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

恢复P53活性的治疗可能为癌症治疗提供突破，因为P53在 很多癌症。成功靶向p53是一种未得到满足的临床需求，缺乏FDA批准的证据 这一类的毒品。我们合作开发并测试了ReACP53，这是一种能重新激活P53的多肽 通过防止其聚集来发挥作用。我们以前的工作证明了ReACP53单一疗法的有效性 在针对高级别浆液性卵巢癌(HGSOC)方面，HGSOC是以P53缺失为特征的肿瘤 功能。HGSOC是致命的妇科恶性肿瘤，每年夺走14,000名美国妇女的生命 尽管接受了根治性手术和卡铂标准化疗。我们假设 ReACP53可使耐铂的HGSOC对卡铂增敏。这种联合疗法可能会预防和 以这种侵袭性癌症的复发为目标。 在我们以前工作的基础上，我们提出了以下目标，以促进我们的临床翻译 治疗：(1)确定耐铂卵巢癌细胞在治疗时是否可以对卡铂增敏 使用ReACP53。一种新的体外三维微量有机类药物检测方法将用于72种原发药物的敏感性测试 HGSOC在这一目标中的作用。Subaim 1.1将专注于针对新诊断的HGSOC测试这种疗法 在接触新佐剂卡铂后，对铂耐药细胞进行了浓缩。这一回应将是 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 这种联合疗法在靶向复发的铂耐药HGSOC方面的有效性。急性淋巴细胞白血病p53基因突变状态的研究 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 有效地靶向抗铂的HGSOC。(2)确定P53基因突变对细胞周期调控的影响 用体外和体内肿瘤模型研究ReACP53和卡铂的反应。在这里，我们将采取遗传方法 通过改造耐铂的p53缺失的卵巢肿瘤细胞来表达已知和常见的p53突变 在HGSOCs中报告。这些肿瘤细胞对联合治疗的反应将在Subaim 2.1进行体外测试 在苏巴伊姆2.2的活体中。结果将证明，在卡铂中加入ReACp53是否可以增强细胞 表达常见p53突变的耐铂卵巢癌细胞中高达30%的人死亡 HGSOC。(3)检测ReACP53与卡铂联合治疗对铂耐药的疗效 HGSOC PDX。在许多癌症中，P53基因突变与铂耐药密切相关。这里, 我们将测试在卡铂中加入ReACP53是否可以恢复复发的人HGSOC对铂的敏感性 使用PDX型号。在Subaim 3.1中，将由3个敏感和3个抗铂HGSOC建立PDX 对基于体外药物测试的联合治疗具有抵抗力。在Subaim 3.2中，携带PDX的小鼠将被治疗 用赋形剂、ReACP53、卡铂或联合治疗。体内肿瘤反应将与 (A)体外药物敏感性和(B)p53突变状态。研究结果可能会为选择 在未来的临床试验中，可能会从这种治疗方法中受益的肿瘤。 总而言之，通过恢复P53功能和定义对这种治疗反应的生物标记物，我们可能能够 为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基因驱动的卵巢癌。我们工作的潜在影响是广泛的，可能会延伸到女性退伍军人之外 由于这种疗法可以适用于20,000名被诊断为侵袭性p53的女性和男性退伍军人- 每年都有突变的肿瘤。

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.