The incidence of myelodysplastic syndromes (MDS) is likely to increase as the U.S. population ages. Nonetheless, there are no satisfactory treatments. Furthermore, standard classification systems fail to explain much of the variability in either the natural history of these illnesses or their outcome after treatment. These problems reflect a lack of knowledge of the """"""""biology"""""""" of MDS. New methods for clarifying the molecular pathogenesis of MDS have recently become available. This Program Project Grant (PPG) brings together investigators with clinical, molecular biological, and statistical expertise to address the problems noted above. The primary goal of the PPG is to develop new therapies for both low and high-risk forms of MDS. Project 1 will explore the role of new-targeted therapies in the treatment of high-risk MDS and assess the relevance to survival and quality of life of the new category """"""""minor response"""""""" recently promulgated by an NCI Working Group. Therapy for low risk MDS (Project 5) will be based on Dr.Molldrem's hypothesis that peptides derived from normal tissue proteins can be autoantigens for cytotoxic T-lymphocytes (CTL) if peptide overexpression breaks immune tolerance. Preliminary data supporting this hypothesis and suggesting that vaccination with proteinase 3-derived epitopes can induce remissions are presented. Project 5 patients developing high-risk MDS despite the vaccination strategy will be treated on Project 1. Both Projects will use a common approach to evaluate quality-of-life and both employ therapies directed at targets that are quantifiable in the laboratory, thus motivating statistical evaluation of relationships between laboratory-based endpoints and clinical outcome. The PPG's second goal is gain further insight into the molecular pathogenesis of MDS Although activating mutations in FLT3(Project 2), RAS or PTPN11(Core B), or HOX gene overexpression (Project 4) occur in 10-25% of MDS patients, large population-based studies that simultaneously monitor these mutations, or attempt to uncover new ones(Project 2), as the disease evolves are lacking. Interactions between Projects 2, 4, and Core B should, for example, permit evaluation of the hypothesis implicit in the Gilliland-Griffin model that while activating """"""""type 1"""""""" mutations that confer a survival advantage (e.g. RAS.PTPN11, FLT3) will regularly be accompanied by """"""""type 2 """"""""aberrations that block differentiation (e.g. HOX gene overexpression), two type 1 mutations will not occur in the same patient. The role played by epigenetic phenomena, e.g. hypermethylation, in MDS pathogenesis/progression will be examined in Project 3; up to 30% of MDS patients have hypermethylated genes, but this phenomenon has never been examined in the context of activating mutations or HOX overexpression. The PPG's third goal is to enhance the ability to provide accurate prognoses. To do this we will test the hypothesis that the findings from the laboratory-based projects (Projects 2- 5) will provide information that will complement the information provided by the FAB, WHO, or IPSS systems. Preliminary data for example suggests that hypermethylation of a gene known as Ril confers a particularly poor prognosis. Achievement of these goals will be facilitated by the 240 patients seen annually at M.D. Anderson and the frequency with which these patients return for follow-up.
Showing the most recent 10 out of 80 publications
