Flourine-18 labeled MDM2 antagonists for PET imaging

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ABSTRACT The tumor suppressor protein p53 plays a critical role in protecting cells against oncogenic transformation. Consistent with this role, nearly 50% of all human cancers have a mutation in the p53 gene, rendering the p53 protein inactive. In tumors that are wild-type p53, the p53 function is often inhibited by the overexpression of its negative regulatory protein, murine double minute 2 (MDM2). Studies suggests that MDM2 is overexpressed in several human cancers, including breast cancer, sarcomas and glioblastoma, although at different rates. MDM2 interacts with p53 in a negative feedback loop and targets the p53 protein for proteasomal degradation, thereby inhibiting the tumor suppressive function of p53 in wild-type p53 tumors. Hence, inhibition of MDM2 with small molecule antagonists or other molecular scaffolds such as stapled peptides is being pursued as a therapeutic strategy for activating the p53 pathway in wild-type p53 cancers. Whilst the preclinical and the early clinical data have demonstrated the promise of this therapeutic approach, recent phase 1 clinical trials with small molecule MDM2 antagonists have indicated significant association between pre-treatment MDM2 expression levels and therapeutic response in patients with acute myeloid leukemia. These data suggest the need for selecting appropriate patients for MDM2 inhibition therapies and the potential usefulness of MDM2 as a predictive biomarker for MDM2 targeted therapies. One of the critical barriers for such studies is the lack of a noninvasive method for determining MDM2 overexpression status in tumors. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), the most commonly used methods for assessing MDM2 gene amplification and MDM2 protein overexpression in tumors, respectively, are invasive and do not permit monitoring the treatment response in vivo. To address these needs, we propose to develop radiolabeled probes for imaging the MDM2 protein expression levels in tumors noninvasively with positron emission tomography (PET), a highly sensitive molecular imaging technique. Building on the preliminary data we obtained in support of the project, we will synthesize fluorine-18 labeled compounds that bind to the MDM2 protein with high affinity (Aim 1). The labeled compounds will be evaluated for their potential to bind on MDM2 expressing tumors cells in vitro (Aim 2) and in mouse models of breast cancer and soft tissue sarcomas in vivo (Aim 3) to identify a lead molecule for MDM2 imaging with PET. To the best of our knowledge, this project would be the first study to develop PET imaging agents for the oncoprotein MDM2. Successful development of a PET imaging approach for the MDM2 protein will provide a valuable tool for studying MDM2-p53 biology in vivo and for investigation of novel therapies targeting MDM2 in wild-type p53 cancers.