Maria R. Baer, M.D. joined the University of Maryland Marlene and Stewart Greenebaum Cancer Center as Director of Hematologic Malignancies in April, 2007, and is Professor of Medicine and Professor of Molecular Medicine, University of Maryland School of Medicine. She previously served as Chief of the Leukemia Section of Roswell Park Cancer Institute and Professor of Medicine and Associate Professor of Molecular Pharmacology and Cancer Therapeutics at the University at Buffalo School of Medicine and Biomedical Sciences in Buffalo, New York. Dr. Baer graduated magna cum laude from Harvard University and earned her medical degree from the Johns Hopkins University School of Medicine. She completed her residency in Medicine and fellowship in Hematology and was a National Research Service trainee at Vanderbilt University. She has conducted and participated in numerous clinical trials in leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Her laboratory focuses on mechanisms of drug resistance in leukemia cells.
Work in Dr. Baer's laboratory focuses on focuses on mechanisms of drug resistance in leukemia cells and strategies for overcoming them.
In previous work, we have studied expression and function of ATP-binding cassette (ABC) proteins associated with multi-drug resistance in leukemia cells, and have characterized inhibitors of these drug-resistance proteins and novel chemotherapeutic agents that are not susceptible to these resistance mechanisms.
Recent work has focused on the role of the serine/threonine kinase Pim-1 in regulating drug resistance proteins. Pim-1 has been found to phosphorylate the multidrug resistance-associated ABC proteins P-glycoprotein (Pgp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) and to enable their translocation to the cell surface, where they function as cellular drug efflux pumps. We recently demonstrated that Pim-1 phosphorylates Pgp in its core-glycosylated form and protects it from both proteasomal and proteolytic degradation, thereby stabilizing it and enabling its glycosylation and cell surface translocation. Current work focuses on further defining the effect of Pim-1 phosphorylation on BCRP expression and function.
We have also demonstrated that inhibition of Pim-1 kinase increases cytotoxicity of Pgp and/or BCRP substrate chemotherapy drugs, but not non-substrate drugs, in cells overexpressing these proteins, but not in dug-sensitive cells. We are determing whether inhibiting Pim-1 kinase enhances the cytotoxicity of chemotherapy in leukemia stem cells, using an in vivo transplant model. This work is supported by a Leukemia and Lymphoma Translational Research Program grant,
Our laboratory has also served as the reference laboratory for acute leukemia multidrug resistance studies in the cancer cooperative group Cancer and Leukemia Group B. In a collaborative study funded by an NIH grant, polymorphisms of the genes encoding the ABC proteins Pgp, BCRP and multidrug resistance protein-1 (MRP1) are being correlated with expression and function of these proteins in pretreatment AML cells from patients treated on Cancer and Leukemia Group B AML clinical trials, and with treatment outcome.
Lab Techniques and Equipment:
- Cell culture- cell lines and leukemia samples
- Flow cytometry
- Cell survival assays
- Colony formation assays
- Western blots
- Mutagenesis PCR
Bhullar J, Natarajan K, Shukla S, Mathias T, Sadowska M, Ambudkar SV, Baer MR. The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. PLoS One 8:e71266, 2013. Epub 2013 Aug 14.
Natarajan K, Xie Y, Burcu M, Linn DE, Qiu Y, Baer MR. Pim-1 kinase phosphorylates and stabilizes 130 kDa FLT3 and promotes aberrant STAT5 signaling in acute myeloid leukemia with FLT3 internal tandem duplication. PLoS One 8:e74653, 2013. Epub 2013 Sep 5.
Natarajan K, Bhullar J, Shukla S, Burcu M, Chen Z-S, Ambudkar SV, Baer MR. The Pim kinase inhibitor SGI-1776 decreases cell surface expression of ABCB1 and ABCG2 and drug transport by Pim-1-dependent and -independent mechanisms. Biochemical Pharmacology. Biochemical Pharmacology 85:514-24, 2013.
Sen R, Natarajan K, Bhullar J, Shukla S, Fang H, Cai L, Chen Z-S, Ambudkar SV, Baer MR. The novel BCR-ABL and FLT3 inhibitor ponatinib is a potent inhibitor of the multidrug resistance-associated ATP-binding cassette transporter ABCG2. Molecular Cancer Therapeutics 11:2033-44; 2012.
Baer MR, George SL, Sanford BL, Marzek K, Kolitz JE, Moore JO, Stone RM, Powell BL, Anastasi J, Caligiuri MA, Bloomfield CD, Larson RA. Escalation of daunorubicin and addition of etoposide in the ADE regimen in acute myeloid leukemia patients aged 60 years and older: Cancer and Leukemia Group B Study 9720. Leukemia 25:800-807, 2011.
Xie Y, Burcu M, Linn DE, Qiu Y, Baer MR. Pim-1 kinase protects P-glycoprotein from degradation and enables its glycosylation and cell surface expression. Molecular Pharmacology 78:310-318, 2010.
Lancet J, Gojo I, Burton M, Quinn M, Tighe SM, Kersey K, Zhong Z, Albitar MX, Bhalla K, Hannah AL, Baer MR. Phase I, pharmacokinetic and pharmacodynamic study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia. Leukemia 24:699-705, 2010.
Burcu M, O’Loughlin KL, Ford LA, Baer MR. Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia 22:2110-2115, 2008.
Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Marzek K, Kolitz JE, Powell BL, Moore JO, Stone RM, Anastasi J, Bloomfield CD, Larson RA. Low-dose interleukin-2 immunotherapy does not improve outcome of patients 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B study 9720. Journal of Clinical Oncology 30:4934-4939, 2008.
Qadir M, O'Loughlin KL, Fricke SM, Williamson NA, Greco WR, Minderman H, Baer MR. Cyclosporin A is a broad-spectrum multidrug resistance modulator. Clinical Cancer Research 11: 2320-2326, 2005.
Baer MR, George SL, Dodge RK, O’Loughlin KO, Minderman H, Caligiuri MA, Anastasi J, Powell BL, Kolitz JE, Schiffer CA, Bloomfield CD, Larson RA. Phase III study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B study 9720. Blood 100:1224-1232, 2002.
Baer MR, Stewart CC, Dodge RK, Leget G, Sule N, Mrozek K, Schiffer CA, Powell BL, Kolitz JE, Davey FR, Carroll AJ, Larson RA, Bloomfield CD. High frequency of immunophenotype changes in acute myeloid leukemia at relapse: Implications for residual disease detection (Cancer and Leukemia Group B Study 8361). Blood 97:3574-3580, 2001.
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