Complexities in the genetic landscape of tumors significantly impact the design of optimal strategies for the effective treatment of cancer. Our goal in Cancer Pharmacology/Translational Research at Levine Cancer Institute is to support and develop novel paradigms for cancer care.
With this objective in mind, we have adopted a bidirectional "Bench to Bedside" and "Bedside to Bench" strategy for advancing preclinical findings into the clinic. Our ongoing translational research in acute myeloid leukemia (AML) is focused on signaling events regulated by the nuclear enzyme topoisomerase II in differentiation. A key event in the development of AML is the disruption of the myeloid differentiation program and the aberrant self-renewal of leukemic stem cells.
Differentiation therapy with the retinoic acid analog, all-trans retinoic acid (ATRA), has been successful for treating acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of AML. However, ATRA has shown little promise in differentiation therapy of other subtypes of AML. To develop strategies that would improve differentiation therapy for other forms of AML, our ongoing studies with AML cell lines and AML blast cells from relapsed/refractory patients demonstrate the therapeutic efficacy of ATRA can be potentiated by targeting topoisomerase IIβ, either by deleting the enzyme or inhibiting its activity. Specifically, the combination of ATRA and catalytic topoisomerase II inhibitors, such as ICRF-193 or dexrazoxane (a clinically active topoisomerase II inhibitor), leads to enhanced differentiation and preferential activation of the cell death pathway, as compared to differentiation-coupled growth arrest induced by ATRA alone.
Based on this preclinical finding, the labis now poised to test this hypothesis in preclinical mouse models that mimic relapsed/refractory AML. Outcome from this study will serve as a platform for developing a clinical protocol for differentiation therapy of AML.
In the arena of clinical trials in hematological malignancies, we have developed exploratory studies to determine whether genotypic differences are responsible for pharmacokinetic variability and toxicity in patients receiving pre- and post- bone marrow transplant treatment regimens. These data could be helpful in reducing toxicity and improving outcome for transplant patients.
Chikamori, K., Hill, J.E., Grabowski, D.R., Zarkhin, E., Grozav, A.G., Vaziri, S.A.J., Wang, J., Gudkov, A.V., Rybicki, L.R., Bukowski, R.M., Yen, A., Tanimoto, M., Ganapathi, M.K., and Ganapathi, R. Down regulation of topoisomerase IIb in myeloid leukemia cell lines leads to activation of apoptosis following all-trans-retinoic acid-induced differentiation/growth arrest. Leukemia 20: 1809 - 1818, 2006.
Chikamori, K., Grozav, A. G., Kozuki, T., Grabowski, D., Ganapathi, R., Ganapathi, M. K. DNA Topoisomerase II enzymes as molecular targets for cancer chemotherapy. Curr. Cancer Drug Targets. 10: 758-771, 2010.