VDX-111: A novel targeted therapeutic for triple-negative breast cancer

项目摘要 三阴性乳腺癌（TNBC）对研究乳腺癌的基础科学家来说是一个重大挑战。 疾病的分子基础，以及直接处理这种最致命， 乳腺癌的治疗抵抗。目前，缺乏治疗TNBC的靶向方法。 该项目直接解决了这一关键的未满足需求。我们开发了VDX-111，一种新型药物， 在TNBC细胞系中具有有效的促凋亡作用，但有趣的是，对大多数非凋亡细胞系几乎没有影响或没有影响。 TNBC和非致瘤性乳腺细胞。在体内，VDX-111减少来自TNBC细胞系的肿瘤异种移植物生长 和TNBC患者来源的异种移植物（PDX）模型。为了阐明VDX-111的作用机制，我们进行了 设计了一个全基因组的shRNA功能基因组学筛选，以鉴定VDX-111作用所需的基因 并提供对潜在耐药机制的深入了解。这个屏幕上排名最高的是 编码致癌磷酸酶PRL-3的基因PTP 4A 3。探讨血清催乳素-3（PRL-3）水平的临床意义 我们在TCGA数据库里搜索了一下PRL-3在大约50%的侵袭性TNBC中扩增。我们 验证PRL-3作为VDX-111的靶标。PRL-3的敲低显著削弱了VDX-111的能力， 诱导细胞凋亡。VDX-111直接阻断PRL-3的催化活性，促进PRL-3的降解 PRL-3 VDX-111抑制PRL-3依赖性TNBC细胞迁移和侵袭。这些发现表明 PRL-3是TNBC中VDX-111的主要靶标，并且可能是对VDX-111的响应的预测生物标志物。 在TNBC细胞中，VDX-111与经常给予TNBC患者的标准护理药物协同作用， 强调其作为组合治疗剂的潜力， 化疗药物。在第一阶段，我们将扩展我们的VDX-111的体外概念验证研究， 在小鼠TNBC PDX肿瘤模型中，与多柔比星和紫杉醇组合。发展 VDX-111的商业化潜力，最终目标是将其投入临床试验， 研究提出。在第二阶段，我们将（i）完成生物分析方法的开发和验证， 临床试验和（ii）在两个物种中完成IND使能安全性、毒性和PK/PD试验。II期研究 将为我们随后的IND批准和人体试验的启动做好准备。此外，实现 拟议的第二阶段目标将使VDX-111的商业化和投资成为可能， 用于TNBC的诊所。这些研究的预期结果将使VDX-111的优化， TNBC患者的治疗选择，并确定IND前研究所需的安全性和PK/PD参数 与FDA会面。这些结果将为获得支持提供有吸引力的投资机会 需要使VDX-111成为TNBC患者护理标准的组成部分。

PROJECT SUMMARY Triple-negative breast cancers (TNBC) represent a significant challenge to basic scientists studying the molecular underpinnings of the disease and to patients and clinicians who deal directly with this most deadly and therapy-resistant of breast cancers. Presently, targeted approaches toward the treatment of TNBC are lacking. This project directly addresses this critical unmet need. We have developed VDX-111, a novel drug that exerts potent pro-apoptotic action in TNBC cell lines but, interestingly, has little or no effect on the majority of non- TNBC and non-tumorigenic breast cells. In vivo, VDX-111 reduces tumor xenograft growth from TNBC cell lines and a TNBC patient-derived xenograft (PDX) model. To elucidate the mechanism of VDX-111action, we carried out a genome-wide shRNA functional genomics screen designed to identify genes required for VDX-111 action in TNBC and provide insight into potential resistance mechanisms. The highest-ranking hit from this screen was the gene, PTP4A3, encoding the oncogenic phosphatase, PRL-3. To evaluate the clinical significance of PRL-3 in TNBC, we probed the TCGA database. PRL-3 is amplified in approximately 50% of invasive TNBCs. We validated PRL-3 as a target of VDX-111. Knockdown of PRL-3 significantly impaired the ability of VDX-111 to induce apoptosis. VDX-111 directly blocked the catalytic activity of purified PRL-3 and promotes the degradation of PRL-3. VDX-111 inhibited PRL-3-dependent TNBC cell migration and invasion. These findings indicate that PRL-3 is a major target for VDX-111 in TNBC and is potentially a predictive biomarker for response to VDX-111. In TNBC cells, VDX-111 synergizes with standard of care drugs frequently administered to TNBC patients, highlighting its potential as a combinatorial therapeutic agent that could bolster efficacy while reducing the doses of the chemotherapeutics. In Phase I we will extend our in vitro proof of concept studies of VDX-111 in combination with doxorubicin and paclitaxel in murine TNBC PDX tumor models. To develop the commercialization potential of VDX-111, with the ultimate goal of moving it into clinical trials, IND-enabling studies are proposed. In Phase II we will (i) complete development and validation of bioanalytical methods for clinical testing and (ii), complete IND-enabling safety, toxicity, and PK/PD testing in two species. Phase II studies will position us for subsequent IND approval and the initiation of human trials. Moreover, accomplishing the proposed Phase II goals will empower the commercialization and investment required to bring VDX-111 to the clinic for use in TNBC. The expected outcomes of these studies will enable optimization of VDX-111 for improved therapeutic options for TNBC patients and determine the safety and PK/PD parameters required for a pre-IND meeting with the FDA. These outcomes will establish an attractive investment opportunity to acquire the support needed to make VDX-111 an integral part of standard of care for patients with TNBC.