A treatment drug for triple negative breast cancer

总结 三阴性乳腺癌（TNBC）是一种毁灭性的疾病， 对于转移性疾病患者，1年以上。伴有高度纤维化间质肿瘤的TNBC患者 预后更差。没有可用于TNBC的特异性靶向疗法， 唯一的治疗选择是广泛的细胞毒性化疗药物，尽管效果不太好， 这些药物的副作用。抗肿瘤治疗有效性的一个主要障碍是 致密的纤维化间质和失调的肿瘤血管，这有助于失败的 治疗有证据表明，癌相关成纤维细胞（CAF）产生基质细胞。 胶原CAF制定的ECM被认为是 对已建立的疾病疗法的抗性。TNBC具有高血管生成活性。密集 肿瘤血管与从诊断到复发和从复发到复发的时间较短相关。 死亡TNBC肿瘤中的血管结构失调通常导致血流阻力 进入肿瘤，这是药物递送的另一个重要屏障。消耗CAF和废除 肿瘤血管生成可以显著提高现有TNBC癌症治疗的功效。 然而，目前，没有批准的疗法能够消耗CAF和肿瘤。 TNBC癌症中的血管生成。我们已经开发了一种新的治疗蛋白（ProAgio）， 合理的蛋白质设计ProAgio被设计为在新位点（而不是配体）靶向整合素β 3。 结合位点）。ProAgio特异性地诱导整合素p53表达细胞的凋亡， 通过新的药物作用机制（在细胞质中募集和激活caspase 8） 域）。我们推断，由于CAF和血管生成内皮细胞（aEC）表达 更高水平的整合素Adv β 3，并且由于ProAgio在诱导整合素Adv β 3的细胞凋亡方面非常有效， ProAgio既能消耗CAF，又能消除肿瘤内血管生成血液， TNBC肿瘤内和周围的血管。这种独特的策略可能在治疗中被证明是有利的 关于TNBC这一直接的第二阶段SBIR应用的主要目标是产生一个明确的 数据集，以使ProAgio的发展成为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作为单药的II期推荐剂量（RP2D）正在进行中。目标1将 描述毒性和耐受性，并确定推荐的II期剂量（RP2D） ProAgio与吉西他滨（Gem）联合使用。目标2将获得初步的抗癌 ProAgio和ProAgio + Gem在TNBC患者中的活性数据。目标3将分析 ProAgio在患者肿瘤中的作用，以验证药物在患者中的作用机制。本临床研究 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TNBC新治疗方法。

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.