Carolinas HealthCare System

Tumor genes are complex and significantly impact the way we establish new cancer treatments. The goal of the Cancer Pharmacology Department at Levine Cancer Institute is to support research for developing new treatments for cancer by moving ideas from the laboratory to the clinic (known as translational research).

Our ongoing research program in blood cancers is focused on testing and developing new drug combinations for treating relapsed multiple myeloma and acute myeloid leukemia (AML). We are also evaluating genetic differences in these cancers that may influence whether new drugs are effective at killing these cancer cells, whether they contribute to the success of bone marrow transplants, and also how toxic they are for patients.

Our research focus in multiple myeloma is directed toward understanding the mechanisms that lead to drug resistance (where the cancer cells somehow protect themselves against chemotherapy), a major problem contributing to disease recurrence. The Cancer Pharmacology Department will develop laboratory models of multiple myeloma (for example, growing myeloma cells in test tubes) from patients resistant to treatment and use these model systems to test combinations of drugs that can ultimately be tested clinically.

All-trans Retinoic Acid (ATRA) in Combination with Other Drugs

Unlike the many new treatments for multiple myeloma, which have significantly evolved in the past few years, fewer new treatment options are available for AML. The exception is a subtype of AML, referred to as acute promyelocytic leukemia, which is very responsive to a metabolite of vitamin A called all-trans retinoic acid (ATRA). Using laboratory cell culture model systems and patient samples, the Cancer Pharmacology Department was able to demonstrate that ATRA can be effective in this type of AML when used in combination with a drug already in clinical use which interferes with the way genes work when the cancer is trying to grow.

We are now poised to test this hypothesis in experimental models that mimic relapsed AML, to see if this improves the killing of leukemia cells, and therefore to determine whether an effective clinical treatment can be developed for the treatment of AML.

Pre- and Post- Bone Marrow Transplant Drug Responses

Bone marrow transplant is a curative treatment for blood cancers, such as leukemia. However, several pre- and post-transplant drugs must be administered to ensure optimal outcomes, either making the cancer treatment more effective or reducing the side effects on the patient. Drug response is highly variable, as both toxicity and efficacy of these drugs may be partially influenced by the DNA within the patient's genes.

Cancer Pharmacology Department hasbegun studies to identify genetic differences that are responsible for how long the anticancer drug stays in the body and the resulting toxicity in patients receiving pre- and post- bone marrow transplant treatment regimens.

The goal of these studies is to develop strategies to reduce side effects and improve patient outcomes. Thus, our bidirectional "Bench to Bedside" and "Bedside to Bench" strategy in cancer pharmacology and translational research in hematological malignancies is focused on rapidly advancing our laboratory findings, if they suggest the potential for better clinical outcomes, into the clinic.

Select Publications

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.

Patel JN, Mcleod HL. Pharmacogenomics and Cancer Therapy: Somatic and Germ-line Polymorphisms. In: Figg WD, McLeod HL, eds. Handbook of Anticancer Pharmacokinetics and Pharmacodynamics. 2nd ed. Totowa, New Jersey: Humana Press; 2014; pp 255-272

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