A Novel Therapeutic Strategy for Ovarian Cancer

卵巢癌的新治疗策略

基本信息

批准号：
10446419
负责人：
Paul Hergenrother
金额：
$ 59.78万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
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：
2022-03-08 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446419
关键词：
Antineoplastic Agents Aromatase Inhibitors Binding Biological Breast Cancer Model Breast Cancer therapy Cancer Etiology Cancer Model Cancer Patient Cell Death Cells Cessation of life Chemicals Clinical Trials Data Development Discipline Disease Drug resistance Estrogen Receptor alpha Evaluation Excision Funding Gleevec Goals Human Lead Malignant Neoplasms Malignant neoplasm of ovary Modeling Modernization Mus Operative Surgical Procedures Outcome Peritoneal Pharmaceutical Preparations Platinum Proteins Proteomics Recurrence Selective Estrogen Receptor Modulators Series Serous Structure-Activity Relationship Therapeutic Index Time Toxic effect Translations Trastuzumab Tumor Debulking Variant Woman Work anti-cancer base cancer cell cellular targeting chemotherapy clinical candidate design effective therapy experience hormone therapy in vivo inhibitor malignant breast neoplasm melanoma mouse model novel novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model patient population patient subsets response success targeted agent targeted treatment tool trait translation to humans tumor

项目摘要

Abstract High-grade serous ovarian cancer (HGSOC) causes 70-80% of all deaths from ovarian cancer. The overexpression of estrogen receptor α (ERα) has been observed in ~80% of HGSOC tumors, but despite ERα being targeted by endocrine therapies in breast cancer (using aromatase inhibitors and selective estrogen receptor modulators and degraders), dozens of clinical trials with endocrine therapies for ovarian cancer have been disappointing, and no endocrine therapy is approved for treating HGSOC. We have been taking a different approach to ERα-expressing cancers, developing a suite of compounds that selectively kill via a mechanism distinct from endocrine therapies, through hyperactivation of the anticipatory unfolded protein response (a-UPR) in an ERα-dependent fashion. We have had notable success with this strategy for ERα-positive breast cancer; as detailed in the Background, we synthesized the novel compound ErSO, which has remarkable selectivity for killing ERα-positive cancer cells (IC50 values of ~30 nM) compared to ERα-negative cells (IC50 values of ~12 µM), and induces complete regression in multiple mouse models of ERα-positive breast cancer. While ErSO also has activity against ERα-positive ovarian cancer, it is not suitable for advancement in this setting as its reduced potency combined with its toxicity in vivo give it an insufficient Therapeutic Index. We now seek to build off the promising data on ErSO to develop novel therapeutics for ERα-positive ovarian cancer that operate through hyperactivation of the a-UPR. In Aim 1 we will use the structure-activity relationship for ErSO and physiochemical predictors to construct derivatives that will be iteratively evaluated for their potency against HGSOC and their tolerability in mice, based on the premise that compounds with better LipE values will be better tolerated in vivo. Indeed, using this guiding principle and constructing just a handful of derivatives, we have already identified a promising compound (called ErSO-DFP) that retains potency and selectively against ERα+ ovarian cancer cells but is markedly better tolerated in vivo as compared to ErSO, suggesting great potential for our iterative synthesis/evaluation plan. Top compounds will advance to Aim 2 where they will be assessed in challenging mouse models of HGSOC, including orthotopic, drug-resistant models, and patient-derived xenograft (PDX) models. In Aim 3 we will utilize alkynlyated derivatives and proteomics to identify, in ovarian cancer cells, the precise binding partner(s) of these highly promising anticancer agents and potent a-UPR hyperactivators. Our goal is to have identified a compound suitable for translation to human clinical trials between years 3 and 5 of the funding period. This tightly-focused, hypothesis-driven proposal from a team of experts who have previously brought anticancer drugs to human clinical trials and who have decades of experience in all the necessary disciplines could provide an impactful targeted therapy for HGSOC; this would be a major breakthrough for this vastly underserved patient population.

抽象的高级别浆液性卵巢癌 (HGSOC) 导致卵巢癌死亡人数的 70-80%。在约 80% 的 HGSOC 肿瘤中观察到雌激素受体 α (ERα) 过度表达，但尽管 ERα 乳腺癌内分泌治疗的目标（使用芳香酶抑制剂和选择性雌激素受体调节剂和降解剂），数十项卵巢癌内分泌治疗临床试验令人失望的是，没有内分泌疗法被批准用于治疗 HGSOC，我们一直在采取不同的方法。治疗表达 ERα 的癌症的方法，开发出一套通过机制选择性杀死的化合物与内分泌疗法不同，通过预期未折叠蛋白反应（a-UPR）的过度激活以 ERα 依赖性方式，我们在治疗 ERα 阳性乳腺癌方面取得了显着的成功；正如背景中详细介绍的，我们合成了新型化合物 ErSO，它对与 ERα 阴性细胞（IC50 值~12）相比，杀死 ERα 阳性癌细胞（IC50 值~30 nM） µM），并在多种 ERα 阳性乳腺癌小鼠模型中诱导完全消退。也具有抗 ERα 阳性卵巢癌的活性，但不适合在这种情况下进行进展，因为其效力降低加上体内毒性使其治疗指数不足。基于 ErSO 的有希望的数据，开发 ERα 阳性卵巢癌的治疗小说在目标 1 中，我们将使用 ErSO 和的结构-活性关系。构建衍生物的理化预测因子将被迭代评估其对抗病毒的效力 HGSOC及其在小鼠中的耐受性，基于LipE值更好的化合物会更好的前提事实上，利用这一指导原则并构建了少数衍生物，我们已经获得了体内耐受性。已经发现了一种有前途的化合物（称为 ErSO-DFP），它保留了效力并选择性地对抗 ERα+ 但与 ErSO 相比，卵巢癌细胞在体内的耐受性明显更好，这表明其具有巨大的潜力我们的迭代合成/评估计划将进入目标 2，并在其中进行评估。具有挑战性的 HGSOC 小鼠模型，包括原位模型、耐药模型和患者来源的异种移植模型 (PDX) 模型中，我们将利用炔化衍生物和蛋白质组学来识别卵巢癌细胞中，这些非常有前途的抗癌药物和有效的 a-UPR 过度激活剂的精确结合伴侣。我们的目标是找到一种适合在 3 至 5 年间转化为人体临床试验的化合物这项由专家团队提出的重点突出、假设驱动的提案曾将抗癌药物进行人体临床试验，并在所有领域拥有数十年的经验必要的学科可以为 HGSOC 提供有效的靶向治疗，这将是一个重大课题；对于这一服务严重不足的患者群体来说，这是一项突破。