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

VDX-111：三阴性乳腺癌的新型靶向治疗药物

• 批准号: 10836599
• 负责人: Hamid H Gari
• 金额: $ 99.51万
• 依托单位: VONA ONCOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10836599
• 关键词: Active Sites; Acute; Address; Antineoplastic Agents; Apoptotic; Applications Grants; Binding; Biological Assay; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Canis familiaris; Cell Proliferation; Cells; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Data; Databases; Development; Diagnosis; Disease; Documentation; Dose; Doxorubicin; Drug Combinations; Drug Targeting; Drug resistance; Genes; Goals; Growth; Human; Impairment; In Vitro; Induction of Apoptosis; Invaded; Investments; Lead; Malignant Neoplasms; Methods; Mission; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncogenic; Outcome; Outcome Study; Paclitaxel; Patient Care; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Phase; Phosphoric Monoester Hydrolases; Positioning Attribute; Publishing; Rattus; Research; Risk-Benefit Assessment; Route; Safety; Scientist; Serum; Small Business Innovation Research Grant; Specificity; Survival Rate; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Translating; United States National Institutes of Health; Validation; Xenograft procedure; black women; cell killing; cell motility; chemotherapeutic agent; chemotherapy; clinical development; clinically significant; combinatorial; commercialization; design; detection method; disorder subtype; drug development; empowerment; experience; functional genomics; genome-wide; high risk; improved; improved outcome; in silico; in vitro activity; in vivo; insight; knock-down; malignant breast neoplasm; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 study; pre-Investigational New Drug meeting; pre-clinical; predictive marker; prevent; relapse risk; research clinical testing; resistance mechanism; response biomarker; side effect; small hairpin RNA; standard of care; synergism; targeted treatment; therapy resistant; timeline; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor xenograft; young woman

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 nonTNBC 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.

项目总结 三阴性乳腺癌(TNBC)对研究乳腺癌的基础科学家来说是一个巨大的挑战 这种疾病的分子基础以及直接与这种最致命和 乳腺癌的治疗耐药。目前，对TNBC的治疗缺乏有针对性的方法。 该项目直接解决了这一关键的未得到满足的需求。我们已经开发出VDX-111，一种新药，它能产生 在TNBC细胞系中有很强的促凋亡作用，但有趣的是，对大多数非TNBC和非致癌乳腺细胞几乎没有影响。VDX-111体内抑制TNBC细胞异种移植瘤生长 和TNBC患者来源的异种移植(PDX)模型。为了阐明VDX-111的作用机制，我们进行了 推出全基因组shRNA功能基因组学屏幕，旨在识别VDX-111作用所需的基因 并提供对潜在耐药机制的洞察。这个屏幕上排名最高的热门歌曲是 该基因名为PTP4A3，编码致癌磷酸酶PRL-3。评价PRL-3的临床意义 在TNBC中，我们探索了TCGA数据库。PRL-3在大约50%的侵袭性TNBCs中扩增。我们 已将PRL-3验证为VDX-111的目标。PRL-3基因敲除显著削弱VDX-111 诱导细胞凋亡。VDX-111直接阻断纯化的PRL-3的催化活性，促进其降解 PRL-3。VDX-111可抑制依赖PRL-3的TNBC细胞的迁移和侵袭。这些发现表明， PRL-3是VDX-111在TNBC中的主要靶点，也是VDX-111应答的潜在预测生物标志物。 在TNBC细胞中，VDX-111与经常用于TNBC患者的标准护理药物具有协同作用， 强调其作为一种组合治疗剂的潜力，可以在降低剂量的同时提高疗效 化疗药物。在第一阶段，我们将把VDX-111的体外概念验证研究扩展到 阿霉素联合紫杉醇治疗小鼠TNBC-PDX肿瘤模型的研究要开发 VDX-111的商业化潜力，最终目标是将其投入临床试验，使IND成为可能 提出了研究建议。在第二阶段，我们将(I)完成生物分析方法的开发和验证 临床测试和(Ii)在两个物种中完成启用IND的安全性、毒性和PK/PD测试。第二阶段研究 将为我们随后的IND批准和人体试验的启动做好准备。而且，实现了 提议的第二阶段目标将增强将VDX-111引入市场所需的商业化和投资 在TNBC中使用的诊所。这些研究的预期结果将使VDX-111的优化得到改进 TNBC患者的治疗选择，并确定IND前所需的安全性和PK/PD参数 与食品和药物管理局会面。这些结果将建立一个有吸引力的投资机会，以获得支持 需要使VDX-111成为TNBC患者标准护理的组成部分。