Homologous recombination (HR), which is a defense and repair mechanism, when dysregulated or elevated can lead to significant genetic changes leading to development or progression of cancer. Considerable evidence, from our laboratory and others indicates that recombination activities are both genetically modulated and inducible in mammalian cells, as they are known to be in bacteria and yeast. If homologous recombination becomes constitutively activated, such cells clearly have increased rates of subsequent mutation, which could facilitate the acquisition and progression of a tumor and/or drug resistant phenotype. This proposal will investigate an overall hypothesis that elevated HR mediates DNA instability in myeloma and may therefore contribute to acquisition, progression and development of drug resistance in MM. To evaluate this hypothesis and develop methods to overcome dysfunctionbal HR in myeloma we will follow 3 Specific Aims. To test the hypothesize that increase in HR activity is an early step in the development and progression of myeloma in Specific Aim 1, we plan To evaluate HR function in normal plasma cells, MGUS, and myeloma. To test the hypothesize that molecular mechanisms which regulate HR in normal cells are disrupted in MM, Specific Aim 2 will evaluate molecular mechanisms associated with increased HR activity and its molecular consequence in multiple myeloma. To this end we will determine 2A. the impact of recombination-related transgenic over- expression (gain of function) and manipulations on replicative potential, mutation rate, and development of drug resistance in vitro;and 2B. Determine the impact of HR inhibition on replicative potential, mutation rate, and development of drug resistance in vitro.
Specific Aim 3 To develop small molecule inhibitors of HR pathway using a high-throughput, cell-based, phenotypic screen to prevent development of drug resistance and progression in myeloma. Narrative The proposed studies will improve our understanding of progression of MM and development of drug resistance and may facilitate the development of prognostic tests for disease progression and identify successful therapeutic strategies for myeloma that can also be extrapolated to number of other cancers.
|Bae, Jooeun; Keskin, Derin B; Cowens, Kristen et al. (2015) Lenalidomide Polarizes Th1-specific Anti-tumor Immune Response and Expands XBP1 Antigen-Specific Central Memory CD3(+)CD8(+) T cells against Various Solid Tumors. J Leuk (Los Angel) 3:|
|Wang, X; Yan, Z; Fulciniti, M et al. (2014) Transcription factor-pathway coexpression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma. Leukemia 28:894-903|
|Bae, Jooeun; Munshi, Aditya; Li, Cheng et al. (2013) Heat shock protein 90 is critical for regulation of phenotype and functional activity of human T lymphocytes and NK cells. J Immunol 190:1360-71|
|Bae, Jooeun; Song, Weihua; Smith, Robert et al. (2012) A novel immunogenic CS1-specific peptide inducing antigen-specific cytotoxic T lymphocytes targeting multiple myeloma. Br J Haematol 157:687-701|
|Bae, Jooeun; Smith, Robert; Daley, John et al. (2012) Myeloma-specific multiple peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma and other plasma cell disorders. Clin Cancer Res 18:4850-60|
|Magrangeas, Florence; Avet-Loiseau, Herve; Munshi, Nikhil C et al. (2011) Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood 118:675-8|
|Calimeri, T; Battista, E; Conforti, F et al. (2011) A unique three-dimensional SCID-polymeric scaffold (SCID-synth-hu) model for in vivo expansion of human primary multiple myeloma cells. Leukemia 25:707-11|
|Papaemmanuil, E; Cazzola, M; Boultwood, J et al. (2011) Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med 365:1384-95|
|Fulciniti, Mariateresa; Amin, Samir; Nanjappa, Puru et al. (2011) Significant biological role of sp1 transactivation in multiple myeloma. Clin Cancer Res 17:6500-9|
|Munshi, Nikhil C; Avet-Loiseau, HervÃ© (2011) Genomics in multiple myeloma. Clin Cancer Res 17:1234-42|
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