Project 2: Clinical Development of the Pancreatic Cancer Drug Conjugate SW v-49

项目摘要 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6%该提案的目的是临床评估一种新的治疗方法， 为了提高存活率， 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向PDAC递送治疗有效载荷的可能性 肿瘤细胞通过化学键与我们的配体。我们已经成功地使用S2配体在结构上递送 包括肽和小分子治疗剂（经典化学治疗剂 [雷帕霉素]和肽模拟物）在体外和体内进入癌细胞。在每种情况下，活动 缀合物的分布远远大于分离的组分或它们的等摩尔组合。 基于这种传递机制，我们将S2配体的肿瘤选择性与一种有前途的药物相结合， 在PDAC中选择性诱导细胞死亡的货物，以产生单个小分子缀合物（SW V-49）。我们 已经表明，这种缀合物在富含基质的胰腺癌肿瘤模型中有效地杀死肿瘤细胞， 有限的全身毒性。 该项目将进行药理学和毒性试验，并在临床试验中测试结合物。

PROJECT SUMMARY Pancreatic cancer is a devastating disease that is refractory to standard chemotherapies, as demonstrated by the low five-year survival rate of 6%. The objective of this proposal is to clinically evaluate a novel therapeutic for the treatment of pancreatic cancer with in order to improve survival rates 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 a therapeutic payload 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 mechanism, we combined the tumor selectivity of the S2 ligand with a promising drug cargo that induces cell death selectively in PDAC, to create a single small molecule conjugate (SW V-49). We have shown that this conjugate efficiently kills tumor cells in stroma-rich pancreatic cancer tumor models with limited systemic toxicity. This project will perform pharmacology and toxicity assays, and test the conjugate in a clinical trial.