Reactivating p53 Function with a Novel Structure-based Peptide as a Therapeutic Approach for Overcoming Platinum Resistance

使用基于新型结构的肽重新激活 p53 功能作为克服铂电阻的治疗方法

• 批准号: 10553625
• 负责人: Sanaz Memarzadeh
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553625
• 关键词: 3-Dimensional; Adjuvant Chemotherapy; Apoptotic; Biological Assay; Carboplatin; Carcinoma; Categories; Cell Cycle Progression; Cell Death; Cell Survival; Cells; Chemoresistance; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; DNA Damage; DNA Repair; Diagnosis; Diagnostic tests; Disease Resistance; Engineering; Exposure to; FDA approved; Female; Future; Genes; Genetic Engineering; Genome; Goals; Human; In Vitro; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Mus; Mutate; Mutation; Neoadjuvant Therapy; Newly Diagnosed; Operative Surgical Procedures; Organoids; Patient Selection; Patients; Peptides; Pharmaceutical Preparations; Platinum; Play; Proteins; Randomized; Recurrence; Relapse; Reporting; Resistance; Role; Sampling; Serous; Specimen; Stress; Structural Biologist; Structure; TP53 gene; Testing; Therapeutic; Treatment Efficacy; Tumor Promotion; Veterans; Woman; Work; alternative treatment; cancer cell; cancer therapy; chemotherapy; clinical application; clinical translation; companion diagnostics; disease-in-a-dish; drug sensitivity; drug testing; druggable target; efficacy testing; efficacy validation; exome sequencing; experimental study; genetic approach; in vitro testing; in vivo; male; mouse model; mutant; mutational status; neoplastic cell; novel; ovarian neoplasm; patient derived xenograft model; peptide drug; precision medicine; predicting response; predictive marker; prevent; response; response biomarker; restoration; therapeutic evaluation; tool; translational impact; treatment response; treatment strategy; tumor

Treatments that restore p53 activity could provide a breakthrough in cancer therapy given that p53 is mutated in many cancers. Successful targeting of p53 is an unmet clinical need evidenced by the lack of FDA-approved drugs in this category. We have collaboratively developed and tested ReACp53, a peptide that re-enables p53 function by preventing its aggregation. Our previous work demonstrated the efficacy of ReACp53 monotherapy in targeting high-grade serous ovarian cancers (HGSOCs), which are tumors characterized by loss of p53 function. HGSOCs are deadly gynecologic malignancies that claim the lives of 14,000 U.S. women annually despite radical surgeries and administration of carboplatin standard chemotherapy. We hypothesize that ReACp53 can sensitize platinum-resistant HGSOCs to carboplatin. This combination therapy may prevent and target recurrence of this aggressive cancer. Building on our previous work, we propose the following aims that will facilitate clinical translation of our therapeutic: (1) Determine if platinum-resistant ovarian cancer cells can be sensitized to carboplatin when treated with ReACp53. A novel in vitro 3D miniring organoid drug assay will be used to test the sensitivity of 72 primary HGSOCs in this aim. Subaim 1.1 will focus on testing this therapy in targeting newly-diagnosed HGSOCs enriched for platinum-resistant cells following exposure to neoadjuvant carboplatin. This response will be compared to matched pre-therapy tumor specimens from the same patient. In Subaim 1.2 we will test the efficacy of this combination in targeting recurrent platinum-resistant HGSOCs. p53 mutation status in all specimens will be correlated with drug response. Results will demonstrate if this therapeutic approach can be efficacious in targeting platinum-resistant HGSOCs. (2) Determine the effect of p53 mutations on modulating ReACp53 and carboplatin response using in vitro and in vivo tumor models. Here, we will take a genetic approach by engineering platinum-resistant p53-null ovarian tumor cells to express known and common p53 mutations reported in HGSOCs. Response of these tumor cells to combination therapy will be tested in vitro in Subaim 2.1 and in vivo in Subaim 2.2. Results will demonstrate if the addition of ReACp53 to carboplatin can potentiate cell death in platinum-resistant ovarian cancer cells expressing common p53 mutations found in up to 30% of all HGSOCs. (3) Test the efficacy of ReACp53 and carboplatin combination therapy in targeting platinum-resistant HGSOC PDXs. p53 mutations are highly implicated in mediating platinum resistance in many carcinomas. Here, we will test if the addition of ReACp53 to carboplatin can restore platinum sensitivity of recurrent human HGSOCs using PDX models. In Subaim 3.1 PDXs will be established from platinum resistant HGSOCs, 3 sensitive and 3 resistant to combination therapy based on in vitro drug testing. In Subaim 3.2, mice bearing PDXs will be treated with vehicle, ReACp53, carboplatin, or the combination therapy. In vivo tumor response will be correlated with (a) in vitro drug sensitivity and (b) p53 mutation status. Findings may provide the rationale and tools for selecting tumors that may benefit from this therapeutic approach in future clinical trials. Collectively, by restoring p53 function and defining biomarkers of response to this therapy, we may be able to define a new and more effective precision medicine therapeutic approach for Veteran patients diagnosed with p53-driven ovarian cancers. The potential impact of our work is broad and may extend beyond female Veterans as this therapy can be applicable to the 20,000 female and male Veterans diagnosed with aggressive p53- mutated tumors each year.

恢复p53活性的治疗可能为癌症治疗提供突破，因为p53在肿瘤中发生突变。 许多癌症。成功靶向p53是一个未满足的临床需求，这一点通过缺乏FDA批准的 这类药物。我们已经合作开发和测试了ReACp53，一种能够重新激活p53的肽， 防止其聚集。我们之前的工作证明了ReACp53单药治疗的疗效 针对高级别浆液性卵巢癌（HGSOC），这是一种以p53缺失为特征的肿瘤， 功能HGSOC是致命的妇科恶性肿瘤，每年夺去14，000名美国妇女的生命 尽管进行了根治性手术和卡铂标准化疗。我们假设 ReACp53可使铂耐药HGSOC对卡铂敏感。这种联合治疗可以预防和 针对这种侵袭性癌症的复发。 在我们以前工作的基础上，我们提出了以下目标，这将有助于我们的临床翻译 治疗：（1）确定铂耐药卵巢癌细胞在治疗时是否能对卡铂敏感 ReACp53一种新的体外3D微型类器官药物测定将用于测试72种原发性肿瘤的敏感性。 HGSOCs在这方面。Subaim 1.1将专注于测试这种疗法在新诊断的HGSOC中的作用 在暴露于新辅助卡铂后富集铂抗性细胞。这一反应将是 与来自同一患者的匹配的治疗前肿瘤标本进行比较。在Subaim 1.2中，我们将测试 这一组合在靶向复发性铂耐药HGSOC中的功效。p53突变状态 标本将与药物反应相关。结果将证明这种治疗方法是否可以 有效靶向铂抗性HGSOC。(2)确定p53突变对调节 使用体外和体内肿瘤模型的ReACp53和卡铂反应。在这里，我们将采取遗传学的方法 通过设计铂抗性p53缺失卵巢肿瘤细胞以表达已知和常见的p53突变， 在HGSOC中报告。这些肿瘤细胞对联合治疗的反应将在Subaim 2.1中进行体外测试。 在Subaim 2.2中，结果将证明，将ReACp53添加到卡铂中是否可以增强细胞凋亡。 在高达30%的卵巢癌患者中发现表达常见p53突变的铂耐药卵巢癌细胞死亡 HGSOC。(3)测试ReACp53和卡铂联合治疗在靶向铂耐药患者中的疗效 HGSOC PDX。p53突变与许多癌中介导的铂耐药性密切相关。在这里， 我们将测试在卡铂中加入ReACp53是否可以恢复复发性人类HGSOC的铂敏感性 使用PDX模型。在Subaim 3.1中，将从铂耐药HGSOC中建立PDX，3个敏感和3个 基于体外药物测试，对联合治疗具有抗性。在Subaim 3.2中，将治疗携带PDX的小鼠 与载体、ReACp53、卡铂或联合治疗。体内肿瘤缓解将与 (a)体外药物敏感性和（B）p53突变状态。调查结果可能提供选择的理由和工具 在未来的临床试验中可能受益于这种治疗方法的肿瘤。 总的来说，通过恢复p53功能和确定对这种治疗反应的生物标志物，我们可能能够 为被诊断患有以下疾病的退伍军人患者定义一种新的、更有效的精准医学治疗方法 p53基因导致的卵巢癌我们工作的潜在影响是广泛的，可能超出女性退伍军人 因为这种疗法可以适用于20，000名被诊断患有侵袭性p53的女性和男性退伍军人， 每年都发生肿瘤突变。