Progesterone is a steroid hormone that binds to its receptor and functions as a transcription factor in the nucleus where it binds to progesterone responsive elements in the DNA. Progesterone receptors (PR) are expressed in 90% of benign and grade I breast tumors and are typically found in less than 20% of aggressive and invasive cancers. Low grade endometrial cancers express progesterone receptor, and loss of receptor is associated with poor prognosis. A non-invasive means of determining the hormone receptor status of breast or endometrial tumors would determine treatment options, identify the size and exact location of the tumor, and provide an additional tool for detecting cancer when traditional imaging strategies miss or confuse lesions. Few methods are currently available for imaging breast and endometrial tumors in vivo and none of these agents facilitate the molecular or therapeutic profiling of the tumor. It is the thesis of this grant proposal that gadolinium(III) conjugated progesterone contrast agents can target hormone receptor positive cells and function to non-invasively image breast and endometrial tumor size and receptor status and improve treatment decisions. Our preliminary studies have identified gadolinium (Gd) conjugated progesterone compounds as capable of traversing the cell membrane, binding to progesterone receptors, initiating gene transcription, and enhancing contrast in mammalian cells imaged using magnetic resonance. The most promising of these agents is termed """"""""ProGlow. This proposal focuses on the application of ProGlow to enhance the imaging of steroid receptor tumors and tissues in vivo.
Specific Aim 1 will investigate if xenografted tumors can be classified as progesterone receptor positive using ProGlow and if changes in tumor volume can be quantified.
Specific Aim 2 focuses on the application of ProGlow not only for breast but also uterine cancers.
Specific Aim 3 will present a series of strategies to increase relaxivity and specificity for targeted tissues to improve ProGlow for targeted molecular profiling using MRI. A critical problem in cancer diagnosis is the determination of molecular markers that influence treatment and prognosis without performing invasive biopsies. ProGlow is a possible solution to this problem in that it will allow for noninvasive diagnosis, molecular characterization, and treatment determination of progesterone-related cancers.
The determination of molecular markers in breast and endometrial cancers is necessary because these markers decide the prognosis and treatment options for patients, but this requires invasive biopsies that are painful and subject to error due to the use of only small portions of a tumor. The proposed research develops cancer-targeted magnetic resonance imaging contrast agents that can be used to noninvasively diagnose and molecularly characterize entire tumors and metastases in order to improve treatment decisions and monitor these diseases and recurrences.
|Sukerkar, Preeti A; MacRenaris, Keith W; Townsend, Taryn R et al. (2011) Synthesis and biological evaluation of water-soluble progesterone-conjugated probes for magnetic resonance imaging of hormone related cancers. Bioconjug Chem 22:2304-16|
|Sukerkar, Preeti A; MacRenaris, Keith W; Meade, Thomas J et al. (2011) A steroid-conjugated magnetic resonance probe enhances contrast in progesterone receptor expressing organs and tumors in vivo. Mol Pharm 8:1390-400|
|Song, Ying; Zong, Hong; Trivedi, Evan R et al. (2010) Synthesis and characterization of new porphyrazine-Gd(III) conjugates as multimodal MR contrast agents. Bioconjug Chem 21:2267-75|