Ipatasertib Dihydrochloride

近年来，CDK12基因突变型前列腺癌（PCa）的研究揭示了其与基因组不稳定性及耐药性密切相关。然而，CDK12突变是如何驱动癌症发展的具体机制仍未得到充分理解。为解决这一科学难题，中国科学院上海有机化学研究所丁克研究员与密歇根大学Rogel癌症中心Arul Chinnaiyan教授通过合作，分别于2024年9月30日和10月4日在Cell子刊Cell Reports Medicine杂志背靠背发表两篇关于CDK12的前沿研究，不仅在理论上揭示了CDK12突变驱动癌症发展的具体机制，还提出了具有应用潜力的治疗策略，极大地推动了前列腺癌领域的研究进展。 CDK12缺失驱动前列腺癌进展的分子机制 1. CDK12缺失引发前癌性病变和T 细胞浸润 在CDK12缺失小鼠模型中，前列腺上皮细胞出现显著的前癌性病变，并伴随T细胞浸润（CD3+T细胞显著增加），提示局部免疫微环境的改变。γH2AX 标记显著上升，表明DNA损伤增加。Ki67阳性细胞增多则显示出增殖活性增加。这些结果表明CDK12缺失能够推动前癌性病变和免疫浸润，进一步促进癌变发展。 2. CDK12缺失通过转录-复制冲突（TRCs）导致基因组不稳定 RNA-seq和ChIP-seq数据表明，CDK12缺失的前列腺类器官中存在大范围的TRCs和基因组不稳定性。基因组水平上，DDR基因（BRCA1、ATM）表达显著下调，而DNA断裂数量显著增加。通过中性彗星实验和细胞周期分析显示，CDK12缺失细胞中的DNA损伤和G1/S阻滞显著升高，揭示了TRCs是推动前列腺癌发展及基因组不稳定性的关键机制。 3. CDK12/Trp53双敲除小鼠模型对免疫检查点抑制剂的敏感性 CDK12和Trp53双敲除小鼠表现出高度侵袭性的前列腺癌，且在PD-1 抑制剂（如Nivolumab）治疗下显示出显著的肿瘤缩小效果（肿瘤体积缩小超过50%）。CD8+T细胞浸润显著增加，表明CDK12/Trp53双突变模型对免疫治疗响应率较高。这一发现提示免疫检查点抑制剂联合CDK12靶向治疗可能是治疗这一亚型前列腺癌的有效策略。 4. CDK12缺失导致对同源基因CDK13靶向治疗的合成致死效应 通过CRISPR筛选和基因敲除实验，CDK13抑制在CDK12缺失细胞中引发的合成致死效应显著增加，诱导细胞凋亡（Caspase-3活性显著上升），而未在野生型细胞中观察到。这表明靶向CDK13的策略可以在CDK12突变型前列腺癌中实现合成致死，为联合靶向治疗提供了实验依据。 CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13 开发新型CDK12/CDK13降解剂YJ1206：精准靶向的治疗新策略 5. 开发新型口服CDK12/CDK13降解剂YJ1206 研究团队通过PROTAC技术设计并优化了新型降解剂YJ1206，能够高效选择性降解CDK12和CDK13。在前列腺癌细胞系（VCaP、22Rv1）中，YJ1206的IC50值分别为33.55nM和85.74 nM，而在正常前列腺上皮细胞中（如 RWPE1）IC50 高于500nM。YJ1206在体内小鼠模型中能够显著抑制肿瘤生长，并降低DNA损伤相关基因（如 BRCA1、ATM）的表达，显示其作为临床候选药物的潜力。 6. YJ1206在多种前列腺癌模型中显示出优异的抗肿瘤活性 在体内前列腺癌异种移植小鼠模型（VCaP和22Rv1）中，YJ1206的治疗能够显著抑制肿瘤生长。治疗18天后，73%的小鼠肿瘤体积缩小超过50%。免疫组化分析显示，YJ1206处理后肿瘤组织中DDR相关基因（BRCA1、ATM）表达下降，TUNEL阳性细胞增加，表明其能够有效诱导细胞凋亡。 7. YJ1206与AKT抑制剂联用的合成致死效应 在探索CDK12/13降解剂的耐药机制时，研究团队发现YJ1206降解CDK12/13后，AKT信号通路会被激活，导致治疗效果降低。为了克服这一问题，研究团队将YJ1206与AKT抑制剂（如Ipatasertib, Uprosertib, MK2206）联合使用。实验显示，联合治疗能够显著增强YJ1206的抗肿瘤活性，诱导癌细胞凋亡，并减少细胞增殖。这一联合策略在多个小鼠CDX以及PDX异种移植模型中均表现出优异的抗肿瘤效果，联合治疗组肿瘤体积显著缩小，表明该策略能够有效克服YJ1206单药使用时可能出现的耐药性问题。 8. YJ1206 在体内外实验中表现出较少的副作用与其他CDK12抑制剂（如THZ531）相比，YJ1206在体内显示出更好的耐受性和较少的毒性。在小鼠实验中，YJ1206的治疗未导致体重变化和正常组织毒性，同时肿瘤体积显著缩小（P < 0.01），进一步验证了其作为新型抗癌药物的应用潜力。 Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition 研究重大意义与未来展望 这两项研究首次揭示了CDK12在前列腺癌进展中的关键作用，并开发了靶向CDK12/13的新型降解剂YJ1206，为CDK12突变相关癌症的精准治疗带来了新的希望。通过揭示CDK12/13在维持基因组稳定性及调控DDR中的冗余作用，研究团队提出了将CDK12/13降解剂与AKT抑制剂联合使用的合成致死策略。这一发现不仅为CDK12突变型前列腺癌的治疗提供了新的思路，也为未来其他癌症的治疗策略开发奠定了基础。 正如Arul Chinnaiyan教授所言：“当我们首次发现CDK12突变型前列腺癌这一新的亚型时，我们意识到必须深入了解这种基因变异如何驱动癌症的发展，并寻找精准靶向这一突变的新治疗策略。通过两篇研究论文，我们不仅揭示了CDK12缺失诱导癌症的分子机制，还开发了一种能够同时降解CDK12和CDK13的潜在治疗药物。这项工作展示了跨国、跨学科合作在推动癌症研究和药物开发中的巨大潜力，并为未来的临床应用铺平了道路。”。未来，研究团队将进一步优化YJ1206的药物特性，并计划开展更多的临床前研究，最终将其推进至临床试验阶段，为全球前列腺癌患者提供更为精准和有效的治疗选择。 原文链接： https://doi.org/10.1016/j.xcrm.2024.101758 https://doi.org/10.1016/j.xcrm.2024.101752 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！ 长按关注本公众号  粉丝群/投稿/授权/广告等 请联系公众号助手 觉得本文好看，请点这里↓

The lack of showing for Truqap in gene-altered patients was disappointing as the AstraZeneca AKT inhibitor was expected to work better in this subgroup. As if a limited initial FDA approval was not bad enough, AstraZeneca’s Truqap has recorded a pivotal trial flop that could raise additional doubts around the first-in-class AKT inhibitor. From AZ’s perspective, a company executive argued the failure was probably a one-off.Through and through, the phase 3 CAPItello-290 study was a bust. Truqap, when added to the chemotherapy paclitaxel, failed to extend the lives of patients with newly diagnosed metastatic triple-negative breast cancer or those in a subgroup with alterations in one of the PIK3CA, AK1 and PTEN genes.It was not a close call at all. The death risks between chemo and the Truqap-chemo combo were roughly the same in both analyses, according to data presented at the European Society for Medical Oncology Congress 2024. Patients in the Truqap arm lived a median 17.7 months, versus 18 months for control. In patients with the gene-altered tumors, the median overall survival was the same at 20.4 months between the two arms.While the study was designed to measure the drug’s survival benefits as the primary endpoint, Truqap did show a numerical advantage in reducing the risk of disease progression or death. The AZ drug reduced this risk by 28% compared with paclitaxel in the overall trial population and 30% in the gene-altered subgroup. Apparently, that didn’t translate into any life-extension benefit.The lack of showing in gene-altered patients was particularly disappointing as Truqap was expected to work better in this subgroup. The drug’s initial FDA nod in HR-positive, HER2-negative breast cancer, obtained in November, is limited to gene-altered patients because the FDA saw the most convincing effects there. The addition of Truqap to chemotherapy led to new toxicities in CAPItello-290. Notably, among adverse events that are grade 3 or above, the rates of diarrhea were 12.7% and 0.7% for Truqap and control, respectively. The rate of neutropenia was also slightly higher for AZ's medicine. Adverse events led to an 8.5% rate of treatment discontinuations in the experimental arm, compared with 4.9% in control.Cristian Massacesi, AstraZeneca’s chief medical officer and oncology chief development officer, argued that safety wasn’t the reason behind Truqap’s defeat in TNBC. Instead, he said that the data speak to “the fact that the practice is changing.” Although Massacesi didn’t elaborate, new therapies such as Gilead Sciences’ Trodelvy have emerged as later-line treatments for TNBC since CAPItello-290 commenced in 2019. Strong subsequent therapies may sometimes muddy the effect of a first-line drug, especially around overall survival.The control arm in CAPItello-290 performed markedly better than the control group in the phase 2 PAKT trial, which prompted AZ to move Truqap into phase 3 testing in first-line TNBC. Patients who received chemo alone lived a median 12.6 months in that phase 2 trial but 18 months in the new phase 3 study. In control patients with gene-altered tumors, the median progression-free survival time was 3.7 months in phase 2, versus 5.6 months in phase 3.TNBC was not meant to be Truqap’s core indication, and the CAPItello-290 failure does not affect AZ’s understanding of the drug in other ongoing phase 3 trials, including in HR+/HER2- breast cancer and prostate cancer, Massacesi told Fierce.The CAPItello-292 study was intended to move Truqap one line earlier in the treatment sequence than its existing U.S. indication. Unlike TNBC, the relevance of the PI3K/AKT pathway is very well-established in HR+/HER2- breast cancer, Massacesi noted. There, Novartis’ PI3K inhibitor Piqray has been approved in patients with PIK3CA-mutated tumors.As for prostate cancer, the CAPItello-281 trial, which could read out this year, is only being conducted in metastatic hormone-sensitive prostate cancer that’s PTEN-deficient. In addition, the phase 3 CAPItello-280 trial is testing the addition of Truqap to docetaxel in metastatic castration-resistant prostate cancer (mCRPC). That study was started because AKT activation seems to be a rescue mechanism prostate cancer develops to evade docetaxel, Massacesi explained. The idea is to block that alternative pathway and maximize the effect of docetaxel. Nevertheless, AKT inhibitors’ track record in prostate cancer has not been great. Roche previously dropped development of its AKT inhibitor ipatasertib. The drug showed a tumor progression benefit in a phase 3 trial in mCPRC with PTEN loss but didn’t move the needle on overall survival. Like Truqap, ipatasertib had also failed in TNBC in the IPATunity-170 trial.Truqap might have a different fate; after all, ipatasertib had also missed the mark in HR+/HER2- breast cancer, where Truqap was successful at least in the gene-altered population.Truqap didn’t have the best start when the FDA’s initial approval in HR+/HER2- breast cancer left out patients without mutations along the PI3K/AKT pathway despite a positive phase 3 trial readout in the overall population. AZ is still following the phase 3 CAPItello-290 trial for a longer overall survival analysis, and Massacesi said the company will share more data when the time is right.