Preclinical development of the novel inhibitor of apoptosis proteins S2/IAPinh for cancer therapy

用于癌症治疗的新型凋亡蛋白抑制剂 S2/IAPinh 的临床前开发

基本信息

批准号：
10568409
负责人：
WILLIAM G HAWKINS
金额：
$ 34.67万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-29 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10568409
关键词：
Abraxane Address Anticholesteremic Agents Apoptosis CASP3 gene Cancer Patient Caspase Cell Death Cell Line Cell Survival Cells Chemicals Cholesterol Clinical DNA Damage Data Development Dose Drug Combinations Drug Delivery Systems Drug Efflux Drug Formulations Drug Kinetics Drug resistance Enhancers Epithelial ovarian cancer Evaluation Excipients Foundations Frequencies Goals Gold Grant Human In Vitro Inhibition of Apoptosis Lead Ligands Link Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Maximum Tolerated Dose Mediating Mitochondria Ovarian Paclitaxel Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Pre-Clinical Model Regimen Resistance Route Signal Transduction Sodium Chloride Specificity Stress TNF gene Testing Therapeutic Toxic effect Treatment Protocols Variant Work cancer cell cancer therapy carcinogenesis chemical conjugate chemotherapy combination cancer therapy cytotoxic cytotoxicity drug candidate drug development effective therapy efficacy evaluation gemcitabine genetic signature improved in vivo inhibitor inhibitor therapy inhibitor-of-apoptosis protein innovation mouse model neoplastic cell novel novel drug combination novel therapeutics performance tests pre-clinical preclinical development promoter resistance mechanism response sigma-2 receptor small molecule standard of care systemic toxicity targeted cancer therapy targeted treatment therapy resistant triple-negative invasive breast carcinoma tumor tumor eradication uptake x-linked inhibitor of apoptosis protein

项目摘要

Scientific abstract Epithelial ovarian cancer (EOC) and pancreatic ductal adenocarcinoma (PDAC) are two of the most devastating human malignancies in desperate need for improved treatment concepts. Treatment resistance in cancer therapy frequently includes, among others, reduced drug uptake, increased drug efflux, improved adaptation to chemotherapy-induced stress/DNA damage and inhibition of apoptosis. An example of such a resistance mechanism is the X-linked inhibitor of apoptosis proteins (XIAP), a potent negative regulator of caspases and promoter of cancer cell survival in both ovarian and pancreatic cancer. Inhibition of XIAP has been studied to increase apoptosis and to overcome drug resistance in vitro and in preclinical mouse models. Second mitochondria-derived activator of caspases (SMAC) is an endogenous inhibitor of both XIAP and cellular IAP (cIAP) by reactivating caspase activity (XIAP blockade) and cIAP degradation, leading to cancer cell death. These findings have initiated the development of synthetic small molecule mimics of endogenous SMAC, which have been studied in a wide variety of human malignancies either as single agents but also in combination with systemic chemotherapy as a means to further improve patient outcomes. The foundation of our work with respect to small molecule drug development is based on sigma-2 ligands (S2) that facilitate fast and selective uptake into the cancer cells due to ~10-fold higher abundancy of the corresponding sigma-2 receptor (S2R) compared to normal host cells. By generating chemical conjugates between S2 and a variety of small molecule drug cargos, we are now capable of delivering therapeutic payloads more efficiently and selectively than their non-targeted counterparts to the tumors (targeted therapy). LCL161 is a clinically explored IAP inhibitor (IAPinh) that induces target activation but failed to demonstrate objective responses in patients. In this grant, we propose to study an innovative experimental cancer therapeutic by chemically linking IAPinh (LCL161) to S2 ligand SW43, resulting in S2/IAPinh for tumor- selective drug delivery and therapy. We hypothesize that S2/IAPinh can be combined with systemic, low-dose chemotherapy to result in synergistic treatment regimens that lead to tumor eradication while systemic toxicities are reduced to a minimum. The overall goal of our current study is to find effective therapies for ovarian and pancreatic cancer. The proposed aims maximize the chance that a novel drug candidate, S2/IAPinh, will be effective clinically. This is envisioned either as single-agent, low-dose S2/IAPinh therapy in the context of a TNF-α gene signature in patient tumors or as combination regimens with clinically approved pathway enhancers, such as Nab-paclitaxel (Abraxane) (ovarian cancer) and Gemcitabine/Nab-paclitaxel (pancreatic cancer) but also statin-based inhibitors of cholesterol de novo synthesis. Our new findings represent an exciting innovative opportunity to enhance the activity profile of S2/IAPinh employing novel drug combinations for the benefit of cancer patients.

科学摘要上皮性卵巢癌（EOC）和胰腺导管腺癌（PDAC）是最常见的两种毁灭性的人类恶性肿瘤迫切需要改进的治疗理念。癌症治疗通常包括减少药物摄取、增加药物流出、改善适应化疗引起的应激/DNA 损伤和抑制细胞凋亡就是一个例子。耐药机制是X连锁凋亡蛋白抑制剂（XIAP），它是一种有效的负调节因子 XIAP 具有抑制卵巢癌和胰腺癌中的半胱天冬酶和癌细胞存活的促进剂的作用。已在体外和临床前小鼠模型中研究了增加细胞凋亡并克服耐药性。第二种线粒体衍生的半胱天冬酶激活剂 (SMAC) 是 XIAP 和 XIAP 的内源性抑制剂细胞 IAP (cIAP) 通过重新激活 caspase 活性（XIAP 阻断）和 cIAP 降解，导致癌症这些发现启动了内源性小分子模拟物的开发。 SMAC，已在多种人类恶性肿瘤中进行了研究，无论是作为单一药物，还是在与全身化疗相结合，进一步改善患者的预后。我们小分子药物开发工作的基础是基于 sigma-2 配体 (S2) 由于约 10 倍的丰度，促进癌细胞快速、选择性地摄取与正常宿主细胞相比，通过产生化学缀合物，产生相应的 sigma-2 受体 (S2R)。在 S2 和各种小分子药物货物之间，我们现在能够提供治疗性药物与非靶向肿瘤相比，有效载荷更有效、更有选择性地作用于肿瘤（靶向治疗）。 LCL161 是一种临床探索的 IAP 抑制剂 (IAPinh)，可诱导靶标激活，但未能证明在这项资助中，我们建议研究一种创新的实验性癌症。通过将 IAPinh (LCL161) 与 S2 配体 SW43 化学连接，产生 S2/IAPinh 来治疗肿瘤我们勇敢地说S2/IAPinh可以与全身、低剂量相结合。化疗产生协同治疗方案，在全身治疗的同时根除肿瘤毒性被降低到最低限度。我们当前研究的总体目标是寻找卵巢癌和胰腺癌的有效疗法。拟议的目标是最大限度地提高新候选药物 S2/IAPinh 在临床上有效的机会。设想在 TNF-α 基因特征背景下作为单药、低剂量 S2/IAPinh 疗法患者肿瘤或与临床批准的途径增强剂（例如白蛋白结合型紫杉醇）联合使用 (Abraxane)（卵巢癌）和吉西他滨/白蛋白结合型紫杉醇（胰腺癌）以及他汀类药物我们的新发现代表了一个令人兴奋的创新机会。采用新型药物组合增强 S2/IAPinh 的活性，造福癌症患者。