Application of Mucolytic Therapy in Patient-Derived Models of Pseudomyxoma Peritonei

摘要 腹膜假性粘液瘤(PMP)是一种潜在的但致命的恶性肿瘤，指的是腹膜转移。 粘液性阑尾肿瘤(人)。PMP对全身化疗的反应很差，而且经常 尽管进行了积极和病态的局部手术治疗，但还是复发了。对于低级PMP(LG-PMP)，几乎所有 有害的临床后果与过量生产造成的压迫器官功能障碍有关。 腹内少细胞粘液堆积(主要由粘蛋白2[MUC2]蛋白组成)。 相反，高级别PMP(HG-PMP)更具细胞性和侵袭性，细胞外粘液丰富 为癌细胞的繁衍提供了保护性环境。我们假设减少细胞外粘液 积聚将通过减少PMP的粘液肿瘤负担而将受压器官功能障碍降至最低 (尤其是LG-PMP)，并通过去除保护性药物来提高化疗或靶向药物的疗效 肿瘤细胞(尤其是HG-PMP)周围的粘液屏障。在这项提案中，我们将测试 菠萝酶(BR)+N-乙酰半胱氨酸(NAC)联合粘液溶解细胞外粘液 在临床相关的体外和体内患者衍生的LG-和HG-MAN/PMP模型中。成功的结果 将克服治疗PMP的一个主要障碍，即质量效应和 细胞保护--丰富的胞外粘液的作用。此外，我们提出的研究还提供了一种新颖的 PMP的治疗维度可能适用于粘液性结直肠癌、胰腺癌和卵巢癌。我们的 建议是可行的，因为我们是管理PMP患者的主要转介中心，建议 药物组合有效地溶解了硅胶中的粘液，我们已经开发出了体外和体内患者衍生的 代表临床疾病的MAN/PMP模型。

Abstract Pseudomyxoma peritonei (PMP), an insidious but lethal malignancy, refers to peritoneal metastases from mucinous appendix neoplasms (MAN). PMP is poorly responsive to systemic chemotherapy and frequently recurs despite aggressive and morbid locoregional surgical therapy. For low-grade PMP (LG-PMP), nearly all of the deleterious clinical consequences are related to compressive organ dysfunction from excessive production and intra-abdominal accumulation of paucicellular mucus (predominantly composed of mucin 2 [MUC2] protein). Conversely, high-grade PMP (HG-PMP) is more cellular and invasive, and the abundant extracellular mucus provides a protective environment for cancer cells to thrive. We hypothesize that reducing extracellular mucus accumulation will minimize compressive organ dysfunction by decreasing the mucinous tumor burden of PMP (especially LG-PMP) and improve the efficacy of chemotherapeutic or targeted drugs by removing the protective mucus barrier surrounding neoplastic cells (especially HG-PMP). In this proposal, we will test the efficacy of combinatorial mucolytic therapy, using bromelain (BR) + N-acetylcysteine (NAC), to dissolve extracellular mucus in clinically relevant in vitro and in vivo patient-derived models of LG- and HG-MAN/PMP. Successful outcome of the proposed studies will overcome a major hurdle for treating PMP, which is the mass-effect and cytoprotective-effect of abundant extracellular mucus. In addition, our proposed research provides a novel treatment dimension for PMP that may be applied to mucinous colorectal, pancreatic and ovarian cancers. Our proposal is feasible since we are a major referral center for the management of patients with PMP, the proposed drug combination effectively dissolves mucus in-silico, and we have developed in vitro and in vivo patient-derived models of MAN/PMP that are representative of the clinical disease.