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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.

恢复p53活性的治疗可能会为癌症治疗提供突破，因为p53是突变的