A treatment drug for triple negative breast cancer

一种治疗三阴性乳腺癌的药物

基本信息

批准号：
10643890
负责人：
Zhi-Ren Liu
金额：
$ 99.96万
依托单位：
PRODA BIOTECH, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10643890
关键词：
Aftercare Animal Model Binding Sites Biopsy Biotechnology Blood Vessels Blood flow Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment CASP8 gene Cell Survival Cells Cessation of life Clinical Clinical Research Collagen Cytoplasmic Tail Cytotoxic Chemotherapy Data Data Set Deposition Development Diagnosis Disease Disease Progression Dose Drug Delivery Systems Drug resistance Endothelial Cells Enrollment Extracellular Matrix FDA approved Fibroblasts Foundations Genetically Engineered Mouse Goals Histologic Induction of Apoptosis Institutional Review Boards Integrins Invaded Legal patent Letters Licensing Life Ligand Binding MDA MB 231 Malignant Neoplasms Maximum Tolerated Dose Medical Mission Modeling Monkeys Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Neoplasms in Vascular Tissue Nude Mice Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Play Prognosis Property Protein Engineering Proteins Rattus Recommendation Relapse Research Research Project Grants Resistance Role Safety Sampling Site Small Business Innovation Research Grant Solid Neoplasm Structure Study models Technology Testing Therapeutic Time Toxic effect Translating Treatment Failure Treatment Protocols Treatment-related toxicity Tumor Angiogenesis Tumor-Associated Vasculature United States National Institutes of Health Universities Validation Xenograft procedure aggressive breast cancer anticancer activity cancer cell cancer subtypes cancer therapy clinical center cohort commercialization cytokine design drug action drug candidate drug mechanism effective therapy gemcitabine improved innovation invention mouse model novel novel strategies novel therapeutic intervention novel therapeutics orthotopic breast cancer phase 1 study polyoma middle tumor antigen pre-clinical preclinical study rational design recruit response side effect targeted agent targeted treatment therapeutic protein therapy resistant triple-negative invasive breast carcinoma tumor tumorigenic

项目摘要

Summary Triple negative breast cancers (TNBC) are devastating diseases with a median survival of less than 1-year for patients with metastatic disease. TNBC patients with tumor of high fibrotic stroma have even worse prognosis. There are no specific targeted therapies available for TNBC, and the only treatment option is broadly cytotoxic chemotherapy drugs, despite less effective and strong unwanted side effects of such drugs. One major barrier to efficacy of anti-tumor therapeutics is the dense fibrotic stromal and dysregulated tumor blood vessels which contribute to failure of therapies. Evidence suggests that cancer associated fibroblasts (CAF) produce the stromal collagen. The ECM laid down by CAF is considered to be one of the major contributors of resistance to established therapies of the diseases. TNBC has high angiogenic activity. Dense tumor vasculature associated with a shorter time from diagnosis to relapse and from relapse to death. The dysregulated vessel structure in TNBC tumor often leads to resistance to blood flow into tumor, which is another important barrier for drug delivery. Depleting CAF and abrogating tumor angiogenesis could significantly improve efficacy of existing TNBC cancer treatments. However, currently, there are no approved therapies that are able to deplete CAF and tumor angiogenesis in TNBC cancer. We have developed a novel therapeutic protein (ProAgio) using rational protein design. ProAgio is designed to target integrin v3 at a novel site (not the ligand binding site). ProAgio specifically induces apoptosis of integrin v3 expressing cells with high efficacy by a novel mechanism of drug action (recruiting & activating caspase 8 at cytoplasmic domain of). We reasoned that, since both CAF and angiogenic endothelial cells (aEC) express high levels of integrin v3, and since ProAgio is very effective in inducing apoptosis of integrin v3 expressing cells, ProAgio should both deplete CAF, eliminate intratumoral angiogenic blood vessels in and around TNBC tumors. This unique strategy may prove advantageous in treatment of TNBC. The main objective of this direct phase II SBIR application is to generate a definitive dataset to enable the development of ProAgio as a viable therapeutic option for TNBC patients. Characterization of the toxicity and tolerability and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of ProAgio as a single agent is on-going. Aim 1 will characterize the toxicity and tolerability and determine the recommended phase II dose (RP2D) of ProAgio in combination with gemcitabine (Gem). Aim 2 will obtain preliminary anti-cancer activity data of ProAgio and ProAgio + Gem in TNBC patients. Aim 3 will analyze the effects of ProAgio in patient tumor to validate the mechanism of drug action in patients. This clinical study project will explore new therapeutic avenue for TNBC patients. Our goal is that, through our study, we will introduce a new treatment approach for TNBC with novel mechanism of drug action.

概括三阴性乳腺癌 (TNBC) 是一种毁灭性的疾病，中位生存期低于对于患有高纤维化基质肿瘤的转移性疾病患者，治疗时间超过 1 年。 TNBC 的预后更差，目前还没有特定的靶向治疗方法。唯一的治疗选择是具有广泛细胞毒性的化疗药物，尽管其效果和强度较差此类药物的不良副作用是抗肿瘤治疗效果的一个主要障碍。致密的纤维化基质和失调的肿瘤血管导致失败有证据表明癌症相关成纤维细胞（CAF）产生基质。 CAF 形成的 ECM 被认为是胶原蛋白的主要贡献者之一。 TNBC 具有高血管生成活性。肿瘤血管系统与从诊断到复发以及从复发到复发的时间较短相关 TNBC 肿瘤中失调的血管结构通常会导致血流阻力。进入肿瘤，这是耗尽 CAF 和消除药物的另一个重要障碍。肿瘤血管生成可以显着提高现有 TNBC 癌症治疗的疗效。然而，目前还没有批准的疗法能够消除 CAF 和肿瘤我们利用 TNBC 癌症的血管生成开发了一种新型治疗蛋白 (ProAgio)。 ProAgio 旨在将整合素 v3 定位于新位点（而非配体）。 ProAgio 特异性诱导整合素 αvβ3 表达细胞凋亡。通过一种新的药物作用机制（在细胞质中招募并激活 caspase 8）发挥功效我们推断，因为 CAF 和血管生成内皮细胞 (aEC) 都表达。高水平的整合素 v3，并且 ProAgio 在诱导整合素凋亡方面非常有效表达 v3 的细胞，ProAgio 应该消耗 CAF，消除肿瘤内血管生成的血液 TNBC 肿瘤内及其周围的血管可能在治疗中具有优势。 TNBC 的第二阶段直接 SBIR 申请的主要目标是生成明确的结果。数据集，使 ProAgio 能够开发为 TNBC 患者的可行治疗选择。毒性和耐受性表征并确定最大耐受剂量 (MTD) ProAgio 作为单一药物的 II 期推荐剂量 (RP2D) 正在进行中，目标 1 正在进行中。表征毒性和耐受性并确定推荐的 II 期剂量 (RP2D) ProAgio与吉西他滨（Gem）联合使用将获得初步的抗癌效果。 ProAgio 和 ProAgio + Gem 在 TNBC 患者中的活动数据将分析 TNBC 患者的效果。 ProAgio 在患者肿瘤中验证药物作用机制这一临床研究。项目将为 TNBC 患者探索新的治疗途径。我们的目标是，通过我们的研究，我们将推出一种新的药物作用机制的 TNBC 治疗方法。