Professor of Pharmacology and of Oncology
Larry Matherly, Ph.D.
Larry Matherly, Ph.D.
Karmanos Cancer Institute
4100 John R Street
Detroit, MI 48201
Office Phone(313) 578-4280
Office Fax(313) 578-4287
Research in the Matherly laboratory spans both basic and translational studies of cancer therapy. A major focus is on 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 pralatrexate. 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 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. Experiments have established extraordinarily potent and selective antitumor activities for many of these agents. Additional studies are determining the detailed structure-activity relationships for PCFT, FR, and RFC transport substrates, mechanisms of action of the novel tumor-targeted antifolates including their intracellular targets, metabolism, and modes of inducing tumor cell death, and their in vivo antitumor efficacies. The goal of these comprehensive preclinical studies is to develop a new generation of tumor-targeted chemotherapy agents with tumor selectivity over normal tissues, based on their transport specificities, which can be advanced to clinical trials. Other studies on PCFT are focusing on transcriptional and posttranscriptional regulatory mechanisms, and on structural determinants of PCFT function, all with the goal of identifying strategies for therapeutically modulating this physiologically and pharmacologically important transporter.
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. Additional leukemia biology research involves 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. Recent studies of Notch1 in PTEN-null T-ALL and downstream signaling pathways (AKT, AMPK, mTOR) identified a novel regulation of PP2A phosphatase by Notch1. These studies have far reaching ramifications to T-ALL biology and therapy and suggest that depending on Notch1 and PTEN status, modifications in types or dosing of standard chemotherapy drugs may be needed, or combinations of agents capable of directly targeting Notch1 and downstream pathways (e.g., AKT, mTOR) may be warranted for treating T-ALL.
B.S., Biology, New Mexico State University, University Park, NM, 1976
Ph.D., Biochemistry, Pennsylvania State University, State College, PA, 1981
Hou Z, Gattoc L, O'Connor C, Yang S, Wallace-Povirk A, George C, Orr S, Polin L, White K, Kushner J, Morris RT, Gangjee A, Matherly LH. Dual targeting of epithelial ovarian cancer via folate receptor α and the proton-coupled folate transporter with 6-substituted pyrrolo[2,3-d]pyrimidine antifolates. Mol Cancer Ther. 2017 Jan 30. pii: molcanther.0444.2016. [Epub ahead of print]
Wilson MR, Hou Z, Wilson LJ, Ye J, Matherly LH. Functional and mechanistic roles of the human proton-coupled folate transporter transmembrane domain 6-7 linker. Biochem J. 2016;473:3545-62.
Golani LK, Wallace-Povirk A, Deis SM, Wong J, Ke J, Gu X, Raghavan S, Wilson MR, Li X, Polin L, de Waal PW, White K, Kushner J, O'Connor C, Hou Z, Xu HE, Melcher K, Dann CE 3rd, Matherly LH, Gangjee A. Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis. J Med Chem. 2016;59:7856-76.
Deis SM, Doshi A, Hou Z, Matherly LH, Gangjee A, Dann CE 3rd. Structural and Enzymatic Analysis of Tumor-Targeted Antifolates That Inhibit Glycinamide Ribonucleotide Formyltransferase. Biochemistry. 2016;55:4574-82.
Golani LK, George C, Zhao S, Raghavan S, Orr S, Wallace A, Wilson MR, Hou Z, Matherly LH, Gangjee A. Correction to Structure-Activity Profiles of Novel 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Antifolates with Modified Amino Acids for Cellular Uptake by Folate Receptors α and β and the Proton-Coupled Folate Transporter. J Med Chem. 2016;59:4032.
Wilson MR, Hou Z, Yang S, Polin L, Kushner J, White K, Huang J, Ratnam M, Gangjee A, Matherly LH. Targeting Nonsquamous Nonsmall Cell Lung Cancer via the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]Pyrimidine Thienoyl Antifolates. Mol Pharmacol. 2016;89:425-34.
Wang L, Wallace A, Raghavan S, Deis SM, Wilson MR, Yang S, Polin L, White K, Kushner J, Orr S, George C, O'Connor C, Hou Z, Mitchell-Ryan S, Dann CE 3rd, Matherly LH, Gangjee A. 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor α and the Proton-Coupled Folate Transporter in Human Tumors. J Med Chem. 2015;58:6938-59.
Wilson MR, Kugel S, Huang J, Wilson LJ, Wloszczynski PA, Ye J, Matherly LH, Hou Z. Structural determinants of human proton-coupled folate transporter oligomerization: role of GXXXG motifs and identification of oligomeric interfaces at transmembrane domains 3 and 6. Biochem J. 2015;469:33-44.
Wang Y, Mitchell-Ryan S, Raghavan S, George C, Orr S, Hou Z, Matherly LH, Gangjee A. Novel 5-substituted pyrrolo[2,3-d]pyrimidines as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and as potential antitumor agents. J Med Chem. 2015;58:1479-93.
Matherly, L.H., M.R. Wilson, Z. Hou, The Major Facilitative Folate Transporters SLC19A1 and SLC46A1: Biology and Role in Antifolate Chemotherapy of Cancer, Drug Distribution and Metabolism 2014;42:632-649.