Imaging and targeting metastatic disease

成像和靶向转移性疾病

• 批准号: 8532859
• 负责人: Sridhar Nimmagadda
• 金额: $ 31.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532859
• 关键词: AMD3100; Affinity; Binding; Biological Assay; Bone Marrow; Breast Cancer Cell; Breast Cancer Model; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cancer Patient; Cell Survival; Cells; Characteristics; Clinical; Detection; Development; Disease; Distant; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Kinetics; ERBB2 gene; Encapsulated; Estrogen receptor negative; Excision; Goals; Growth; Image; Immunoblotting; Immunocompetent; In Vitro; Incidence; Kinetics; Label; Lead; Lesion; Ligands; Liposomes; Liver; Luciferases; Lung; Malignant Neoplasms; Messenger RNA; Metabolism; Metastatic Lesion; Modeling; Molecular; Molecular Weight; Monitor; Morbidity - disease rate; Mus; Myelogenous; Neoplasm Metastasis; Optics; Outcome; Patients; Performance; Phenotype; Population; Positron; Positron-Emission Tomography; Predictive Value; Primary Neoplasm; Progesterone Receptors; Radioisotopes; Radiolabeled; Recording of previous events; Recurrence; Refractory Disease; Reporter; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensitivity and Specificity; Signal Transduction; Site; Staining method; Stains; Stem cells; Stromal Cell-Derived Factor 1; Stromal Cells; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic Studies; Toxic effect; Translations; Xenograft Model; analog; angiogenesis; base; bone; breast cancer diagnosis; cancer cell; chemokine receptor; clinically relevant; dosimetry; experience; fluorodeoxyglucose positron emission tomography; imaging probe; improved; in vivo; inhibitor/antagonist; insight; lymph nodes; malignant breast neoplasm; migration; molecular phenotype; mortality; multimodality; outcome forecast; overexpression; radiotracer; scaffold; single photon emission computed tomography; triple-negative invasive breast carcinoma; tumor; tumor growth

DESCRIPTION (provided by applicant): Metastasis is the major cause of morbidity and mortality in cancer. Approximately 30-40% of all diagnosed breast cancers eventually develop lesions in lymph nodes, lung, liver and bone. The stromal-derived factor SDF-1 (or CXCL12) is secreted by stroma in potential metastatic sites and attracts circulating chemokine receptor 4 (CXCR4) expressing cells. CXCR4 is often overexpressed in breast cancer cells and CXCR4- CXCL12 signaling is central not only for the migration of cancer cells but also for the survival and growth of micrometastatic and primary tumors. Inhibitors targeting CXCR4 reduce the incidence of metastasis. Of the known molecular phenotypes, triple negative (TN) [estrogen receptor (ER), progestin receptor (PR) and HER-2 negative] breast cancer patients have the worst prognosis, with most patients likely to experience distant recurrence and refractory disease. Nearly 75% of TN breast cancers have high levels of activated CXCR4 and this overexpression in TN breast cancers results in poor clinical outcome. Because of its critical role in cancer cell survival, invasion, recruitment of myeloid bone marrow-derived cells and angiogenesis, noninvasive imaging of CXCR4 receptor in TN breast cancer is important to evaluate elevated CXCR4 expression in primary and metastatic tumors. CXCR4 based imaging probes can be used i) to evaluate primary tumors for elevated CXCR4 expression and therapeutic intervention; ii) to screen for secondary metastatic spread to both local and distant sites; and, iii) for therapeutic monitoring. We previously developed and evaluated the positron emission tomography (PET) imaging agent [64Cu]AMD3100 in orthotopic and experimental lung metastatic models of breast cancer to detect CXCR4 expression. More recently, we developed the positron-emitting monocyclam analog [64Cu]AMD3465, which has nearly 16-fold higher binding affinity to CXCR4 when compared to [64Cu]AMD3100, and has provided the clearest images with very high target selectivity. Our purpose here is to develop an 18F-labeled AMD3465 analog for rapid clinical translational imaging of breast cancer. Also, TN breast cancers particularly lack the benefit of targeted therapy and show higher recurrence rates and shorter survival than other phenotypes. Targeting and selective depletion of lethal CXCR4 positive cancer cell populations within the tumors and metastases would likely to result in reduced metastatic burden. Because CXCR4 is highly expressed in TN breast cancers, we will develop therapeutic agents decorated with clinically available CXCR4 binding motifs and multimodality imaging reporters for targeting CXCR4 positive TN breast cancers. Relevance CXCR4 based imaging probes and CXCR4 targeted therapeutic agents that selectively eliminate CXCR4 positive cells within the primary tumors and metastases will be developed for imaging and targeting of triple negative breast cancer.

描述（由申请人提供）：转移是癌症发病率和死亡率的主要原因。大约30-40%的所有确诊乳腺癌最终发展为淋巴结、肺、肝和骨病变。基质衍生因子SDF-1（或CXCL 12）由潜在转移部位的基质分泌，并吸引表达循环趋化因子受体4（CXCR 4）的细胞。CXCR 4通常在乳腺癌细胞中过表达，CXCR 4-CXCL 12信号传导不仅对于癌细胞的迁移而且对于微转移和原发性肿瘤的存活和生长都是至关重要的。靶向CXCR 4的抑制剂降低了转移的发生率。在已知的分子表型中，三阴性（TN）[雌激素受体（ER）、孕激素受体（PR）和HER-2阴性]乳腺癌患者的预后最差，大多数患者可能发生远处复发和难治性疾病。近75%的TN乳腺癌具有高水平的活化CXCR 4，并且这种在TN乳腺癌中的过表达导致不良的临床结果。由于其在癌细胞存活、侵袭、骨髓源性细胞的募集和血管生成中的关键作用，TN乳腺癌中CXCR 4受体的非侵入性成像对于评估原发性和转移性肿瘤中CXCR 4表达升高是重要的。基于CXCR 4的成像探针可用于i）评估原发性肿瘤的CXCR 4表达升高和治疗干预; ii）筛选局部和远端部位的继发性转移扩散;和iii）用于治疗监测。我们之前开发并评价了正电子发射断层扫描（PET）显像剂[64 Cu] AMD 3100在乳腺癌原位和实验性肺转移模型中的应用，以检测CXCR 4表达。最近，我们开发了正电子发射的monoclam类似物[64 Cu] AMD 3465，与[64 Cu] AMD 3100相比，它与CXCR 4的结合亲和力高出近16倍，并提供了具有非常高的靶选择性的最清晰图像。我们的目的是开发一种18F标记的AMD 3465类似物，用于乳腺癌的快速临床转化成像。此外，TN乳腺癌尤其缺乏靶向治疗的益处，并且比其他表型显示出更高的复发率和更短的生存期。靶向和选择性消除肿瘤和转移灶内的致死性CXCR 4阳性癌细胞群可能导致转移负荷降低。由于CXCR 4在TN乳腺癌中高度表达，我们将开发用临床可用的CXCR 4结合基序和多模态成像报告物修饰的治疗剂，用于靶向CXCR 4阳性TN乳腺癌。将开发基于CXCR 4的成像探针和CXCR 4靶向治疗剂，选择性消除原发性肿瘤和转移灶内的CXCR 4阳性细胞，用于三阴性乳腺癌的成像和靶向。