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

基本信息

批准号：
10155344
负责人：
Hamid H Gari
金额：
$ 39.85万
依托单位：
VONA ONCOLOGY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155344
关键词：
Active Sites Acute Address Antineoplastic Agents Apoptosis 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 Indium-111 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 TimeLine Tissues Toxic effect Translating United States National Institutes of Health Validation Xenograft procedure base black women cell killing cell motility chemotherapeutic agent chemotherapy clinical development clinically significant combinatorial commercialization design detection method disorder subtype drug development experience functional genomics genome-wide high risk improved improved outcome in silico in vitro activity in vivo insight knock-down malignant breast neoplasm meetings 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-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 triple-negative invasive breast carcinoma tumor tumor growth tumor xenograft young woman

项目摘要

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.

项目概要三阴性乳腺癌（TNBC）对研究乳腺癌的基础科学家来说是一个重大挑战该疾病的分子基础，以及直接处理这种最致命和最严重的疾病的患者和临床医生乳腺癌的治疗耐药性。目前，缺乏针对 TNBC 的治疗的针对性方法。该项目直接解决了这一未满足的关键需求。我们开发了VDX-111，一种发挥作用的新药在 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 TNBC 和非致瘤性乳腺细胞。在体内，VDX-111 可减少 TNBC 细胞系的肿瘤异种移植物生长以及 TNBC 患者来源的异种移植（PDX）模型。为了阐明 VDX-111 的作用机制，我们进行了进行全基因组 shRNA 功能基因组筛选，旨在识别 VDX-111 作用所需的基因 TNBC 并提供对潜在耐药机制的见解。此屏幕上排名最高的点击量是 PTP4A3 基因编码致癌磷酸酶 PRL-3。评估PRL-3的临床意义在 TNBC，我们调查了 TCGA 数据库。 PRL-3 在大约 50% 的侵袭性 TNBC 中被扩增。我们验证 PRL-3 作为 VDX-111 的靶标。 PRL-3 的敲低显着损害了 VDX-111 的能力诱导细胞凋亡。 VDX-111直接阻断纯化的PRL-3的催化活性并促进降解 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 VDX-111 反应的预测生物标志物。在 TNBC 细胞中，VDX-111 与 TNBC 患者经常使用的标准护理药物具有协同作用，强调其作为组合治疗剂的潜力，可以在减少剂量的同时增强疗效的化疗药物。在第一阶段，我们将扩展 VDX-111 的体外概念验证研究与阿霉素和紫杉醇联合用于小鼠 TNBC PDX 肿瘤模型。开发 VDX-111的商业化潜力，最终目标是将其进入临床试验，并获得IND支持提出了研究。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 IND 安全性、毒性和 PK/PD 测试。二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促进将 VDX-111 推向市场所需的商业化和投资用于 TNBC 的诊所。这些研究的预期结果将能够优化 VDX-111，以改善 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 FDA 会面。这些成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 患者护理标准的一个组成部分。