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

科学摘要 卵巢上皮癌(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。治疗中的耐药性 癌症治疗通常包括减少药物摄取，增加药物外排，改善 适应化疗引起的应激/DNA损伤和抑制细胞凋亡。这是一个这样的例子 抗性机制是X连锁的凋亡抑制蛋白(XIAP)，它是一种强有力的负调控因子 卵巢癌和胰腺癌中癌细胞存活的半胱氨酸天冬氨酸酶和促进剂。对XIAP的抑制有 在体外和临床前小鼠模型中，已经研究过增加细胞凋亡和克服耐药性。 线粒体衍生的半胱氨酸天冬氨酸酶第二激活因子(SMAC)是XIAP和XIAP的内源性抑制因子 通过重新激活caspase活性(XIAP阻断)和CIAP降解而导致细胞IAP(CIAP)，导致癌症 细胞死亡。这些发现开启了内源性合成小分子模拟物的发展 Smac，已经在多种人类恶性肿瘤中进行了研究，既作为单一的药物，也在 联合全身化疗作为进一步改善患者预后的手段。 我们在小分子药物开发方面的工作的基础是基于sigma-2配体(S2)。 它促进了癌细胞的快速和选择性摄取，因为它的丰度增加了约10倍 相应的Sigma-2受体(S2R)与正常宿主细胞相比。通过产生化学偶联物 在S2和各种小分子药物之间，我们现在有能力提供治疗 有效载荷比肿瘤的非靶向对应物更有效和更有选择性(靶向治疗)。 LCL161是一种临床研究的IAP抑制剂(IAPinh)，它可以诱导靶点激活，但未能证明 患者的客观反应。在这笔拨款中，我们建议研究一种创新的实验癌症 通过化学连接IAPinh(LCL161)和S2配体SW43进行治疗，导致S2/IAPinh治疗肿瘤- 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 化疗导致协同治疗方案，导致肿瘤根除，同时全身 毒性被减少到最低限度。 我们目前研究的总体目标是找到治疗卵巢癌和胰腺癌的有效方法。这个 提议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 设想为单药，低剂量的S2/IAPinh治疗，在肿瘤坏死因子-α基因签名的背景下 患者肿瘤或AS与临床批准的途径增强剂的联合方案，如NAB-紫杉醇 (Abraxane)(卵巢癌)和吉西他滨/NAB-紫杉醇(胰腺癌)，但也基于他汀类药物 胆固醇从头合成的抑制剂。我们的新发现代表着一个令人兴奋的创新机会 利用新的药物组合提高S2/IAPinh的活性，使癌症患者受益。

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.