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

• 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
• 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

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.

科学抽象 上皮性卵巢癌（EOC）和胰腺导管腺癌（PDAC）是两种最常见的卵巢癌。 毁灭性的人类恶性肿瘤迫切需要改进的治疗概念。耐药性 癌症治疗通常尤其包括减少药物摄取、增加药物流出、改善治疗效果、以及减少或减少对癌症的治疗。 适应化疗诱导的应激/DNA损伤和抑制细胞凋亡。一例这样的 耐药机制是X连锁凋亡抑制蛋白（XIAP），一种有效的负调节剂， 在卵巢癌和胰腺癌中，caspase和癌细胞存活的启动子。XIAP的抑制具有 已经在体外和临床前小鼠模型中研究了增加细胞凋亡和克服耐药性。 第二种胱天蛋白酶衍生物激活剂（SMAC）是XIAP和caspase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 细胞死亡这些发现已经启动了内源性免疫抑制剂的合成小分子模拟物的开发。 SMAC，已在多种人类恶性肿瘤中作为单一药物进行了研究，但也在 联合全身化疗作为进一步改善患者结局的手段。 我们在小分子药物开发方面的工作基础是基于sigma-2配体（S2） 这有助于快速和选择性地摄取到癌细胞中，这是由于约10倍的高吸收， 相应的σ-2受体（S2 R）。通过生成化学共轭物 在S2和各种小分子药物货物之间，我们现在能够提供治疗药物， 有效载荷比它们的非靶向对应物更有效和选择性地作用于肿瘤（靶向治疗）。 LCL 161是一种临床探索的IAP抑制剂（IAPinh），可诱导靶点激活，但未能证明 患者的客观反应。在这项资助中，我们计划研究一种创新的实验性癌症 通过化学连接IAPinh（LCL 161）与S2配体SW 43的治疗，产生用于肿瘤的S2/IAPinh， 选择性药物输送和治疗。我们假设S2/IAPinh可与全身性低剂量 化疗产生协同治疗方案，导致肿瘤根除，同时全身 毒性被降低到最低限度。 我们目前研究的总体目标是找到卵巢癌和胰腺癌的有效疗法。的 提出的目标是最大限度地增加一种新的候选药物S2/IAPinh在临床上有效的机会。这是 在TNF-α基因特征的背景下， 患者肿瘤或作为与临床批准的途径增强剂如Nab-紫杉醇的组合方案 （Abraxane）（卵巢癌）和吉西他滨/白蛋白结合型紫杉醇（胰腺癌），但也有基于他汀类药物的 胆固醇从头合成的抑制剂。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的活性特征，以造福癌症患者。