On the path to the clinic: Lead optimization and pathway analysis of the pancreatic cancer-selective drug conjugate SW V-49

胰腺癌是一种毁灭性的疾病，对标准化疗是难治性的，如 五年生存率低至8%本提案的目的是评估一种新颖的、非常有前途的 采用全面的体外和临床前体内研究， 在临床评价研究之前进行测试。 σ-2（S2）受体在胰腺癌中过表达，并且该受体的小分子配体 定位于这些肿瘤。此外，PDAC癌细胞快速内化选定的σ-2配体。这 这一发现促使我们探索使用这些配体来提供额外治疗有效载荷的可能性 通过与我们的配体的化学键连接到PDAC肿瘤细胞。我们已经成功地使用S2配体来递送 包括肽和小分子治疗剂（经典的 化疗药物[雷帕霉素]和肽模拟物）在体外和体内进入癌细胞。在每个 偶联物的活性远大于分离组分或它们的等摩尔浓度 组合。 基于这种递送概念，我们将S2配体SV 119的肿瘤选择性与有希望的 通过产生单个小分子，在PDAC中选择性诱导细胞死亡的药物货物（dm-Erastin） 偶联物（SW V-49）。我们已经证明，这种缀合物有效地杀死富含基质的胰腺癌中的肿瘤细胞。 仅具有有限的全身毒性迹象的癌症模型。 本项目的主要任务是利用PDAC细胞系进行体外药理学和毒性药物试验 （鼠和人）、原代患者来源的3D类器官体外培养物以及同基因（小鼠）和 胰腺癌的患者来源的异种移植模型（PDX）。

Pancreatic cancer is a devastating disease that is refractory to standard chemotherapies, as demonstrated by the low five-year survival rate of 8%. The objective of this proposal is to assess a novel, highly promising therapeutic for the treatment of pancreatic cancer, employing comprehensive in vitro and preclinical in vivo testing prior to clinical evaluation studies. The sigma-2 (S2) receptor is overexpressed in pancreatic cancer, and small molecule ligands to this receptor localize to these tumors. In addition, PDAC cancer cells rapidly internalize selected sigma-2 ligands. This finding prompted us to explore the possibility of using these ligands to deliver additional therapeutic payloads to PDAC tumor cells via chemical linkage with our ligands. We have successfully used S2 ligands to deliver structurally diverse compounds including both peptides and small molecule therapeutics (classic chemotherapeutics [rapamycin] and peptidomimetics), into the cancer cells both in vitro and in vivo. In each case, the activity profiles of the conjugates were far greater than the isolated components or their equimolar combinations. Based on this delivery concept, we combined the tumor selectivity of the S2 ligand SV119 with a promising drug cargo that induces cell death selectively in PDAC (dm-Erastin), by creating a single small molecule conjugate (SW V-49). We have shown that this conjugate efficiently kills tumor cells in stroma-rich pancreatic cancer models with only limited signs of systemic toxicity. The key tasks of this project involve pharmacology and toxicity drug testing employing PDAC cell lines in vitro (murine and human), primary patient-derived 3D organoid in vitro cultures as well as syngeneic (mouse) and patient-derived xenograft models (PDX) of pancreatic cancer.