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

项目总结 胰腺癌是一种毁灭性的疾病，对标准的化疗方法难以奏效，这一点如下所示 较低的五年存活率为6%。这项建议的目的是临床评估一种新的治疗方法。 用于治疗胰腺癌，以提高存活率 Sigma-2(S2)受体在胰腺癌中过度表达，该受体的小分子配体 定位到这些肿瘤。此外，PDAC癌细胞能迅速内化选定的Sigma-2配体。这 这一发现促使我们探索使用这些配体向PDAC输送治疗有效载荷的可能性 肿瘤细胞通过与我们的配体进行化学连接。我们已经成功地使用S2配体在结构上传递 多种化合物，包括多肽和小分子疗法(经典化疗药物 [雷帕霉素]和多肽仿制药)，在体外和体内都能进入癌细胞。在每种情况下，活动 结合物的轮廓远大于孤立组分或它们的等摩尔组合。 基于这种递送机制，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中选择性地诱导细胞死亡的货物，以产生单个小分子结合物(SWV-49)。我们 已经证明这种结合物有效地杀死了基质丰富的胰腺癌肿瘤模型中的肿瘤细胞 有限的全身毒性。 该项目将进行药理和毒性分析，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.