My principal area of focus is in the design of new therapeutic strategies for patients with acute myeloid leukemia (AML) and myelodysplasia, which are fatal diseases for the majority of patients. The retinoid all-trans-retinoic acid (ATRA) is highly effective therapy for acute pro-myelocytic leukemia (APL), with 70% of patients achieving remission when treated with ATRA alone. Several attempts have been made to re-produce the efficacy of ATRA in non-APL AML but none have been successful. Malfunction of the ATRA regulated transcription factor RARA (retinoic acid receptor alpha), is likely to play an important role in the pathogenesis of non-APL AML. It has been widely reported that RARA function is blocked in these leukemias by mechanisms other than through chromosomal translocation (which characterizes the driver lesion in APL). Defining and understanding these alternative lesions may help in extending the role of ATRA beyond APL. Data published from our lab in Nature Medicine has shown that the RARA promoter is suppressed due to the loss of activating histone methylation marks. Additional experiments in non-APL cell lines confirmed over-expression of the de-methylase LSD1, which blocks RARA promoter function by directly de-methylating di- and mono-methyl lysine 4 on histone H3. Importantly, LSD1 can be inhibited by monoamine oxidase inhibitors (MAOIs) because of sequence homology between LSD1 and cellular monoamine oxidases. By overcoming LSD1 negative regulation, non-APL cells are re-sensitized to ATRA induced differentiation. The combination of TCP (an approved MAOI, Parnate, GSK) potently synergizes with ATRA in non-APL AML to induce differentiation, post differentiation apoptosis and exhaustion of the leukemic stem cell pool (see figure below), without adversely affecting normal hematopoietic stem cells (HSC). Based on these published data, the studies proposed in this project will test the combination of TCP with ATRA for leukemia patients to extend the success of ATRA into other forms of AML.
Acute Myeloid Leukemia is a fatal disease for the majority of patients. New therapies are urgently needed. We have discovered that combined therapy with a retinoic acid derivative (ATRA) and an anti-depressant (TCP, tranylcypromine) have potent anti-leukemic activity in the laboratory. Both of these drugs are licensed for other disease states. We plan to re-purpose these orally available, cheap and non-cytotoxic treatments for patients with AML, who are in desperate need of better and safer therapies.
| Zheng, Shuhua; Leclerc, Gilles M; Li, Bin et al. (2018) Inhibition of the NEDD8 conjugation pathway induces calcium-dependent compensatory activation of the pro-survival MEK/ERK pathway in acute lymphoblastic leukemia. Oncotarget 9:5529-5544 |
