Studies of Project 1 showed that protein kinase A isozyme switching, via eliciting differential cAMP signaling in the cell, might provide a tumor target-based gene therapy for cancer treatment [1]. PKA isozyme switching can be achieved in many ways, including use of site-selective PKA activators such as 8-Cl-cAMP, viral and non-viral vector-mediated gene overexpression, antisense DNAs, siRNAs, and targeted gene repair/replacement therapy methodologies. Our study clearly warrants translational research. GEM 231 (RIa antisense) is under Phase I-II clinical studies.8-Cl-cAMP for Translational ResearchThis study is performed in conjunction with NIH FY2005 Bench-to-Bedside Awards to Yoon S. Cho-Chung, M.D., Ph.D., and Constantine A Stratakis, M.D., NICHD, on the project entitled, """"""""Site-Selective cAMP Analogs for Treatment of Carney Complex.""""""""Carney complex (CNC), the complex of spotty skin pigmentation that can accompany multiple endocrine neoplasia, is attributed to the mutational loss of PRKARIA, the gene that codes for the RIa subunit of cAMP-dependent protein kinase type I (PKA-I) [2]. Patients often have tumors of two or more endocrine glands, including primary pigmented nodular adrenocortical disease (PPNAD), pituitary adenoma, thyroid adenoma or carcinoma, testicular neoplasms, and ovarian tumors. The skin is affected by multiple lesions that are either pigmented (lentigines, caf-au-lait spots, common and blue nevi) or not pigmented (mainly myxomas and other skin tags). The genes responsible for CNC have been mapped to chromosome 2p16 and 17122-24 [2]. In affected subjects, tumor-specific loss of heterozygosity (LOH) has been found within the 17q region [2]. The presence of tumor-specific LOH suggested that the CNC gene is a tumor suppressor gene. PKA exists in two isoforms, PKA-I and PKA-II. The PKA isozymes are expressed in a balance of cell growth and differentiation. It has been shown that the PKA-I to PKA-II ratio is reversed in primary clinical tumors and transformed tumor cell lines compared to their normal counterparts, and that the experimental approaches that induce PKA-isozyme switching in cancer cells result in tumor cell growth arrest and induction of tumor reversion [1] (Project 1). The objective of this study is to restore the PKA-I to PKA-II ratio in the adrenal glands and other related tumors of Carney complex to that of normal tissue by the following experimental approaches: (1) Use of a site-selective cAMP analog, 8-Cl-cAMP [3], to restore normal PKA activity in adrenal glands and tumors of CNC patients in the setting of an 8-Cl-cAMP phase II-III clinical study; (2) Use of unhydrolyzable Rp-8-Cl-cAMPS and Sp-8-Br-cAMPS with 8-Cl-cAMP to enhance PKA-II activation [4]; (3) Use of the cAMP (CRE response element)-transcription factor decoy to inhibit tumor growth without harming normal cell growth [5]. A long-term goal is the RIa gene transfer/gene therapy of our patients; in the context of this grant we will test this in CNC tumor cell lines.In summary, Carney complex is an incurable disease and currently there is no treatment method for it other than the individual surgeries for the various types of tumors associated with it. We will attempt to restore the abnormally inactivated PKA activity back to the normal physiological state. Because of the loss of PRKARIA gene, the gene coding for RIa regulatory subunit of PKA-I is considered causative of Carney complex, we will attempt to restore the unbalanced PKA-I to PKA-II ratio back to its normal state by using the site-selective cAMP analog, 8-Cl-cAMP, which selectively activated PKA-II in a phase I clinical setting.
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