A treatment drug for triple negative breast cancer

一种治疗三阴性乳腺癌的药物

• 批准号: 10483825
• 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
• 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/10483825
• 关键词: Aftercare; Animal Model; Apoptosis; 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; Institutional Review Boards; Integrins; 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; Relapse; Research; Research Project Grants; Resistance; Role; Safety; Sampling; Savings; 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; cytokine; design; drug action; drug candidate; drug mechanism; effective therapy; gemcitabine; improved; innovation; invention; mouse model; novel; novel strategies; novel therapeutics; orthotopic breast cancer; phase 1 study; pre-clinical; preclinical study; rational design; recruit; response; side effect; targeted agent; targeted treatment; therapeutic protein; triple-negative invasive breast carcinoma; tumor; tumorigenic

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 三重阴性乳腺癌（TNBC）是毁灭性疾病，中位存活率较少 转移性疾病患者比1年。 TNBC患有高纤维化基质肿瘤的患者 预后更糟糕。 TNBC没有特定的靶向疗法， 唯一的治疗选择是广泛的细胞毒性化学疗法药物，绝望地效果较差和强大 此类药物的不良副作用。抗肿瘤疗法有效性的一个主要障碍是 致密的纤维化基质和失调的肿瘤血管，导致失败 疗法。有证据表明癌症相关的成纤维细胞（CAF）产生了基质 胶原。 CAF裁定的ECM被认为是 对疾病既定疗法的抗药性。 TNBC具有较高的血管生成活性。稠密 肿瘤脉管系统与从诊断到缓解的时间较短以及从浮雕到较短的时间有关 死亡。 TNBC肿瘤中的血管结构失调通常会导致对血流的抗性 进入肿瘤，这是药物输送的另一个重要障碍。耗尽咖啡馆和废除 肿瘤血管生成可以显着提高现有TNBC癌症治疗的效率。 但是，目前尚无能力复制CAF和肿瘤的批准疗法 TNBC癌的血管生成。我们已经开发了一种新型的热蛋白（proagio） 理性蛋白质设计。 Proagio旨在靶向整合素v3在新型位置（不是配体） 绑定位点）。 proagio特异性诱导整联蛋白v3表达较高的细胞的凋亡 通过新颖的药物作用机理（募集和激活caspase 8）的功效 ）。我们认为，由于CAF和血管生成内皮细胞（AEC）表达 高水平的整联蛋白V3，并且由于proagio在诱导整合素的凋亡中非常有效 v3表达细胞，proagio既应属于CAF TNBC肿瘤中及其周围的血管。这种独特的策略可能在治疗方面有利 TNBC。该直接II阶段SBIR应用的主要目的是生成确定的 数据集使Proagio成为TNBC患者的可行治疗选择。 毒性和耐受性的表征，并确定最大耐受剂量（MTD） 并推荐了Proagio作为单个代理的II期剂量（RP2D）正在进行中。目标1意志 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）结合使用。 AIM 2将获得初步的反癌 TNBC患者中Proagio和Proagio + GEM的活性数据。 AIM 3将分析 患者肿瘤中的Proagio验证患者药物作用机制。这项临床研究 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 我们将通过新颖的药物作用机理引入针对TNBC的新治疗方法。