In the limited number of normal tissues in which the folate receptor (FR) type alpha is expressed, the receptor is restricted to apical (luminal) surfaces, where it is inaccessible via the circulation. As a consequence, FR-alpha is regarded as a promising tumor target, particularly in major subtypes of gynecological cancers, for the selective delivery of a broad range of diagnostic and therapeutic agents through the blood stream. Even though a large and growing body of evidence from pre-clinical and clinical studies supports the feasibility of developing such diagnostics/therapies, translating the success obtained in animal models to human cancer is confounded by variability and heterogeneity in the expression levels of FR-alpha in the tumors. We have previously shown that antiestrogens will up-regulate the FR-alpha gene in estrogen receptor (ER)-positive tumors. We now show that the FR-alpha gene can be transcriptionally modulated by the progesterone receptor (PR), the glucocorticoid receptor (GR) and the androgen receptor (AR), greatly expanding the histologic range of FR-alpha+ tumors in which the receptor expression may be optimized for effective targeting. Agonists of PR, GR and AR enhance FR-alpha transcription by apparently distinct mechanisms and in the absence of classical hormone response elements and further, trichostatin A, a histone deacetylase (HDAC) inhibitor, appears to potentiate these effects, overcoming cell context-dependent co-regulator limitations. The actions of PR, GR and AR on the FR-alpha gene will be studied in sufficient mechanistic detail in vitro and in the physiologic milieu of animal tumor xenograft models to establish the biological contexts and clinical conditions in which FR-alpha expression may be controlled through these nuclear receptors.
The specific aims are: (i) Mechanistic studies of nuclear receptor modulation of FR-alpha: Elucidate the individual modes of action (direct vs. indirect) of the nuclear receptors, establish co-regulator requirements/limitations, map the sites of action of PRa, PRb, GR and AR in the FR-alpha promoter, identify and relate the dynamics of the relevant transcription factors, examine the effects of well tolerated HDAC inhibitors and test various synthetic agonists; (ii) Develop and study stable recombinant cell lines that will express the steroid receptors individually and in combination, together with FR-alpha to reflect their in vivo (co)expression patterns in tumors and characterize individual and combined nuclear receptor mediated modulation of FR-alpha in these cells in vitro and mechanisms of potential cross-talk; (iii) Test the effects of the appropriate steroid receptor agonists and antagonists and HDAC inhibitors in animal tumor xenograft models using representative model cell lines developed in Aim ii and FR-targeted imaging agents. It is anticipated that the proposed studies will systematically establish a foundation for clinical trials of this concept of manipulating tumor tissues to enhance the sensitivity of whole body imaging and the therapeutic efficacy of FR-targeted agents.
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