 |
Larry H. Matherly, Ph.D. |
RESEARCH INTERESTS:
Folates are essential for life and folate deficiency contributes to a host of health problems including cancer. Antifolates, typified by methotrexate and pemetrexed, continue to occupy a unique niche among the modern day pharmacopoeia for cancer. The Matherly laboratory has been studying the structure and regulation of the reduced folate carrier (RFC), the predominant transport system for folates in mammalian cells. RFC levels are important determinants of antitumor effectiveness of antifolates and defects in RFC result in impaired drug transport and resistance. Structural studies of human RFC involve use of specific affinity ligands, site-directed mutagenesis and scanning cysteine accessibility methods to probe membrane topology, identify amino acids that contribute to substrate binding and translocation, and establish helix packing and dynamic structural changes that accompany substrate binding and translocation. Other RFC studies involve the complex regulation of the RFC gene, including its transcriptional and epigenetic controls, and post-translational mechanisms. The regulation of RFC levels and activity in vivo is being explored through the use of “humanized” mouse models in which the mouse RFC gene has been replaced by the human RFC gene. Finally, in collaboration with medicinal chemists, the laboratory is developing a new catalog of small molecule ligands to probe structural features critical for drug binding to RFC and that may have potential for clinical application for cancer. Related studies are focusing on approaches for chemotherapy drug targeting via high affinity folate receptors and a proton-coupled folate transporter expressed on the surface of solid tumors.
In collaboration with pediatric oncologists, the Matherly laboratory studies molecularly-based prognostic markers of treatment response in pediatric leukemias. These translational studies range from characterizing responses to chemotherapy in relation to polymorphisms in drug-specific genes such as RFC, to probing other aspects of leukemia biology such as the relationships between characteristic chromosomal alterations [e.g., hyperdiploidy and t(12;21) in B-precursor acute lymphoblastic leukemia] or aberrant signaling pathways (e.g., Notch1 in T-cell acute lymphoblastic leukemia) and treatment response. Results of these studies should identify new prognostic features and entirely new mechanistically-based strategies for treating acute lymphoblastic leukemia in both children and adults.
Selected recent publicationsMatherly, 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.
Payton, S.G., Haska, C.L., Flatley, R.M., Ge, Y., Matherly, L.H. : Effects of 5’untranslated region diversity on the posttranscriptional regulation of the human reduced folate carrier. Biochim. Biophys. Acta 1769: 131-8, 2007
Ge, Y., Haska, C.L., LaFiura, K., Devidas, M., Linda, S.B., Liu, M., Thomas, R., Taub, J.W., Matherly, L.H.: Prognostic role of the reduced folate carrier, the major membrane transporter for methotrexate, in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Clin. Cancer Res. 13: 451-7, 2007.
Liu, M., Ge, Y., Payton, S.G., Aboukameel, A., Buck, S., Flatley, R.F., Haska, C., Mohammad, R., Taub, J.W., Matherly, L.H.: Transcriptional regulation of the human reduced folate carrier in childhood acute lymphoblastic leukemia cells. Clin. Cancer Res. 12: 608-616, 2006.
Hou, Z., Ye, J., Haska, C.L., Matherly, L.H.: Transmembrane domains 4, 5, 7, 8, and 10 of the human reduced folate carrier are important structural or functional components of the transmembrane channel for folate substrates. J. Biol. Chem. 281:33588-96, 2006.
Search PubMed for publications from the Matherly Lab
