Larry H. Matherly

 

 

 

 

 

 

Larry H. Matherly, Ph.D.
Eunice and Milton Ring Endowed Chair for Cancer Research
Associate Center Director for Basic Sciences
Director, Cancer Biology Graduate Program
Barbara Ann Karmanos Cancer Institute
Wayne State University School of Medicine
421 East Canfield
Detroit, MI 48201-1976
Ph: 313-578-4280
Fax: 313-578-4287
email: matherly@karmanos.org

Mentoring: Michael Wilson ( Graduated 08/23/2016 ) and Adrianne Wallace-Povirk  (Year 3) and Aamod Dekhne (MD/PhD)

Read about Dr. Matherly's Kales Award in Oncology

Research Interests:

•Basic biology of membrane transporters
•Cancer metabolism
•Biology and therapeutic applications of folates and related analogs
•Drug discovery
•Translational studies of chemotherapy response and resistance

Research Description:

Folates are essential for life and folate deficiency contributes to cardiovascular disease, fetal abnormalities, neurologic disorders, and cancer. Folates serve indispensable roles in one-carbon (C1) metabolism, including biosynthesis of thymidylate, purines, serine and methionine, and in supporting biological methylation reactions from S-adenosylmethionine.  C1 metabolism encompasses cytosolic and mitochondrial pathways connected by an interchange between serine, glycine and formate.  Since mammals cannot synthesize folates de novo, their cellular uptake from the extracellular milieu is essential. Uptake of folates into tissues is primarily mediated by the reduced folate carrier (RFC), folate receptors (FRs) α and β, and the proton-coupled folate transporter (PCFT). Once internalized, folates are transported from the cytosol into mitochondria via a mitochondrial folate transporter (SLC25A32) where they participate in C1 metabolism unique to mitochondria and do not further exchange with cytosolic folates.

Research in the Matherly laboratory spans the basic biology of these processes in relation to cancer. This includes studies of the plasma membrane transport of folate cofactors and cytotoxic folate analogs and C1 metabolism in the cytosol and mitochondria.  RFC levels and function are primary determinants of cellular uptake of  folate cofactors and antifolates and are critical determinants of anti-tumor efficacy of antifolate drugs used for cancer therapy, including methotrexate and newer agents typified by pemetrexed and pralatrexate.  Based on patterns of tumor-selective expression and/or function of FRs and PCFT, recent studies have focused on the discovery of novel cytotoxic drugs with selective transport and tumor targeting by these other transporters over RFC. For instance, solid tumors such as ovarian carcinomas express high levels of FRs, and many solid tumors are characterized by acidic microenvironments that  favor membrane transport by PCFT over RFC.  Based on these concepts, novel 5- and 6-substituted pyrrolo[2,3-d]pyrimidine compounds were discovered with excellent PCFT- and/or FR transport activity.  Our experiments have established extraordinarily potent and selective antitumor activities for many of these agents that can be directly attributed to their inhibition of critical cytosolic and mitochondrial C1 metabolic targets. These agents offer a novel and uniquely powerful approach for studying C1 metabolism in cancer and are in themselves  exciting new therapeutic agents with tumor selectivity and outstanding promise of clinical application.

Selected Publications:

Ravindra M, Wilson MR, Tong N, O'Connor C, Karim M, Polin L, Wallace-Povirk A, White K, Kushner J, Hou Z, Matherly LH, Gangjee A. Fluorine-Substituted Pyrrolo[2,3- d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis. J Med Chem. 2018; 61:4228-8.

Matherly LH, Hou Z, Gangjee A. The Promise and Challenges of Exploiting the Proton-coupled Folate Transporter for Selective Therapeutic Targeting of Cancer. Cancer Chemother Pharmacol. 2018; 81: 1-15.

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; 16:819-830

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.

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.

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;42:632-49.

Education and Training:

PhD (1981): Pennsylvania State University, State College, Pennsylvania

Cancer Biology Courses Taught:

CB7210 Fundamentals of Cancer Biology
CB7240 Principles of Cancer Therapy (Course Director)
CB7300 Special Topics F31 Grant Writing Course