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

基本信息

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
项目类别：
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

项目摘要

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.

鉴于 p53 在体内发生突变，恢复 p53 活性的治疗可能会为癌症治疗带来突破。许多癌症。成功靶向 p53 是一项未满足的临床需求，缺乏 FDA 批准就证明了这一点此类药物。我们合作开发并测试了 ReACp53，这是一种重新启用 p53 的肽通过阻止其聚集来发挥作用。我们之前的工作证明了 ReACp53 单一疗法的功效靶向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 名美国女性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 可以使铂耐药 HGSOC 对卡铂敏感。这种联合疗法可以预防和针对这种侵袭性癌症的复发。基于我们之前的工作，我们提出以下目标，以促进我们的临床转化治疗：（1）确定铂耐药卵巢癌细胞在治疗时是否可以对卡铂敏感与 ReACp53。一种新型体外 3D 微型类器官药物测定法将用于测试 72 种主要药物的敏感性 HGSOC 就是为了这个目标。 Subaim 1.1 将重点测试该疗法针对新诊断的 HGSOC 的效果暴露于新辅助卡铂后富集铂耐药细胞。此响应将是与同一患者的匹配治疗前肿瘤标本进行比较。在 Subaim 1.2 中我们将测试该组合在针对复发性铂耐药 HGSOC 方面的功效。全部 p53 突变状态样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针对耐铂 HGSOC。 (2)确定p53突变对调节的影响使用体外和体内肿瘤模型的 ReACp53 和卡铂反应。在这里，我们将采用遗传方法通过改造铂抗性 p53 缺失的卵巢肿瘤细胞来表达已知和常见的 p53 突变 HGSOC 中报告。这些肿瘤细胞对联合治疗的反应将在 Subaim 2.1 中进行体外测试以及 Subaim 2.2 中的体内。结果将证明在卡铂中添加 ReACp53 是否可以增强细胞活性高达 30% 的表达常见 p53 突变的铂耐药卵巢癌细胞死亡 HGSOC。（3）测试ReACp53与卡铂联合治疗针对铂类耐药的疗效 HGSOC PDX。 p53 突变与介导许多癌症的铂耐药性密切相关。这里，我们将测试在卡铂中添加 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，PDX 将从铂抗性 HGSOC 中建立，其中 3 个敏感，3 个根据体外药物测试，对联合治疗有抵抗力。在 Subaim 3.2 中，携带 PDX 的小鼠将接受治疗使用媒介物、ReACp53、卡铂或联合疗法。体内肿瘤反应将与 (a) 体外药物敏感性和 (b) p53 突变状态。研究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 功能并定义对该疗法反应的生物标志物，我们也许能够为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 驱动的卵巢癌。我们工作的潜在影响是广泛的，可能不仅限于女性退伍军人因为这种疗法适用于 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有突变的肿瘤。