人AT/RT细胞的治疗功效， 肿瘤模型在目标1中，将针对一组扩大的人AT/RT测试抗IGF-1 R PDC候选物 细胞系，用于对细胞活力、细胞凋亡、细胞毒性和细胞迁移和侵袭的影响。在目标2中，系统性 将探索（静脉内）和直接（肿瘤内）给药策略，以确定剂量暴露反应 关系，并确定最大耐受剂量。目的3将评估抗IGF-1抗体的体内功效。 1 R PDCs对已建立的AT/RT原位小鼠模型中肿瘤抑制和存活的影响。 完成拟议目标将确定AT/RT实现治疗获益的潜力，并确定 一个领先的PDC候选人，以推进IND使能研究。

PROJECT SUMMARY Atypical teratoid/rhabdoid tumors (AT/RT) are rare embryonal central nervous system malignancies that occur in early childhood and are lethal. Current treatment strategies for children diagnosed with AT/RT are limited to surgery, radiation, and chemotherapy, but to date, none of these have successfully improved survival beyond 18 months, and most are associated with significant toxicities given the young age of patients. Genetic inactivation of the SWI/SNF chromatin remodeling complex underlies AT/RT tumorigenesis; thus, targeted therapies that can correct the epigenetic dysregulation in AT/RT present a compelling therapeutic strategy if these agents can be selectively delivered to tumor cells in the brain. Peptide-drug conjugates (PDCs) are one treatment modality that can accomplish this by linking target-specific peptides to strong cytotoxic drugs to enhance site-specific delivery and tumor-specific therapeutic effects, while limiting exposure of the drug to healthy surrounding tissues. To leverage this approach for AT/RT, NightHawk Biosciences, Inc. has developed a PDC strategy that combines a novel binding peptide (“429”) against the Insulin-like Growth Factor 1 Receptor (IGF-1R), which is highly expressed on the surface of AT/RT cells, with potent cytotoxic drugs for targeted treatment of AT/RT. In this Phase I STTR, NightHawk will partner with Dr. Nadia Dahmane’s laboratory at Weill Cornell Medicine to test two investigational anti-IGF-1R PDCs, one conjugated to the antimitotic toxin monomethyl auristatin E (MMAE), and a second conjugated to the pan-HDAC inhibitor panobinostat, in cell and animal models of AT/RT. In preliminary studies, anti-IGF-1R PDCs are efficacious against IGF-1R-expressing and AT/RT cell lines in vitro. Further, a single intratumoral injection of 429-MMAE significantly reduced tumor volumes following flank implantation of A431, an IGF-1R-expressing epithelial carcinoma. To validate the potential of this approach for AT/RT and define the optimal drug to be used in the final PDC format, we propose to examine anti-IGF-1R PDCs for therapeutic efficacy against human AT/RT cells and in an in vivo orthotopic tumor model. In Aim 1, anti-IGF-1R PDC candidates will be tested against an expanded panel of human AT/RT cell lines for effects on cell viability, apoptosis, cytotoxicity, and cell migration and invasion. In Aim 2, systemic (intravenous) and direct (intratumoral) drug delivery strategies will be explored to define dose-exposure response relationships and to determine the maximum tolerated dose. Aim 3 will evaluate in vivo efficacy of the anti-IGF- 1R PDCs on tumor inhibition and survival in an established orthotopic mouse model of AT/RT. We expect that completion of the proposed aims will determine potential for achieving therapeutic benefit in AT/RT and identify a lead PDC candidate to advance to IND-enabling studies.