Background/Objectives: The PI3K/AKT/mTOR (PAM) pathway is frequently activated in gynecological cancers. Many PAM inhibitors selectively target single PAM pathway nodes, which can lead to reduced efficacy and increased drug resistance. To address these limitations, multiple PAM pathway nodes may need to be inhibited. Gedatolisib, a well-tolerated panPI3K/mTOR inhibitor targeting all Class I PI3K isoforms, mTORC1 and mTORC2, could represent an effective treatment option for patients with gynecologic cancers.Methods: Gedatolisib and other PAM inhibitors (e.g., alpelisib, capivasertib, and everolimus) were tested in endometrial, ovarian, and cervical cancer cell lines by using cell viability, cell proliferation, and flow cytometry assays. Xenograft studies evaluated gedatolisib in combination with a CDK4/6 inhibitor (palbociclib) or an anti-estrogen (fulvestrant). A pseudo-temporal transcriptomic trajectory of endometrial cancer clinical progression was computationally modeled employing data from 554 patients to correlate non-clinical studies with a potential patient group.Results: Gedatolisib induced a substantial decrease in PAM pathway activity in association with the inhibition of cell cycle progression and the decreased cell viability in vitro. Compared to single-node PAM inhibitors, gedatolisib exhibited greater growth-inhibitory effects in almost all cell lines, regardless of the PAM pathway mutations. Gedatolisib combined with either fulvestrant or palbociclib inhibited tumor growth in endometrial and ovarian cancer xenograft models.Conclusions: Gedatolisib in combination with other therapies has shown an acceptable safety profile and promising preliminary efficacy in clinical studies with various solid tumor types. The non-clinical data presented here support the development of gedatolisib combined with CDK4/6 inhibitors and/or hormonal therapy for gynecologic cancer treatment.
背景/目的：PI3K/AKT/mTOR（PAM）通路在妇科癌症中常被激活。许多PAM抑制剂选择性靶向单一通路节点，可能导致疗效降低并增加耐药性。为克服这些局限，可能需要同时抑制多个PAM通路节点。Gedatolisib作为一种耐受性良好的泛PI3K/mTOR抑制剂，能靶向所有I类PI3K亚型、mTORC1和mTORC2，可能成为妇科癌症患者的有效治疗选择。 方法：通过细胞活力检测、细胞增殖实验和流式细胞术，在子宫内膜癌、卵巢癌和宫颈癌细胞系中测试gedatolisib及其他PAM抑制剂（如alpelisib、capivasertib和everolimus）。异种移植研究评估了gedatolisib与CDK4/6抑制剂（palbociclib）或抗雌激素药物（fulvestrant）的联合疗效。基于554例患者数据，通过计算模型构建子宫内膜癌临床进展的伪时序转录组轨迹，以关联非临床研究与潜在患者群体。 结果：Gedatolisib能显著降低PAM通路活性，同时抑制细胞周期进程并降低体外细胞活力。与单节点PAM抑制剂相比，gedatolisib在几乎所有细胞系中均表现出更强的生长抑制效果，且不受PAM通路突变状态影响。在子宫内膜癌和卵巢癌异种移植模型中，gedatolisib联合fulvestrant或palbociclib能有效抑制肿瘤生长。 结论：临床研究表明，gedatolisib联合其他疗法在多种实体瘤治疗中展现出可接受的安全性和良好的初步疗效。本文提供的非临床数据支持将gedatolisib与CDK4/6抑制剂和/或激素疗法联合用于妇科癌症治疗的开发策略。
肿瘤(癌症)患者之家