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：
10436779
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436779
关键词：
3-Dimensional Apoptotic Biological Assay Carboplatin Carcinoma Categories Cell Cycle Progression Cell Death 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 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 Veterans Woman Work alternative treatment base 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在许多癌症。成功靶向p53是缺乏FDA批准的未满足的临床需求该类别的毒品。我们已经合作开发和测试了RECOP53，这是一种可重现P53的肽通过防止其聚合来起作用。我们以前的工作证明了RECP53单一疗法的功效在靶向高级浆液卵巢癌（HGSOC）时，该肿瘤为p53的损失为特征功能。 HGSOC是致命的妇科恶性肿瘤，每年夺取14,000名美国妇女的生命尽管进行了根本手术和卡铂标准化疗的给药。我们假设这一点 REACP53可以将抗铂的HGSOC敏感到卡铂。这种组合疗法可能会预防和这种侵略性癌症的目标复发。在我们以前的工作的基础上，我们提出了以下目标，以促进我们的临床翻译治疗：（1）确定治疗后是否可以将抗铂抗铂卵巢癌细胞敏感与Recocp53。一种新型的体外3D微型器官药物测定将用于测试72个主要的敏感性 HGSOCS在此目标中。 Subaim 1.1将重点介绍该疗法以靶向新诊断的HGSOCS 暴露于新辅助甲状腺素后，富含铂抗性细胞。这个回应将是与同一患者匹配的疗法前肿瘤标本相比。在Subaim 1.2中，我们将测试这种组合在靶向复发铂抗HGSOC方面的功效。 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抗铂的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Recp53和卡铂反应。在这里，我们将采用一种遗传方法通过工程耐铂的p53-null卵巢肿瘤细胞表达已知和常见的p53突变在HGSOC中报告。这些肿瘤细胞对组合疗法的反应将在Subaim 2.1中在体外测试和subaim 2.2的体内。结果将证明在卡铂中添加reccp53是否可以增强细胞在抗铂抗性的卵巢癌细胞中死亡，表达了多达30％的普通p53突变 HGSOCS。（3）测试RECP53和卡铂联合疗法在靶向铂抗性方面的功效 HGSOC PDXS。 p53突变与许多癌中介导铂耐药性高度涉及。这里，我们将测试在卡铂中添加ReCACP53是否可以恢复复发的人类HGSOC的铂敏感性使用PDX型号。在Subaim 3.1中，将通过抗铂抗HGSOC建立PDX，3敏感和3 基于体外药物测试的组合疗法具有抗性。在Subaim 3.2中，将处理带有PDX的小鼠使用媒介物，RECP53，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。调查结果可能会提供选择的理由和工具在将来的临床试验中，这种治疗方法可能受益的肿瘤。总体而言，通过恢复p53功能并定义对该疗法的反应的生物标志物，我们可能能够为被诊断的老将患者定义一种新的，更有效的精确医学治疗方法 P53驱动的卵巢癌。我们工作的潜在影响很广泛，可能会超越女性退伍军人由于这种疗法可适用于20,000名被诊断为侵略性p53-的男性和男性退伍军人每年突变的肿瘤。