Histone acetylation has been linked to gene-specific activation by transcription factors. Recent data have shown that certain oncogenes repress transcription by recruitment of histone deacetylases (HDACs). Three labs have shown that trichostatin A, a potent inhibitor of HDAC, can relieve transcriptional repression and also overcome resistance to all-trans retinoic acid (RA) in experimental models of acute promyelocytic leukemia (APL), even in cell lines that are inherently RA-sensitive. Studies have found that sodium phenylbutyrate (PB) is a non-toxic HDAC inhibitor and that PB alone was ineffective in vitro, but that its use in combination with RA significantly increased cytodifferentiation in APL cells. We have also clinically tested this combination in one APL patient who was highly resistant to both RA and other drugs. PB treatment caused a reversible, time-dependent increase in histone acetylation in blood and bone marrow cells, and the drugs induced a complete clinical and molecular remission. The investigators propose to expand these preliminary observations, and this application requests support for the following specific aims: 1. To establish """"""""proof of principle"""""""" that inhibition of histone deacetylase is feasible as a method of human anticancer therapy in patientswith various tumor types. 2. To evaluate the safety and pharmacokinetics of sodium phenylbutyrate as a clinical prototype of a HDAC inhibitor when used in combination with all- trans retinoic acid. 3. To evaluate the mechanism of action (i.e., differentiation vs apoptosis via caspase activation) whereby HDAC inhibition induces an anticancer effect in APL. 4. To evaluate whether PB can reverse acquired retinoid resistance in APL, the prototype for a retinoid-responsive neoplastic disease. Results from this application are planned to define a clinically tolerable dose schedule of the PB/RA combination, to yield important information with respect to clinical pharmacology and mechanisms of action, to establish the clinical utility of this approach to APL, and to guide future disease-specific clinical investigations with PB and other HDAC inhibitors.
| Maslak, P; Chanel, S; Camacho, L H et al. (2006) Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 20:212-7 |
