Novel therapy targeting refractory colon cancer

针对难治性结肠癌的新疗法

基本信息

批准号：
9150532
负责人：
Ping-Ying Pan
金额：
$ 45.41万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9150532
关键词：
Adjuvant Therapy Affinity American Cancer Society Angiopoietins Apoptosis Blocking Antibodies Cancer Etiology Cancer Relapse Cell Survival Cell surface Cells Cessation of life Colon Carcinoma Colonic Neoplasms Colorectal Cancer Development Diagnosis Disease Disseminated Malignant Neoplasm Epithelial Epithelial Cells Event Excision Exhibits Goals Health Hepatectomy Hepatic Human Immune Immunoglobulins Laboratories Large Intestine Carcinoma Leukocytes Ligands Ligation Maintenance Malignant Neoplasms Malignant neoplasm of lung Mediating Mesenchymal Metastatic Neoplasm to the Liver Microspheres Modality Molecular Mus Myelogenous Myeloid Cells Nature Neoplasm Metastasis Orthologous Gene Patients Phenotype Play Population Proliferating Proteins Radiation therapy Rectal Cancer Recurrence Refractory Relapse Research Resected Resistance Role Selection Criteria Signal Transduction Signaling Molecule Skin Cancer Staging Stress Suppressor-Effector T-Lymphocytes Survival Rate Targeted Radiotherapy Testing Time Tumor Cell Line Woman base cancer cell cancer diagnosis cancer recurrence cancer survival carcinogenesis chemotherapy colon cancer patients conventional therapy insight lifetime risk macrophage men metastatic colorectal neoplastic cell new therapeutic target novel novel therapeutics operation outcome forecast palliative chemotherapy prevent receptor receptor binding receptor-mediated signaling stemness symptom treatment therapeutic target therapy resistant treatment strategy tumor tumor growth tumor microenvironment tumor progression tumorigenic

项目摘要

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.

描述（由申请人提供）：癌症起始细胞（CIC）表现出独特的标记，并且具有高度致瘤性，几个研究小组已经基于不同的细胞表面标记成功分离出结直肠癌起始细胞（CCIC）。靶向大量快速增殖的结直肠癌细胞尽管大部分肿瘤已被根除，但治疗耐药性 CCIC 仍然存在，并且可以分化为非 CCIC 癌症。随着时间的推移，CCIC 子代的肿瘤重新繁殖，最终会导致比最初接受治疗的恶性肿瘤更具侵袭性的表型，在美国，结直肠癌每年导致 56,500 人死亡，仅次于肺癌。每年诊断出 150,000 至 160,000 例新病例，其中 10% 至 20% 已出现肝转移，约占总数的 70%。结直肠癌患者最终会发生肝转移，肝切除是目前唯一能提供长期生存的治疗方式，5年生存率在25%到39%之间，按照目前肝切除的选择标准，只有10%到39%。 20%的患者适合进行根治性手术，其余患者的预后很严峻，姑息化疗和对症治疗是唯一可用的选择，目前没有可靠的治疗方法来控制癌症复发。我们实验室发现配对免疫球蛋白样受体B（PIRB）及其人类直系同源白细胞Ig样受体B（LILRB）在控制结肠癌起始细胞（CIC）的“干性”和诱导中发挥重要作用。最近，血管生成素样蛋白（Angptls）已被确定为 PIRB/LILRB 的天然高亲和力配体。发现 PIRB 激活通过其高亲和力配体、血管生成素样蛋白 2（Angptl-2，小鼠）和 Angptl-2 和 -5（人类），促进骨髓源性抑制细胞获得 M2（替代）巨噬细胞功能表型，诱导结肠肿瘤细胞的 CIC 表型，并增强转移，我们发现通过 Angptl 连接的 PIRB/LILRB 信号可以诱导结肠癌起始的表型。因此，在目标 1 中，我们将确定 Angptls 对结肠癌增殖和维持的影响。结肠肿瘤细胞系的“干性”，基于 PIRB/LILRB 的表达。在目标 2 中，我们将评估化疗诱导的 Angptl 表达对 CIC 和 EMT 表型的影响。 3，我们将评估单独或与化疗联合阻断 PIRB/LILRB 信号传导对结肠癌起始细胞和骨髓分化的影响。我们的研究将确定控制 CCIC 和 EMT 的 Angptl 受体介导的信号传导的分子决定因素。表型，并为设计难治性结直肠癌的新治疗方式提供新信息。