Imaging and targeting metastatic disease

描述(申请人提供)：转移是癌症发病率和死亡率的主要原因。在所有确诊的乳腺癌中，大约有30%-40%的人最终会发展为淋巴结、肺、肝脏和骨骼的病变。基质衍生因子SDF-1(或CXCL12)由潜在转移部位的间质分泌，并吸引表达循环趋化因子受体4(CXCR4)的细胞。CXCR4在乳腺癌细胞中经常过表达，CXCR4-CXCL12信号不仅对癌细胞的迁移起重要作用，而且对微转移和原发肿瘤的生存和生长也有重要作用。靶向CXCR4的抑制剂可降低转移发生率。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]乳腺癌患者预后最差，大多数患者可能经历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CXCR4，这种过度表达会导致不良的临床预后。由于CXCR4受体在癌细胞存活、侵袭、髓系骨髓来源细胞的募集和血管生成中的重要作用，非侵袭性显像对评估原发灶和转移瘤中CXCR4的表达具有重要意义。基于CXCR4的成像探针可用于i)评估原发肿瘤的CXCR4表达升高和治疗干预；ii)筛查局部和远处的继发性转移扩散；以及iii)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[64Cu]AMD3100在乳腺癌原位和实验性肺转移模型中的表达，以检测CXCR4的表达。最近，我们开发了发射正电子的单环类似物[64Cu]AMD3465，它与CXCR4的结合亲和力比[64Cu]AMD3100高近16倍，并提供了最清晰的图像和非常高的靶向选择性。我们的目的是开发一种18F标记的AMD3465类似物，用于乳腺癌的快速临床翻译成像。此外，与其他表型相比，TN乳腺癌尤其缺乏靶向治疗的好处，表现出更高的复发率和更短的生存期。靶向和选择性地清除肿瘤和转移瘤内的致死性CXCR4阳性癌细胞群体可能会减少转移负担。由于CXCR4在TN乳腺癌中高表达，我们将开发具有临床上可用的CXCR4结合基序的治疗剂和多模式成像报告，用于靶向CXCR4阳性的TN乳腺癌。相关将开发基于CXCR4的成像探针和CXCR4靶向治疗剂，选择性地消除原发肿瘤和转移瘤中的CXCR4阳性细胞，用于三阴性乳腺癌的成像和靶向治疗。

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.