PTEN在PI3K/AKT/mTOR通路中充当有效的肿瘤抑制因子。PTEN基因的种系突变是PTEN错构瘤综合征的标志,其中包括Cowden综合征,它们似乎会提高一生的癌症风险。靶向AKT定向治疗已被提出作为具有种系PTEN突变的癌症患者的有效方法。作用机制,在日本的一项I期研究中,已经探索了新型变构AKT抑制剂TAS-117的安全性和给药方案,在该研究中观察到了针对某些肿瘤类型的活性.在这里,我们描述了一个国际的研究协议,由两部分组成的第二阶段研究评估安全性,耐受性,药代动力学,TAS-117在具有种系PTEN失活突变的晚期实体瘤患者中的药效学和抗肿瘤活性。
信号通路控制细胞内的生长和活动。这些途径的过度活动可以鼓励许多类型的癌症发展。肿瘤抑制蛋白可以抑制促进癌症的细胞信号。如果在编码肿瘤抑制蛋白的任何基因中存在错误,则这种保护可能丧失。我们正在进行一项临床研究,以测试TAS-117,一种潜在的新型口服药物,在患有实体瘤的人中,其细胞的基因发生变化,使称为PTEN的肿瘤抑制蛋白失活。TAS-117瞄准可能由于PTEN活动丢失而过度活跃的信令路径的一部分。在早期研究中,TAS-117对某些肿瘤类型显示出有希望的活性。我们的试验将探索TAS-117是否可以为遗传变化导致PTEN活性丧失的罕见癌症提供新的治疗方法。试验注册号:NCT04770246(ClinicalTrials.gov)。
PTEN acts as a potent tumor suppressor within the PI3K/AKT/mTOR pathway. Germline mutations in the PTEN gene are a hallmark of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, where they appear to elevate lifetime risk of cancer. Targeted AKT directed therapy has been proposed as an effective approach in cancer patients having germline PTEN mutations. The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I
study in Japan in which activity was observed against certain tumor types. Here we describe the
study protocol of an international, two-part phase II
study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.
Signaling paths control growth and activities inside cells. Overactivity in these paths can encourage many types of cancers to develop. Tumor suppressor proteins can inhibit cell signals that promote cancer. This protection can be lost if there are errors in any gene coding for a tumor suppressor protein. We are carrying out a clinical
study to test TAS-117, a potential new oral medicine, in people who have solid tumors and whose cells have changes in their genes that inactivate a tumor suppressor protein called PTEN. TAS-117 targets part of a signaling path that may be overactive due to loss of PTEN activity. In early research, TAS-117 has shown promising activity against certain tumor types. Our
trial will explore if TAS-117 can provide a new treatment for rare forms of cancer where genetic changes have led to a loss of PTEN activity. Clinical
Trial Registration: NCT04770246 (ClinicalTrials.gov).