Evaluation of NM404 in endogenous breast cancer models

描述（由申请人提供）： 该提案的总体目标是在两种内源性小鼠乳腺癌模型中评估NM 404（一种新的肿瘤选择性放射成像剂）的肿瘤成像特性。一种模型将允许评价增生性和肿瘤性病变的摄取，另一种将允许对转移性病变进行研究。NM 404是第二代磷脂醚类似物，在21/21异种原发性和转移性啮齿动物肿瘤模型中显示出显著的肿瘤选择性，但尚未在自发性乳腺癌模型中进行评价。这种方法的流行假设是，磷脂醚由于不能被代谢和清除而仅被捕获在肿瘤细胞膜中。因此，磷脂醚从正常细胞与肿瘤细胞的不同清除率形成了这一概念的基础。该提案的具体目标是：1）评估放射性碘标记的NM 404是否可以无创地区分增生性和肿瘤性乳腺病变; 2）评估其准确识别转移的潜力。将通过体内组织分布研究以及随后的放射学和高分辨率microPET成像研究来定量病变摄取。这些功能性脑电成像和PET图像将在解剖学上与在高分辨率microCT扫描仪上获得的CT扫描和组织病理学相关联。在多种其他肿瘤模型中获得的结果表明，NM 404被活的肿瘤细胞隔离并选择性保留，因此定位于原发性和转移性病变中，而不管位置如何，包括在淋巴结中发现的那些。如果它在这些内源性乳腺癌模型中显示出足够的肿瘤细胞选择性，那么它可以潜在地作为一种有效的成像剂，能够在人类乳腺癌患者中提供准确和非侵入性的诊断和分期信息。已经发布了一项医生申办的IND，以评价放射性碘标记的NM 404在人类前列腺癌患者中的作用。从这一探索性资助中获得的积极结果有望刺激快速转化为人类乳腺癌患者。此外，由于其极长的肿瘤保留特性，足够的肿瘤摄取和保留将刺激将该试剂作为放射治疗剂的正式检查。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to evaluate the tumor imaging characteristics of NM404, a new tumor-selective scintigraphic imaging agent, in two endogenous murine breast cancer models. One model will allow evaluation of uptake by hyperplastic and neoplastic lesions, the other will allow studies on metastatic lesions. NM404, a second-generation phospholipid ether analog, has displayed remarkable tumor selectivity in 21/21 xenographic primary and metastatic rodent tumor models, but has not been evaluated in a spontaneous mammary adenocarcinoma model. The prevailing hypothesis of this approach is that phospholipid ethers become trapped exclusively in tumor cell membranes because of their inability to become metabolized and cleared. Thus, the differential clearance rates of phospholipid ethers from normal cells versus tumor cells form the basis of this concept. The specific goals of this proposal are 1) to assess whether radioiodinated NM404 can noninvasively distinguish between hyperplastic and neoplastic breast lesions and 2) to evaluate its potential to accurately identify metastases. Lesion uptake will be quantitated by in vivo tissue distribution studies and subsequently by both scintigraphic, and high-resolution microPET imaging studies. These functional scintigraphic and PET images will be correlated anatomically with CT scans obtained on a high-resolution microCT scanner and with histopathology. Results obtained in a variety other tumor models indicate that NM404 is sequestered and selectively retained by viable tumor cells and therefore localizes in both primary and metastatic lesions regardless of location including those found in the lymph nodes. If it displays sufficient tumor cell selectivity in these endogenous breast cancer models, then it can potentially serve as an effective imaging agent capable of providing accurate and noninvasive diagnostic and staging information in human breast cancer patients. A physician-sponsored IND has been issued to evaluate radioiodinated NM404 in human prostate cancer patients. Positive results obtained from this exploratory grant are expected to stimulate rapid transition into human breast cancer patients. Moreover, sufficient tumor uptake and retention will stimulate a formal examination of this agent as a radiotherapeutic agent due to its extremely long tumor retention properties.