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（由适用提供）：癌症发射细胞（CICS）暴露了不同的标记，并且具有高度肿瘤性。几个研究组已成功地基于不同的细胞表面标记，成功地分离了结直肠癌发射细胞（CCIC）。常规疗法，包括化学疗法和放射性疗法，针对快速增殖的结直肠癌细胞的大量种群。尽管很大一部分肿瘤肿块是放射性的，但抗治疗的CCIC仍保留并可以分化为非CCIC癌细胞。随着时间的流逝，CCIC的后代对肿瘤的重生最终导致比最初预处理的恶性肿瘤更具侵略性的表型。每年有56,500人死亡，有色癌症仅次于肺癌，这是美国癌症死亡的原因。每年，诊断出150,000至160,000例新病例，其中10％至20％的病例已经患有肝转移。大约70％的结直肠癌患者最终发展出肝转移。目前，肝切除术是唯一提供长期生存的治疗形式，5年生存率从25％到39％不等。使用目前的肝切开术标准，只有10％至20％的患者是现代手术的候选者。其余患者的预后对姑息化疗和症状治疗是唯一可用的选择。化学疗法后没有可靠的治疗方式可以控制癌症复发。我们的实验室发现，配对的免疫球蛋白样受体B（PIRB）及其人类直系同源性白细胞Ig样受体B（LILRB）在控制结肠癌引发细胞的“干性”（CIC）（CIC）和上皮 - 腔呼吸过渡（EMT）方面起着重要作用。最近，血管生成素样蛋白（ANGPTL）已被确定为PIRB/LILRB的自然高亲和力配体。我们发现，PIRB通过其高亲和力配体，像蛋白质2（Angptl-2，小鼠）和Angptl-2和-5（人）这样的血管生成素，促进了通过髓样源抑制细胞的M2（替代）巨噬细胞功能表型的获取，诱导的CIC抑制细胞，诱导的CIC均具有结肠tamor的细胞和增强的CIC现象。我们假设PIRB/LILRB信号通过ANGPTL连接可以诱导结肠癌的表型启动细胞和EMT，从而支持化学疗法耐药性的发展。因此，封锁PIRB/LILRB信号传导可能会防止化疗后结肠癌的缓解。提出了三个具体目标。在AIM 1中，我们将根据PIRB/LILRB的表达来确定Angptls对结肠肿瘤细胞系的增殖和维持的影响。在AIM 2中，我们将评估化学疗法诱导的ANGPTL表达对CIC和EMT表型的影响。在AIM 3中，我们将评估单独或与化学疗法疗法结合使用PIRB/LILRB信号传导对结肠癌启动细胞和髓样分化的影响。我们的研究将确定控制CCIC和EMT表型中ANGPTL受体介导的信号传导的分子决定剂，并为设计新型的热模态提供了新的信息，以使其对难治性结直肠癌。