Development of a protein drug for pancreatic cancer treatment

摘要 胰腺癌是一种毁灭性的疾病，五年生存率低于9%。目前， 对于晚期疾病没有有效的治疗方法。抗肿瘤疗效的一个主要障碍是 治疗方法是致密促纤维增生基质反应。有证据表明癌症 相关的胰腺星状细胞（CaPSC）产生基质胶原。ECM制定了 被认为是对现有疗法产生耐药性的主要原因之一 疾病。消耗CaPSC和改变血管密度可显著提高疗效 胰腺导管腺癌（PDAC）治疗的最佳方法。然而，目前， 没有批准的能够消耗PDAC中CaPSC的疗法。我们已经开发出一种新颖 使用合理的蛋白质设计的治疗性蛋白质（ProAgio）。ProAgio旨在靶向整合素 αvβ3位于新位点（而非配体结合位点）。ProAgio特异性诱导整合素凋亡 αvβ3表达细胞通过一种新的药物作用机制（招募& 在β3的胞质结构域激活半胱天冬酶8）。我们推断，由于CAPSC和 血管生成内皮细胞表达高水平的整合素αvβ3，并且由于ProAgio非常 ProAgio能有效诱导表达整合素αvβ3的细胞凋亡， CaPSC和消除胰腺肿瘤内和周围的新血管。这种独特的策略 可以证明在PDAC的治疗中是有利的。我们的STTR I&II期研究表明， ProAgio通过各种癌症模型可能作为PDAC治疗的功效。研究 支持我们的假设，即ProAgio可以通过同时消耗 产生胶原的CaPSC支持肿瘤结缔组织增生和癌细胞生长， 还消除了新生长的与癌症相关的血管，这些血管为癌细胞提供营养并使之能够 癌症转移我们的STTR I&II期研究数据为未来的研究提供了原理证明。 临床试验我们II期研究的结果导致ProAgio作为一种 胰腺癌治疗药物。本阶段IIB申请的主要目的是产生 一个明确的数据集，使ProAgio能够作为PDAC的可行治疗选择进行开发 患者目的1将描述毒性和耐受性，并确定最大耐受剂量 剂量（MTD）和推荐的II期剂量（RP 2D）的ProAgio作为单药和 与G-10的结合。目的2将表征ProAgio在癌症患者中的PK特性， 获得ProAgio和ProAgio + G-Glucose在PDAC患者中的初步抗癌活性数据。目的 3将分析ProAgio在患者肿瘤中的作用，以验证药物作用机制， 患者本研究将为PDAC患者的治疗探索新的途径。

Abstract Pancreatic cancers are devastating diseases with five year survival rate less than 9%. Currently, there is no effective treatment for advanced disease. One major barrier to efficacy of anti-tumor therapeutics is the dense desmoplastic stromal response. Evidence suggests that cancer associated pancreatic stellate cells (CaPSC) produce the stromal collagen. The ECM laid down by CaPSC is considered to be one of the major contributors of resistance to established therapies of the diseases. Depleting CaPSC and altering vessel density could significantly improve efficacy of existing pancreatic ductal adenocarcinoma (PDAC) treatments. However, currently, there are no approved therapies that are able to deplete CaPSCs in PDAC. We have developed a novel therapeutic protein (ProAgio) using rational protein design. ProAgio is designed to target integrin αvβ3 at a novel site (not the ligand binding site). ProAgio specifically induces apoptosis of integrin αvβ3 expressing cells with high efficacy by a novel mechanism of drug action (recruiting & activating caspase 8 at cytoplasmic domain of β3). We reasoned that, since both CaPSC and angiogenic endothelial cells express high levels of integrin αvβ3, and since ProAgio is very effective in inducing apoptosis of integrin αvβ3 expressing cells, ProAgio should both deplete CaPSC and eliminate new blood vessels in and around pancreatic tumors. This unique strategy may prove advantageous in treatment of PDAC. Our STTR phase I&II studies demonstrated efficacy of ProAgio potentially as a PDAC treatment via various cancer models. The studies support our hypothesis that ProAgio can provide treatment benefit by simultaneously depleting the collagen-producing CaPSCs that support tumor desmoplasia and cancer cell growth, while also eliminating newly grown cancer associated blood vessels that feed cancer cells and enable cancer metastasis. Data from our STTR phase I&II studies provides proof of principle for future clinical tests. Results from our phase II studies have led to IND application of ProAgio as a pancreatic cancer treatment drug. The main objective of this phase IIB application is to generate a definitive dataset to enable the development of ProAgio as a viable therapeutic option for PDAC patients. Aim 1 will characterize the toxicity and tolerability and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of ProAgio as a single agent and in combination with G-nP. Aim 2 will characterize PK property of ProAgio in cancer patients and to obtain preliminary anti-cancer activity data of ProAgio and ProAgio + G-nP in PDAC patients. Aim 3 will analyze the effects of ProAgio in patient tumor to validate the mechanism of drug action in patients. This study will explore new therapeutic avenue for PDAC patients.