Kim Seonhee, Jung Bo-Kyoung, Kim Jinju, Jeon Joo Hee, Jang Sung Hoon, Kim Minsoo, Kim Cuk-Seong, Jang Hyun
Libentech Co. Ltd., Daejeon 34013, Republic of Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
Mol Ther Oncol. 2024 Oct 28;32(4):200898. doi: 10.1016/j.omton.2024.200898. eCollection 2024 Dec 19.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and intractable cancer that requires more effective therapies that can improve early detection, enhance treatment efficacy, and provide better patient outcomes. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and reduced phosphatase and tensin homolog (PTEN) protein expression are key factors driving the proliferation and severity of PDAC. To address this, a recombinant Newcastle disease virus (rNDV) containing the PTEN gene (rNDV-PTEN) was created to investigate its PDAC cell-killing and tumor-suppression effects in PDAC cells transplanted into mice. PTEN expression induced by rNDV-PTEN virus infection in KRAS-mutated PDAC cells lowered phosphatidylinositol 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, promoted PDAC cell death, and suppressed tumor growth. PTEN overexpression promotes apoptotic signaling pathways in both PANC-1 cells and orthotopic xenograft mice. Additionally, during virotherapy, rNDV-PTEN-injected mice exhibited a mild immune response and no abnormal responses in blood parameters such as glucose, triglyceride, and total cholesterol levels. These findings support the potential of rNDV-PTEN as a safe and effective therapy for PDAC with highly activated PI3K/AKT/mTOR signaling caused by KRAS and PTEN gene mutations. Thus, PTEN gene-containing rNDV may be a promising candidate for pancreatic cancer treatment.
胰腺导管腺癌（PDAC）是一种极具侵袭性和难治性的癌症，需要更有效的治疗方法来改善早期检测、提高治疗效果并为患者带来更好的预后。 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变和磷酸酶及张力蛋白同源物（PTEN）蛋白表达降低是驱动PDAC增殖和严重程度的关键因素。为了解决这个问题，构建了一种含有PTEN基因的重组新城疫病毒（rNDV-PTEN），以研究其对移植到小鼠体内的PDAC细胞的杀伤和肿瘤抑制作用。rNDV-PTEN病毒感染在KRAS突变的PDAC细胞中诱导的PTEN表达降低了磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（AKT）/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路，促进了PDAC细胞死亡并抑制了肿瘤生长。PTEN过表达促进了PANC-1细胞和原位异种移植小鼠中的凋亡信号通路。此外，在病毒治疗期间，注射rNDV-PTEN的小鼠表现出轻微的免疫反应，并且在血糖、甘油三酯和总胆固醇水平等血液参数方面没有异常反应。这些发现支持了rNDV-PTEN作为一种安全有效的疗法治疗由KRAS和PTEN基因突变引起的PI3K/AKT/mTOR信号高度激活的PDAC的潜力。因此，含PTEN基因的rNDV可能是胰腺癌治疗的一个有前途的候选者。
