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

用于靶向治疗非典型畸胎瘤/横纹肌样瘤的 IGF-1R 靶向肽药物缀合物

基本信息

批准号：
10760549
负责人：
Neil Goldstein
金额：
$ 39.91万
依托单位：
NIGHTHAWK BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10760549
关键词：
Acute Age Animal Model Antibodies Antibody-drug conjugates Antimitotic Agents Apoptosis Attention Autologous Stem Cell Transplantation Binding Biological Biological Assay Biological Sciences Blood Brain Carcinoma Cell Proliferation Cell Survival Cell model Cells Central Nervous System Central Nervous System Neoplasms Cerebellum Chemotherapy-Oncologic Procedure Child Childhood Brain Neoplasm Childhood Malignant Brain Tumor Chromatin Remodeling Factor Chronic Clinical Consensus Cytotoxic agent Diagnosis Disease Dose Drug Administration Routes Drug Delivery Systems Drug Exposure Drug Kinetics Drug Targeting Engraftment Epigenetic Process Excision Exhibits FDA approved Failure Genetic High Dose Chemotherapy Histone Acetylation Histone Deacetylase Inhibitor Human Immunofluorescence Immunologic In Vitro Injections Insulin-Like-Growth Factor I Receptor Intravenous Invaded Laboratories Lead Link Luciferases Malignant Neoplasms Maximum Tolerated Dose Medicine Microtubules Modality Modeling Mus Neurosecretory Systems Operative Surgical Procedures Organ Pathogenesis Patients Penetration Peptides Pharmaceutical Preparations Phase Positioning Attribute Pre-Clinical Model Primary Neoplasm Prognosis Radiation therapy Research Rhabdoid Tumor Risk Route SMARCA4 gene SMARCB1 gene Sampling Site Small Business Technology Transfer Research Standardization Subgroup Surface Systemic Therapy Testing Therapeutic Therapeutic Effect Tissues Toxic effect Toxin Treatment Efficacy Treatment Protocols Tumor Cell Line Tumor Volume Western Blotting Xenograft Model anti-cancer blood-brain barrier penetration cell motility chemotherapy chromatin remodeling cytotoxicity early childhood efficacy evaluation implantation improved in vivo meter mouse model neoplastic cell novel peptide drug rare cancer response side effect systemic toxicity targeted treatment treatment strategy tumor tumor growth tumorigenesis

项目摘要

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.

项目概要非典型畸胎瘤/横纹肌样瘤（AT/RT）是罕见的胚胎中枢神经系统恶性肿瘤目前对诊断为 AT/RT 的儿童的治疗策略仅限于以下几种。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，考虑到患者年龄较小，大多数都与显着的毒性相关。 SWI/SNF 染色质重塑复合物的失活是 AT/RT 肿瘤发生的基础，因此是有针对性的；可以纠正 AT/RT 表观遗传失调的疗法提供了一种令人信服的治疗策略，如果这些药物可以选择性地递送至大脑中的肿瘤细胞，肽-药物缀合物（PDC）就是其中之一。可以通过将目标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，同时限制药物暴露为了利用这种方法进行 AT/RT，NightHawk Biosciences, Inc. 开发了这种方法。结合新型结合肽（“429”）对抗胰岛素样生长因子 1 受体的 PDC 策略 (IGF-1R)，在AT/RT细胞表面高表达，具有强效细胞毒药物靶向作用在第一阶段 STTR 中，NightHawk 将与 Nadia Dahmane 博士在 Weill 的实验室合作。康奈尔医学公司将测试两种研究中的抗 IGF-1R PDC，其中一种与抗有丝分裂毒素结合单甲基 auristatin E (MMAE)，以及与泛 HDAC 抑制剂帕比司他 (panobinostat) 缀合的第二种药物，在细胞和 AT/RT 动物模型中，抗 IGF-1R PDC 对表达 IGF-1R 有效。此外，单次瘤内注射 429-MMAE 显着减少了肿瘤。侧翼植入 A431（一种表达 IGF-1R 的上皮癌）后的体积以验证我们建议这种方法在 AT/RT 中的潜力，并确定最终 PDC 格式中使用的最佳药物检查抗 IGF-1R PDC 对人类 AT/RT 细胞的治疗功效以及在体内原位在目标 1 中，抗 IGF-1R PDC 候选药物将针对扩展的人类 AT/RT 组进行测试。目标 2：系统性细胞系对细胞活力、细胞凋亡、细胞毒性以及细胞迁移和侵袭的影响。将探索（静脉内）和直接（瘤内）给药策略来定义剂量暴露反应关系并确定最大耐受剂量目标 3 将评估抗 IGF-的体内功效。 1R PDC 在已建立的 AT/RT 原位小鼠模型中对肿瘤抑制和存活的影响。拟议目标的完成将确定 AT/RT 中实现治疗效益的潜力，并确定是推进 IND 支持研究的主要 PDC 候选人。