The folate receptor (FR) has been found to be a promising tumor marker and a target for several novel therapeutic approaches in laboratory and in pre-clinical and clinical trials. The applicant's laboratory has contributed substantially to the identification of multiple tissue specific isoforms of the FR and studies of their structure, function, and differential regulation in various malignancies including the establishment of FR type beta as a myeloid differentiation marker and a potential marker for certain myeloid leukemias. The gene structures and the basal promoters for the FR isoforms have been characterized by the applicant's and other laboratories. Preliminary studies show that FR beta is specifically and strikingly upregulated in myeloid leukemia cells by retinoic acid, independent of differentiation. Preliminary studies also indicate that large differences in FR alpha mRNA levels among carcinoma cells occur post-transcriptionally. The applicant proposes to study molecular mechanisms underlying critical regulatory processes in FR expression by (i) identification of putative novel regulatory elements in the FR alpha, beta, and gamma genes that confer their narrow tissue and tumor specificity; (ii) characterization of upstream and downstream molecular events in differentiation- independent retinoid-induced modulation of the FR beta gene in myeloid leukemia cells; and (iii) elucidation of the post-transcriptional mechanisms responsible for the variable expression of FR-alpha among carcinoma cells. All of the above studies with cell lines will be extended to malignant situations in vivo. The proposed studies will resolve key issues of clinical significance in FR regulation and will investigate a promising novel strategy to treat myeloid leukemias refractory to retinoid differentiation therapy. They further promise to reveal novel mechanisms of tissue/tumor specific gene regulation with potential applications in the broad context of future gene therapy strategies.
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