KiSS1 treatment of pancreatic adenocarcinoma

描述(申请人提供)：目前，胰腺癌是美国第四大癌症死亡原因，中位生存期为6个月，5年生存率为1-3%。大多数被诊断为胰腺癌的患者在诊断时都有播散性疾病。由于过去30年进行的临床试验也清楚地表明，在患者生存方面只取得了很小的进展，因此迫切需要新的策略。本研究的目的是开发一种新的治疗方法，使用转移抑制因子来治疗转移性胰腺癌，从而提高患者的存活率。转移抑制因子Kiss1是一种分泌蛋白，可抑制人黑色素瘤、乳腺癌和卵巢癌异种移植模型的转移。胰腺癌患者组织中Kiss1的表达水平明显低于正常胰腺组织。这一建议的假设是，胰腺癌的转移可以通过包括转移抑制因子Kiss1在内的治疗策略来显著减少(或防止)。初步研究表明，在异种小鼠原位移植模型中，Kiss1的过表达大大减少了胰腺癌的肝脏转移(97.5%)和肺转移(99.4%)。在这些数据的基础上，拟议的体外和体内实验将评估Kiss1治疗单独或与化疗联合使用的抗肿瘤和抗转移效果。具体目标#1将评估在异种移植小鼠模型中用化疗方法治疗转移性胰腺癌细胞的效果。目的#2将通过构建传染性增强的、有条件复制能力的Kiss1腺病毒来解决Kiss1的传递问题。目的#3评价Ad-Kiss1病毒治疗转移性肿瘤的效果。具体目标#4将评估Ad-Kiss1病毒和化疗的联合治疗，以在异种移植模型中检查联合细胞毒治疗和抗转移治疗对已建立的转移和原发肿瘤的潜在益处。这些研究将首次检验Kiss1对已建立的转移的治疗，并为未来胰腺癌患者抗转移治疗的潜在益处提供重要信息。

DESCRIPTION (provided by applicant): Currently, pancreatic adenocarcinoma is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate 1-3%. The majority of patients diagnosed with pancreatic adenocarcinoma have disseminated disease at the time of diagnosis. Because clinical trials performed over the last 30 years also clearly demonstrated that only minimal progress has been made in patient survival, new strategies are desperately needed. The goal of this research is to develop a novel therapeutic approach using metastasis suppressors to treat metastatic pancreatic adenocarcinoma and thereby improve patient survival. The metastasis suppressor, KiSS1, is a secreted protein that inhibits metastasis of human melanoma, breast, and ovarian cancer xenograft models. KiSS1 expression levels are significantly lower in pancreatic cancer tissues from patients than normal pancreatic tissues. The hypothesis of this proposal is that metastasis of pancreatic adenocarinoma can be significantly reduced (or prevented) by therapeutic strategies including KiSS1, a metastasis suppressor. Preliminary studies indicate that overexpression of KiSS1 greatly reduces both hepatic (97.5%) and pulmonary metastasis (99.4%) of pancreatic cancer in an orthotopic xenograft mouse model. Building upon these data, the proposed in vitro and in vivo experiments will evaluate KiSS1 treatment alone or combined with chemotherapy as regards anti-tumor and anti-metastatic efficacy. Specific aim #1 will evaluate treatment of metastatic pancreatic cells transfected with KiSS1 plasmid with chemotherapy in a xenograft mouse model. Aim #2 will address KiSS1 delivery, via construction of an infectivity enhanced, conditionally replication competent KiSS1 adenovirus. Aim #3 will evaluate the treatment of metastatic tumors with the Ad-KiSS1 virus. Specific aim #4 will evaluate combination treatment with Ad-KiSS1 virus and chemotherapy to examine potential benefits of combination cytotoxic treatment and anti-metastatic therapy on established metastasis and primary tumors in a xenograft model. These studies will be the first to examine KiSS1 treatment on established metastasis and provide vital information on the potential benefits of anti-metastatic treatment for future pancreatic adenocarcinoma patients.