A treatment drug for triple negative breast cancer

摘要 三重阴性乳腺癌(TNBC)是一种破坏性疾病，中位生存期较低 对于有转移性疾病的患者来说，超过1年。高纤维化间质肿瘤的TNBC患者 预后更差。目前还没有针对TNBC的特定靶向疗法，而且 唯一的治疗选择是广泛的细胞毒性化疗药物，尽管效果较差且强度较大 此类药物的不良副作用。抗肿瘤治疗效果的一个主要障碍是 致密的纤维化间质和调节失调的肿瘤血管导致手术失败 治疗。有证据表明，癌症相关成纤维细胞(Caf)产生间质。 胶原蛋白。CAF制定的ECM被认为是 对已有的疾病治疗方法的抵抗力。TNBC具有较高的血管生成活性。稠密 肿瘤血管系统与从诊断到复发和从复发到 死亡。TNBC肿瘤血管结构紊乱常导致血流阻力 进入肿瘤，这是另一个重要的药物输送障碍。耗尽咖啡厅和废止咖啡厅 肿瘤血管生成可显著提高现有TNBC肿瘤治疗方法的疗效。 然而，目前还没有被批准的治疗方法能够耗尽CAF和肿瘤。 TNBC癌中的血管生成。我们已经开发出一种新的治疗性蛋白质(ProAgio)，它使用 合理的蛋白质设计。ProAgio的设计目的是将整合素v3定位于一个新的位点(而不是配体 结合位点)。ProAgio特异性诱导高表达整合素v-3细胞的凋亡 一种新的药物作用机制(在细胞质上招募和激活caspase 8)的疗效 的域名)。我们推测，由于CAF和血管生成内皮细胞(AEC)都表达 高水平的整合素与3，由于ProAgio在诱导整合素凋亡方面非常有效 v3表达细胞，ProAgio既能清除CAF，又能清除肿瘤内血管生成的血液 TNBC肿瘤内及周围的血管。这种独特的策略在治疗中可能会被证明是有利的。 是TNBC的。此直接第二阶段SBIR应用程序的主要目标是生成最终的 数据集，使ProAgio能够开发为TNBC患者的可行治疗选择。 毒性和耐受性表征及最大耐受量(MTD)的确定 ProAgio作为单一药物的推荐II期剂量(RP2D)正在进行中。目标1将 确定毒性和耐受性，并确定推荐的II期剂量(RP2D) ProAgio联合吉西他滨(Gem)。AIM 2将获得初步抗癌药物 TNBC患者ProAgio及ProAgio+Gem活性测定目标3将分析以下方面的影响 ProAgio在患者肿瘤中的应用，验证药物在患者体内的作用机制。这项临床研究 该项目将为TNBC患者探索新的治疗途径。我们的目标是通过我们的研究， 我们将介绍一种具有新的药物作用机制的治疗TNBC的新方法。

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.