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Larry H. Matherly, Ph.D. |
RESEARCH INTERESTS:
Research in the Matherly laboratory spans the basic biology of membrane transporters relevant to cancer therapy, to drug discovery and translational studies with primary patient specimens. Membrane transport is essential for antitumor activity of many chemotherapy drugs. The Matherly laboratory has long focused on studies of transport processes for natural folates and folate analogs. These include the widely expressed reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), and the high affinity folate receptors (FRs). RFC levels and function are primary determinants of cellular uptake of the natural folates which are essential for nucleotide biosynthesis. RFC is also a critical determinant of uptake of antifolate drugs used for cancer therapy including methotrexate and newer antifolates typified by pemetrexed and raltitrexed. Studies on RFC have focused on RFC transcriptional and posttranscriptional regulatory mechanisms, and on carrier structure and function, all with the goal of identifying strategies for therapeutically modulating this physiologically and pharmacologically important transporter for cancer as well as other diseases. Based on patterns of tumor-selective expression and/or function of FRs and PCFT, recent emphasis has been on identifying novel cytotoxic drugs with selective transport by these other transporters over RFC. For instance, solid tumors such as ovarian carcinomas generally express high levels of FRs, and many solid tumors are characterized by acidic microenvironments which would favor membrane transport by PCFT over RFC. Based on these concepts, novel 6-substituted pyrrolo- and thieno[2,3-d]pyrimidine antifolate analogs have been synthesized and identified with excellent PCFT- and/or FR transport activity and little to no transport activity by RFC. The goal of these preclinical studies is to develop a new generation of chemotherapy agents with tumor selectivity over normal tissues, based on their (anti)folate transport specificities, which can be advanced to clinical trials. Translational studies in the Matherly laboratory have included characterizing (anti)folate transporter levels in mesothelioma (lung) cancers in patients treated with pemetrexed, to identifying molecularly-based prognostic markers for methotrexate or new drug targets for treating pediatric leukemias. Recent studies have characterized the heterodimeric NOTCH1 receptor in T-cell acute lymphoblastic leukemia (T-ALL), and the relationships between high frequency constitutively activating mutations in NOTCH1 and chemotherapy sensitivity or resistance. Results suggest that depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs, or combinations of agents capable of directly targeting NOTCH1 and downstream pathways (e.g., AKT, mTOR) may be warranted for treating T-ALL in children.
Selected Publications
Matherly, L.H., Hou, Z., Deng, Y.: Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer and Metastasis Reviews 26:111-28, 2007.
Zhao R., Matherly, L.H., Goldman, I.D.: Membrane Transporters and Folate Homeostasis; Intestinal Absorption, Transport into Systemic Compartments and Tissues. Expert Reviews in Molecular Medicine, 11:e4, 2009.
Gedman Larson, A., Chen, Q, S. Kugel Desmoulin, Ge, Y., LaFiura, K., Haska, C.L., Devidas, M., Linda, S.B., Taub, J.W., Matherly, L.H.: Association of NOTCH1 mutations in pediatric T-cell acute lymphoblastic leukemia with expression of genes relevant to chemotherapy response: A report from the Children’s Oncology Group, Leukemia, 23:1417-25, 2009.
Hou, Z., Matherly, L.H, Oligomeric Structure of the human reduced folate carrier: identification of homo-oligomers and dominant-negative effects on carrier expression and function, J. Biol. Chem. 284: 3285-93, 2009.
Wang, L., Cherian, C., Kugel Desmoulin, S., Polin, L., Deng, Y., Wu, J., Hou, Z., White, K., Kushner, J., Matherly, L.H., Gangjee, A.: Synthesis and biological activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry. J. Med. Chem. 53:1306-18, 2010.
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