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

基本信息

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
项目类别：
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

项目摘要

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.

PI3K/AKT/MTOR途径的失调是癌症中最常见的遗传改变之一在所有实体瘤中的三分之一以上。该途径的关键成分的抑制剂（MTOR，PI3K，AKT）已经开发了；其中一些已被批准用于乳腺癌和某些其他恶性肿瘤。但是，这些抑制剂的好处受到抵抗的发展的限制，这是通过途径内的酶变化或通过代码信号转导途径的激活或其他转录变化。抑制转录电阻机制可以振兴使用 PI3K/AKT/MTOR抑制剂，对许多癌症患者产生潜在的变革影响。我们建议将PI3K/AKT/MTOR抑制剂与有选择性抑制CDK8/19介质激酶的药物抑制剂结合在一起转录重编程的调节剂，这是耐药性出现所需的关键过程。 CDK8/19抑制剂（CDK8/19I）抑制了对不同抗癌药物的耐药性。在初步研究，由PTEN缺陷乳腺癌细胞形成的特征肿瘤用MTOR处理抑制剂Everolimus。尽管肿瘤生长在最初的7-8周中被完全捕获肿瘤随后恢复了生长，表明抗药性的发展。而用 CDK8/19i作为单个药物对肿瘤生长有适度的影响，与依维莫司（Everolimus）结合使用CDK8/19I 在150天的治疗中完全阻止了阻力的发展。预防依维氏抗性 cdk8/19i与依维莫司对两个肿瘤的转录组效应的反射有关和基质细胞。我们假设我们的选择性CDK8/19I临床前药物将抑制不仅对MTOR而且对PI3K和AKT抑制剂的抗性发展，从而延长了持续时间缓解和可能产生的治疗方法。此阶段I SBIR计划将确定CDK8/19I是否阻止开发对MTOR抑制剂Everolimus，PI3Kα抑制剂Alpelisib和Akt抑制剂的体内耐药性的发展 Capivasertib，在雌激素受体（ER）阳性和三阴性乳腺癌中。在AIM 1下，我们将测试 CDK8/19i防止体内耐药性发展的能力在基于细胞系的ER阳性和三阴性的乳腺癌Xenographictic中。免疫组织化学和转录组分析将用于表征体内肿瘤和基质的机制 CDK8/19抑制阻止的PI3K/AKT/MTOR抑制剂的抗性。在AIM 2下，我们将确定CDK8/19I是否会防止在依维莫司组合的体内耐药性发展 ER阳性和三重的不同临床相关患者衍生的Xenographic（PDX）模型中的CDK8/19i 负乳腺癌。如果CDK8/19I阻止了这些模型中体内抗性的出现，则未来的II期研究将扩展到其他PI3K/AKT/MTOR抑制剂，乳腺癌和其他恶性肿瘤，以确定临床发育的最佳药物组合和适应症。