Identification and targeting of colon cancer initiating cells

 描述(由申请人提供)： 结直肠癌是美国癌症相关死亡的主要原因，也是美国退伍军人发病率和死亡率的主要原因。虽然早期结直肠癌可以通过手术切除高度治愈，但转移性疾病患者的预后仍然很严重。前景看好的结直肠癌靶向治疗，包括血管内皮生长因子抑制剂和抗表皮生长因子受体的单抗，已显著提高了转移性疾病患者的总存活率；然而，现有靶向治疗的临床反应相对短暂或个体受限的性质突显了进一步开发新的治疗策略的紧迫性，这些新的治疗策略可能与癌症干细胞同时针对耐药癌细胞群体。多项研究表明，肿瘤干细胞在人类结直肠癌中的存在及其在结直肠癌转移进展和治疗耐药中的作用。因此，肿瘤干细胞的特异性靶向可以提供一种新的策略来根除目前对系统治疗耐药的癌症。ABCB5是一种新的人类多药耐药介体，最近由申请人在该提案的第一个资助期展示，将在耐药结直肠癌干细胞中表达，并与临床癌症进展相关(Wilson等人)。癌症研究报告，2011)。此外，这项里程碑式的研究是关于ABCB5在结直肠癌中的关键作用的第一项研究，最近得到该领域其他研究人员的独立证实(Kugimiya等人。J细胞Mol Med.2015)，证明ABCB5阻断可以抑制肿瘤的生长和侵袭，并使结直肠癌对5-FU诱导的细胞杀伤增敏。在最初项目资助期的其他开创性结果中，申请人最近确定了ABCB5通过涉及p53稳定的新的抗凋亡功能在正常干细胞维持中的关键作用(Ksander等人)。自然2014)，现在在进一步的初步结果中也建立了这一关键的ABCB5功能在结直肠癌干细胞。基于这些发现，我们假设，针对表达ABCB5的结直肠癌干细胞的特异性靶向有可能导致目前对传统疗法耐药的播散性疾病的根除。因此，我们在这个项目中建议：(I)在ABCB5功能被基因去除的新疾病模型中，剖析ABCB5在结直肠癌干细胞维持、结直肠癌干细胞依赖的肿瘤起始和转移进展以及结直肠癌干细胞治疗耐药中的分子作用；(Ii)利用新的ABCB5报告小鼠遗传和炎症驱动的肠道肿瘤发生模型，建立结直肠癌干细胞对已批准的或新出现的结直肠癌治疗方法的反应；以及(Iii)在人-鼠异种移植模型中以翻译相关的方式以靶向ABCB5阳性的结直肠癌干细胞，或使用新产生的完全人类高亲和力抗ABCB5单抗的新组合策略(Ksander等人。《自然》2014)。这些研究将进一步确定ABCB5在结直肠癌中的临床相关性和治疗重要性，并将为在人类患者中成功靶向ABCB5阳性的结直肠癌干细胞以改进临床治疗铺平道路。

 DESCRIPTION (provided by applicant): Colorectal cancer is a leading cause of cancer-related deaths in the United States and is a major cause of morbidity and mortality among the US Veterans. While early stages of colorectal cancer are highly curable by surgical resection, the prognosis of patients with metastatic disease remains grave. Promising targeted colorectal cancer treatments, including inhibitors of vascular endothelial growth factor and monoclonal antibodies against epidermal growth factor receptor have resulted in significant improvement of overall survival in patients with metastatic disease; however, the relatively transient or individually restricted nature of clinical responses o currently available targeted therapies underlines the urgency for further development of novel therapeutic strategies that specifically target therapy-resistant cancer cell populations, which may coincide with cancer stem cells. Multiple studies have demonstrated the existence of cancer stem cells in human colorectal cancer and their contribution to colorectal cancer metastatic progression and therapeutic resistance. Thus, specific targeting of cancer stem cells could provide for a novel strategy to eradicate cancers currently resistant to systemic therapy. ABCB5 is a novel human multidrug resistance mediator recently shown by the applicant in the first funding period of this proposal to be expressed in therapy-resistant colorectal cancer stem cells and to correlate with clinical cancer progression (Wilson et al. Cancer Res. 2011). Moreover, this landmark study, the first on the critical role of ABCB5 in colorectal cancer and recently independently confirmed by other investigators in the field (Kugimiya et al. J Cell Mol Med. 2015), demonstrated that ABCB5 blockade leads to inhibition of tumor growth and invasion, and sensitizes colorectal cancer to 5-FU-induced cell killing. In additional ground- breaking results during the initial project funding period, the applicant recently identified a criical role of ABCB5 in normal stem cell maintenance through a novel anti-apoptotic function involving p53 stabilization (Ksander et al. Nature 2014) and has now in further preliminary results also established this critical ABCB5 function in colorectal cancer stem cells. Based on these findings we hypothesize that specific targeting of ABCB5-expressing colorectal cancer stem cells has the potential to result in eradication of disseminated disease currently resistant to conventional therapies. We therefore propose in this project to (i) Dissect ABCB5 molecular roles in colorectal cancer stem cell maintenance, colorectal cancer stem cell-dependent tumor initiation and metastatic progression, and colorectal cancer stem cell therapeutic resistance in novel disease models in which ABCB5 function is genetically ablated; (ii) Establish colorectal cancer stem cell therapeutic responses to approved or novel emerging colorectal cancer treatment modalities, utilizing novel ABCB5 reporter mouse models of genetic and inflammation-driven intestinal tumorigenesis; and (iii) Target ABCB5-positive colorectal cancer stem cells in a translationally relevant manner in human-to-mouse xenotransplantation models singly or in novel combination strategies using newly generated fully human high-affinity anti-ABCB5 monoclonal antibodies (Ksander et al. Nature 2014). The proposed studies will further establish the clinical relevance and therapeutic importance of ABCB5 in colorectal cancer and should pave the way to successful targeting of ABCB5_positive colorectal cancer stem cells in human patients for improved clinical therapy.