Preventing in vivo resistance to PI3K/AKT/mTOR inhibitors through Mediator kinase inhibition

通过抑制介体激酶来预防体内对 PI3K/AKT/mTOR 抑制剂的耐药性

• 批准号: 10602700
• 负责人: Eugenia V Broude
• 金额: $ 40万
• 依托单位: SENEX BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602700
• 关键词: Antineoplastic Agents; Breast Cancer Cell; Cancer Patient; Cell Line; Clinic; Clinical; Clinical Trials; Collaborations; Development; Disease remission; Drug Combinations; Drug Exposure; Drug Targeting; Drug resistance; Estrogen Receptors; Estrogen receptor positive; FRAP1 gene; Fibrinogen; Future; Gene Expression; Genetic Transcription; Goals; Growth; Immunohistochemistry; Individual; MCF7 cell; MDA-MB-468; Malignant Neoplasms; Measures; Mediator of activation protein; Modeling; Mutation; Neuroendocrine Tumors; PI3K/AKT; PTEN gene; Pathway interactions; Patient-derived xenograft models of breast cancer; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphotransferases; Prevention; Process; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Renal Cell Carcinoma; Resistance; Resistance development; SDZ RAD; Signal Transduction; Signal Transduction Pathway; Small Business Innovation Research Grant; Solid Neoplasm; Stromal Cells; Testing; Toxic effect; Toxicokinetics; Up-Regulation; Xenograft procedure; alpelisib; base; clinical development; clinically relevant; combinatorial; drug candidate; gene induction; in vivo; inhibitor; leukemia; mTOR Inhibitor; malignant breast neoplasm; neoplastic cell; novel; patient derived xenograft model; phase 2 study; pre-clinical; prevent; programs; resistance mechanism; therapeutically effective; transcription factor; transcriptional reprogramming; transcriptomics; treatment duration; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor xenograft

Dysregulation of the PI3K/AKT/mTOR pathway is one of the most common genetic alterations in cancer, found in more than one third of all solid tumors. Inhibitors of the key components of this pathway (mTOR, PI3K, AKT) have been developed; some of them have been approved for breast cancer and for certain other malignancies. However, the benefits of these inhibitors are limited by the development of resistance, which arises either through enzymatic changes within the pathway or by the activation of compensatory signal transduction pathways or other transcriptional changes. Suppressing transcriptional resistance mechanisms could revitalize the use of PI3K/AKT/mTOR inhibitors, with a potentially transformative impact for many cancer patients. We propose to combine PI3K/AKT/mTOR inhibitors with a drug candidate that selectively inhibits CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, the key process required for the emergence of drug resistance. CDK8/19 inhibitors (CDK8/19i) suppress the emergence of resistance to different anticancer drugs. In preliminary studies, xenograft tumors formed by PTEN-deficient breast cancer cells were treated with mTOR inhibitor everolimus. Although tumor growth was fully arrested for the first 7-8 weeks, all the everolimus-treated tumors subsequently resumed their growth, indicating the development of resistance. While treatment with a CDK8/19i as a single agent had a modest effect on tumor growth, when combined with everolimus, the CDK8/19i fully prevented the development of resistance over 150 days of treatment. Prevention of everolimus resistance by the CDK8/19i was associated with the counteraction of transcriptomic effects of everolimus on both tumor and stromal cells. We hypothesize that our selective CDK8/19i preclinical drug candidate will suppress the development of resistance not only to mTOR but also to PI3K and AKT inhibitors, extending the duration of remission and possibly producing cures. This Phase I SBIR program will determine if the CDK8/19i prevents the development of in vivo resistance to mTOR inhibitor everolimus, PI3Kα inhibitor alpelisib, and AKT inhibitor capivasertib, in estrogen receptor (ER)-positive and triple-negative breast cancers. Under Aim 1, we will test the ability of the CDK8/19i to prevent the development of in vivo resistance to everolimus, alpelisib and capivasertib in cell-line based ER-positive and triple-negative breast cancer xenografts. Immunohistochemistry and transcriptomic analysis will be used to characterize the tumor- and stroma-based mechanisms of in vivo resistance to PI3K/AKT/mTOR inhibitors, which are prevented by CDK8/19 inhibition. Under Aim 2, we will determine if the CDK8/19i will prevent the development of in vivo resistance to the combination of everolimus and CDK8/19i in different clinically relevant patient-derived xenograft (PDX) models of ER-positive and triple- negative breast cancers. If the CDK8/19i prevents the emergence of in vivo resistance in these models, the future Phase II studies will be expanded to other PI3K/AKT/mTOR inhibitors, in breast cancer and other malignancies, to identify the best drug combinations and indications for clinical development.

研究发现，PI3K/AKT/mTOR 通路失调是癌症中最常见的遗传改变之一 超过三分之一的实体瘤。该通路关键成分的抑制剂（mTOR、PI3K、AKT） 已开发；其中一些已被批准用于治疗乳腺癌和某些其他恶性肿瘤。 然而，这些抑制剂的好处受到耐药性发展的限制，这种耐药性是通过 途径内的酶促变化或通过补偿信号转导途径的激活或 其他转录变化。抑制转录抵抗机制可以重振使用 PI3K/AKT/mTOR 抑制剂，对许多癌症患者具有潜在的变革性影响。我们建议 将 PI3K/AKT/mTOR 抑制剂与选择性抑制 CDK8/19 介导激酶（一种 转录重编程的调节因子，这是耐药性出现所需的关键过程。 CDK8/19 抑制剂 (CDK8/19i) 抑制不同抗癌药物耐药性的出现。在 初步研究，用 mTOR 治疗 PTEN 缺陷型乳腺癌细胞形成的异种移植肿瘤 抑制剂依维莫司。尽管肿瘤生长在前 7-8 周内被完全抑制，但所有接受依维莫司治疗的患者 肿瘤随后恢复生长，表明耐药性的发展。治疗时用 CDK8/19i 作为单一药物对肿瘤生长具有适度的影响，当与依维莫司联合使用时，CDK8/19i 经过150天的治疗，完全阻止了耐药性的产生。预防依维莫司耐药 CDK8/19i 与依维莫司对两种肿瘤的转录组效应的抵消有关 和基质细胞。我们假设我们的选择性 CDK8/19i 临床前候选药物将抑制 不仅对 mTOR 产生耐药性，而且对 PI3K 和 AKT 抑制剂也产生耐药性，从而延长了治疗的持续时间 缓解并可能产生治愈方法。该第一阶段 SBIR 计划将确定 CDK8/19i 是否可以防止 对 mTOR 抑制剂依维莫司、PI3Kα 抑制剂 alpelisib 和 AKT 抑制剂产生体内耐药性 capivasertib，用于雌激素受体（ER）阳性和三阴性乳腺癌。在目标 1 下，我们将测试 CDK8/19i 防止体内对依维莫司、alpelisib 和 capivasertib 产生耐药性的能力 在基于细胞系的 ER 阳性和三阴性乳腺癌异种移植物中。免疫组织化学和 转录组分析将用于表征体内基于肿瘤和基质的机制 对 PI3K/AKT/mTOR 抑制剂的耐药性，可通过抑制 CDK8/19 来预防。在目标 2 下，我们将 确定 CDK8/19i 是否会阻止对依维莫司组合产生体内耐药性 和 CDK8/19i 在不同临床相关的 ER 阳性和三重患者来源的异种移植 (PDX) 模型中 阴性乳腺癌。如果 CDK8/19i 阻止这些模型中体内耐药性的出现， 未来的 II 期研究将扩展到其他 PI3K/AKT/mTOR 抑制剂，用于乳腺癌和其他癌症 恶性肿瘤，以确定临床开发的最佳药物组合和适应症。