A Novel Therapeutic Strategy for Ovarian Cancer

卵巢癌的新治疗策略

• 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
• 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

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.

摘要 高级别浆液性卵巢癌（HGSOC）导致70-80%的卵巢癌死亡。的 在约80%的HGSOC肿瘤中观察到雌激素受体α（ERα）过表达，但尽管ERα 作为乳腺癌内分泌治疗的靶点（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疗法的临床试验， 令人失望的是，没有内分泌疗法被批准用于治疗HGSOC。我们一直在采取一种不同的 研究ERα表达癌症的方法，开发一套通过一种机制选择性杀死癌症的化合物， 与内分泌疗法不同，通过过度激活预期未折叠蛋白反应（a-UPR） 以ERα依赖的方式。我们在ERα阳性乳腺癌的治疗中取得了显著的成功; 如背景技术中所详述的，我们合成了新型化合物ErSO，其对 与ERα阴性细胞（IC 50值约为12）相比，杀死ERα阳性癌细胞（IC 50值约为30 nM µM），并在ERα阳性乳腺癌的多种小鼠模型中诱导完全消退。虽然ErSO 也具有抗ERα阳性卵巢癌的活性，但由于其 降低的效力与其体内毒性相结合使其治疗指数不足。我们现在寻求建立 提供了关于ErSO的有希望的数据，以开发用于ERα阳性卵巢癌的新疗法， 通过a-UPR的过度激活。在目标1中，我们将使用ErSO的结构-活性关系， 生理化学预测因子，以构建衍生物，这些衍生物将反复评估其对 HGSOC及其在小鼠中的耐受性，基于具有更好LipE值的化合物将更好的前提 体内耐受。实际上，利用这一指导原则并构造少量导数，我们 已经鉴定出一种有前景的化合物（称为ErSO-DFP），它保留了效力并选择性地对抗ERα+ 卵巢癌细胞，但在体内的耐受性明显优于ErSO，这表明， 我们的迭代综合/评估计划。顶级化合物将进入目标2，在目标2中， HGSOC的挑战性小鼠模型，包括原位、耐药模型和患者来源的异种移植物 (PDX)模型在目标3中，我们将利用炔基化衍生物和蛋白质组学在卵巢癌细胞中鉴定， 这些非常有前途的抗癌剂和有效的α-UPR超活化剂的精确结合配偶体。 我们的目标是在第3年到第5年之间确定一种适合用于人体临床试验的化合物 的融资期。这是一个由专家团队提出的重点突出、假设驱动的建议， 他之前曾将抗癌药物带入人体临床试验，并在所有临床试验中拥有数十年的经验。 必要的学科可以为HGSOC提供有影响力的靶向治疗;这将是一个主要的 为这一严重缺乏服务的患者群体取得了突破。