Development of a protein drug for pancreatic cancer treatment

摘要 胰腺癌是一种毁灭性的疾病，五年生存率不到7%。目前， 对晚期疾病没有有效的治疗方法。抗肿瘤药效的一大障碍 治疗是致密的促结缔组织间质反应。有证据表明，癌症 相关的胰腺星状细胞(CAPaSC)产生间质胶原。ECM制定了 被CAPaSC认为是抵抗建立的主要因素之一 疾病的治疗方法。耗尽CAPaSC和改变血管密度可能会显著 提高现有胰腺导管腺癌(PDAC)治疗的疗效。然而， 目前，还没有被批准的治疗方法能够耗尽PDAC中的CAPaSCs。我们有 利用合理的蛋白质设计开发了一种新型的治疗性蛋白质(ProAgio)。ProAgio是 目的是将整合素v3定位于一个新的位点(而不是配体结合部位)。特别是ProAgio 高效诱导整合素v3表达细胞凋亡的一种新机制 药物作用(在胞浆区域募集和激活caspase8)。我们推断， 由于CAPASC和血管生成内皮细胞均表达高水平的整合素v3，并且 由于ProAgio对整合素v3表达细胞的凋亡诱导非常有效， 应该既消耗CAPaSC，又消除胰腺肿瘤内和周围的新血管。 这一独特的治疗策略可能在治疗PDAC方面具有优势。我们的STTRI期研究 通过各种癌症模型证明了ProAgio作为一种PDAC治疗的潜在疗效。 这些研究支持了我们的假设，即ProAgio可以同时通过 耗尽支持肿瘤结缔组织和癌细胞的胶原生成的CAPaSCs 生长，同时也消除了为癌细胞提供营养的新生长的癌症相关血管 并使癌症转移。我们STTRI阶段研究的数据提供了以下原则证据 未来的临床试验。为了促进未来在PDAC患者中应用ProAgio的临床研究，我们建议 目的：(1)分析ProAgio的临床前毒理学(TOX)和药代动力学(PK)。 老鼠和猴子。毒素/PK研究将使IND应用于美国食品和药物 管理局(FDA)。(目标2)确定ProAgio是否可以 协同作用 加强治疗 免疫检查点阻断的有效性和交付。这项研究将探索新的治疗方法 为PDAC患者准备的大道。

Abstract Pancreatic cancers are devastating diseases with five year survival rate less than 7%. 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 (CAPaSC) produce the stromal collagen. The ECM laid down by CAPaSC is considered to be one of the major contributors of resistance to established therapies of the diseases. Depleting CAPaSC 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 CAPaSCs in PDAC. 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 CAPaSC and angiogenic endothelial cells 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 CAPaSC and eliminate new blood vessels in and around pancreatic tumors. This unique strategy may prove advantageous in treatment of PDAC. Our STTR phase I 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 CAPaSCs 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 studies provides proof of principle for future clinical tests. To facilitate future clinical studies of ProAgio in PDAC patients, we propose to: (Aim 1) analyze the pre-clinical toxicology (TOX) and pharmacokinetics (PK) of ProAgio with rats and monkey. TOX/PK studies will enable IND application with US Food and Drug Administration (FDA). (Aim 2) Determine whether ProAgio can synergistically enhance treatment efficacy and delivery of immune checkpoint blockades. This study will explore new therapeutic avenue for PDAC patients.