Evaluation of NM404 in endogenous breast cancer models

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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.