Novel therapy targeting refractory colon cancer

 描述(申请人提供)：癌症起始细胞(CIC)表现出不同的标记，并具有高度的致瘤性。几个研究小组已经成功地基于不同的细胞表面标记分离出结直肠癌起始细胞(CCICs)。包括化疗和放射治疗在内的传统疗法针对的是大量快速增殖的结直肠癌细胞。尽管很大比例的肿瘤块被根除，但耐药的CCIC仍然存在，并可以分化为非CCIC癌细胞。随着时间的推移，CCICs的后代重新繁殖肿瘤，最终导致比最初治疗的恶性肿瘤更具侵袭性的表型。在美国，每年有56,500人死于结直肠癌，仅次于肺癌。每年确诊的新病例有15万到16万例，其中10%到20%已经有肝转移。大约70%的结直肠癌患者最终发展为肝转移。肝切除是目前唯一能提供长期存活率的治疗方式，5年存活率从25%到39%不等。按照目前肝切除的选择标准，只有10%到20%的患者适合进行根治性手术。其余患者的预后是严峻的，姑息化疗和对症治疗是唯一可用的选择。目前还没有可靠的治疗方法来控制化疗后的癌症复发。我们的实验室发现，成对的免疫球蛋白样受体B(PirB)及其人类同源白细胞Ig样受体B(LILRB)在控制结肠癌起始细胞(CIC)的“干性”和诱导上皮-间充质转化(EMT)方面发挥着重要作用。近年来，血管生成素样蛋白(Angptls)被认为是PirB/LILRBs的天然高亲和力配体。我们发现，PirB通过其高亲和力配体--血管生成素样蛋白2(Angpt1-2，小鼠)和Angpt1-2和-5(人)，促进髓系来源的抑制细胞获得M2(替代)巨噬细胞功能表型，诱导结肠肿瘤细胞的CIC表型，并促进转移。我们推测PirB/LILRB信号通过结扎Angpt1可以诱导结肠癌起始细胞和EMT的表型，从而促进化疗耐药的发生。因此，阻断PirB/LILRB信号通路可防止结肠癌化疗后复发。提出了三个具体目标。在目标1中，我们将基于PirB/LILRB的表达来确定Angptls对结肠癌细胞系增殖和维持“干性”的影响。在目标2中，我们将评估化疗诱导的Angpt1表达对CIC和EMT表型的影响。在目标3中，我们将评估单独或联合化疗阻断PirB/LILRB信号对结肠癌起始细胞和髓系分化的影响。我们的研究将确定Angptl受体介导的信号转导在CCIC和EMT表型控制中的分子决定因素，并为设计新的难治性结直肠癌治疗方案提供新的信息。

 DESCRIPTION (provided by applicant): Cancer initiating cells (CICs) exhibit distinct markers and are highly tumorigenic. Several research groups have successfully isolated colorectal cancer initiating cells (CCICs) based on distinct cell-surface markers. Conventional therapies, including chemotherapies and radiotherapies, target the bulk population of rapidly proliferating colorectal cancer cells. Although a large proportion of tumor mass is eradicated, therapy-resistant CCICs remain and can differentiate into non-CCIC cancer cells. Repopulation of the tumor over time by the progenies of CCICs ultimately results in a more aggressive phenotype than the initial pretreated malignancy. With 56,500 fatalities per year, colorectal cancer is second only to lung cancer as a cause of cancer deaths in the USA. Each year, 150,000 to 160,000 new cases are diagnosed of which 10 to 20% already have liver metastases. About 70% of all colorectal cancer patients eventually develop liver metastases. Hepatic resection is currently the only form of treatment that offers long-term survival, with 5-year survival rates ranging from 25% to 39%. Using the current selection criteria for hepatectomy, only 10% to 20% of all patients are candidates for curative operation. The prognosis for the remaining patients is grim with palliative chemotherapy and symptomatic treatments being the only available options. There are no reliable treatment modalities for controlling cancer recurrence after chemotherapy. Our laboratory has found that paired immunoglobulin-like receptor B (PIRB) and its human ortholog leukocyte Ig-like receptor B (LILRB) play an important role in controlling the "stemness" of colon cancer initiating cells (CIC) and induction of epithelial-mesenchymal transition (EMT). Recently, Angiopoietin-like proteins (Angptls) have been identified as a nature high affinity ligand for PIRB/LILRBs. We found that PIRB activation, through its high affinity ligands, angiopoietin like protein 2 (Angptl-2, mouse) and Angptl-2 and -5 (human), promoted acquisition of an M2 (alternative) macrophage functional phenotype by myeloid-derived suppressor cell, induced CIC phenotypes of colon tumor cells, and enhanced metastases. We hypothesize that PIRB/LILRB signaling through ligation of Angptl can induce the phenotype of colon cancer initiating cell and EMT, thereby facilitating the development of chemotherapy resistance. Thus, blockade of PIRB/LILRB signaling may prevent colon cancer relapse after chemotherapy. Three specific aims are proposed. In Aim 1, we will determine the effect of Angptls on proliferation and maintenance of "stemness" of colon tumor cell lines, based on the expression of PIRB/LILRB. In Aim 2, we will assess the effect of Angptl expression induced by chemotherapy on CIC and EMT phenotypes. In Aim 3, we will evaluate the effect of blocking PIRB/LILRB signaling, alone or in conjunction with chemothrapy therapy, on colon cancer initiating cells and myeloid differentiation. Our study will identify the molecular determinants of Angptl receptor-mediated signaling in control of CCIC and EMT phenotypes, and provide new information for devising a novel therapeutic modality for refractory colorectal cancer.