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.

科学摘要上皮卵巢癌（EOC）和胰腺导管腺癌（PDAC）是最大的两个迫切需要改善治疗概念的人类恶性肿瘤。治疗耐药性癌症疗法经常包括降低药物摄取，药物排出增加，改善适应化学疗法诱导的应激/DNA损伤和抑制细胞凋亡。这样的例子抗性机制是X连锁蛋白质蛋白（XIAP）的X连锁抑制剂，这是潜在的负调节剂卵巢癌和胰腺癌中癌细胞存活的胱天蛋白酶和启动子。 XIAP的抑制具有研究了增加凋亡并在体外和临床前小鼠模型中克服耐药性的研究。第二个线粒体衍生的胱天蛋白酶激活剂（SMAC）是XIAP和细胞IAP（CIAP）通过重新激活caspase活性（XIAP阻断）和CIAP降解，导致癌症细胞死亡。 These findings have initiated the development of synthetic small molecule mimics of endogenous SMAC，已经在各种各样的人类恶性肿瘤中研究过，要么是单一代理结合全身化疗，作为进一步改善患者预后的一种手段。我们关于小分子药物开发的工作的基础是基于Sigma-2配体（S2）由于大约10倍的丰度，该癌细胞的快速和选择性吸收与正常宿主细胞相比，相应的Sigma-2受体（S2R）。通过产生化学共轭物在S2和各种小分子药物中，我们现在能够提供治疗有效载荷比肿瘤的非靶向对应物（有针对性的治疗）更有效，有选择性。 LCL161是一种临床探索的IAP抑制剂（IAPINH），影响目标激活但未能证明患者的客观反应。在这笔赠款中，我们建议研究创新的实验癌通过化学连接IAPINH（LCL161）与S2配体SW43进行治疗，导致S2/IAPINH用于肿瘤 - 选择性药物输送和治疗。我们假设S2/IAPINH可以与全身性低剂量结合化学疗法可导致导致消除肿瘤的协同治疗方案毒性降低至最低。我们当前研究的总体目标是找到有效的卵巢癌和胰腺癌疗法。拟议的目标是最大化新型药物S2/iapinh在临床上有效的机会。这是在TNF-α基因签名的背景下，设想为单剂量的低剂量S2/IAPINH疗法患者肿瘤或与临床认可的途径增强子（例如NAB-列酰胺）的组合方案（abraxane）（卵巢癌）和吉西他滨/NAB-甲曲奈（胰腺癌），但也基于他汀类药物从头合成胆固醇的抑制剂。我们的新发现代表了一个令人兴奋的创新机会使用新型药物组合的癌症患者提高S2/IAPINH的活性特征。