Nature Medicine:“三管齐下”,一种治疗胰腺癌的新组合模式
2016/07/07
免疫疗法对于肺癌、黑色素瘤等癌症而言,已经被证实有良好的治疗效果,但是对于胰腺癌而言,免疫治疗却一直束手无策。近日,一项以小鼠为模型的研究证实,蛋白抑制剂、免疫治疗与化疗结合能够很好的分解胰腺癌肿瘤纤维组织,显著增加患病小鼠的存活率。


免疫疗法对于肺癌、黑色素瘤等癌症而言,已经被证实有良好的治疗效果,但是对于胰腺癌而言,免疫治疗却一直束手无策。近日,一项以小鼠为模型的研究证实,蛋白抑制剂、免疫治疗与化疗结合能够很好的分解胰腺癌肿瘤纤维组织,显著增加患病小鼠的存活率。

来自于华盛顿大学医学院的研究团队完成了这一突破性课题,相关研究成果于7月4日发表在《 Nature Medicine》期刊。团队负责人、助理教授David G. DeNardo表示,利用常规化疗、免疫治疗针对胰腺癌是一种新的治疗模式。

基于这一研究成果,Siteman癌症中心和巴恩斯-犹太医院的医生正在进行针对晚期胰腺癌患者的临床Ⅰ期试验,以测试这种药物组合的安全性。

“三管齐下”:FAK抑制剂+化疗+免疫疗法,延长患病小鼠三倍存活时间

作为一种诊断困难、预后极差、病死率高的消化道恶性肿瘤,胰腺癌一直被认为是“癌症之王”,只有约7.5%的患者能够存活5年以上。与其他癌症不同,胰腺肿瘤存在大量的瘢痕组织。这种额外的纤维组织、细胞会沉淀并对癌变细胞形成保护,阻止免疫系统以及化疗药物的攻击。

DeNardo团队认为,既然肿瘤的纤维环境是胰腺癌的典型特质,那么它可能可以作为免疫治疗的攻克点。他们希望能够找到瓦解这一“防护墙”的方法。

黏着斑激酶(Focal adhesion kinase,FAK)被证实参与许多疾病纤维组织的形成。所以研究人员尝试通过阻断这一关键过程减少纤维化和免疫抑制。他们首次将FAK免疫抑制剂和一种能够激活T细胞攻击肿瘤组织的免疫疗法结合使用,同时用于治疗胰腺癌。

结果显示,当仅仅只接受FAK抑制剂或者免疫疗法一种治疗手段时,患病小鼠最多只能存活2个月。但是,当三种药物结合(FAK抑制剂、免疫疗法、化疗)时却发生了大的逆转:一些患病小鼠存活时间延长了三倍,且在6个月内癌症没有再发生恶化。

“三管齐下”的做法能够通过多种方式对抗癌症,瓦解其微环境增强免疫系统、化疗药物对肿瘤组织的消灭作用。这一动物试验很好地证实了三种药物组合能够有望用于治疗晚期胰腺癌。

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  • Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy

    Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8+ cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-KrasG12D;Trp53flox/+ (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.

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