Evaluation of NM404 in endogenous breast cancer models

描述(由申请人提供)： 这项建议的总体目标是评估一种新的肿瘤选择性核素显像剂NM404在两种内源性小鼠乳腺癌模型中的肿瘤成像特征。一个模型将允许评估增生性和肿瘤性病变的摄取，另一个模型将允许对转移性病变进行研究。NM404是一种第二代磷脂醚类似物，在21/21异种移植原发和转移的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估。这种方法的普遍假设是，磷脂醚被困在肿瘤细胞膜上，因为它们不能被代谢和清除。因此，磷脂醚从正常细胞和肿瘤细胞中的不同清除率构成了这一概念的基础。这项建议的具体目标是1)评估放射性碘标记的NM404是否可以无创地区分乳腺增生性和肿瘤性病变，以及2)评估其准确识别转移的可能性。病变摄取将通过体内组织分布研究以及随后的闪烁照相和高分辨率microPET成像研究来定量。这些功能性核素扫描和正电子发射计算机断层扫描图像将与高分辨率微型CT扫描仪获得的CT扫描和组织病理学进行解剖相关。在其他多种肿瘤模型中的结果表明，NM404被存活的肿瘤细胞隔离并选择性地保留，因此无论在哪里，包括在淋巴结中，NM404都定位于原发灶和转移灶。如果它在这些内源性乳腺癌模型中表现出足够的肿瘤细胞选择性，那么它可能成为一种有效的显像剂，能够为人类乳腺癌患者提供准确和非侵入性的诊断和分期信息。一项由医生赞助的IND已经发布，用于评估放射性碘标记的NM404在人类前列腺癌患者中的应用。从这项探索性赠款中获得的积极结果有望刺激患者迅速转变为人类乳腺癌患者。此外，由于其极长的肿瘤滞留特性，充分的肿瘤摄取和滞留将促使人们将该制剂作为放射治疗剂进行正式检查。

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.