The investigator hypothesizes that the variant receptor mRNA may code for a protein that can modulate glucocorticoid responsiveness, and that in an environment of glucocorticoid excess the expression of the variant increases, resulting in a resistant phenotype. He proposes to test the functional properties of these variant receptors and to determine whether they are capable of interfering with glucocorticoid responsiveness. In addition, patients with multiple myeloma will be screened for variant receptor mRNA transcripts in bone marrow samples obtained at presentation and following relapse on steroid-based therapies. The work will be divided into three specific aims.
The first aim i s to identify the protein products of the variant transcripts isolated from the MM.1 line and to assess their functional capacity in vitro (i.e., hormone binding, reaction with anti-receptor antibodies, nuclear translocation, interaction with glucocorticoid-response elements (GRE's), and regulation of gene transcription.
The second aim will be to determine the potential of the variant receptors to disrupt the function of wild-type receptor.
The third aim will be to develop and test a clinical assay to screen for the variant receptor in bone marrow samples obtained from myeloma patients.
| Halgren, R G; Traynor, A E; Pillay, S et al. (1998) 8Cl-cAMP cytotoxicity in both steroid sensitive and insensitive multiple myeloma cell lines is mediated by 8Cl-adenosine. Blood 92:2893-8 |
| Krett, N L; Zell, J L; Halgren, R G et al. (1997) Cyclic adenosine-3',5'-monophosphate-mediated cytotoxicity in steroid sensitive and resistant myeloma. Clin Cancer Res 3:1781-7 |
