School of Medicine

Wayne State University School of Medicine

Profile

Larry Matherly, Ph.D.
Professor and Associate Center
Director for Basic Science
Basic Science
Elliman Building, Room 3217
421 E Canfield
Detroit, MI 48201
Phone: 313-578-4280
Fax: 313-578-4287
EDUCATION TRAINING

Education
(1981)  Ph.D. Biochemistry: Pennsylvania State University, University Park, PA
(1976)  B.S. Biology: New Mexico State University, Las Cruces, NM

Postgraduate Training
(1981-1984)  Postdoctoral Training: Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298

PROFESSIONAL EXPERIENCE

Faculty Appointments
(2016-Present)  Division Chief for Basic Science, Department of Oncology, Wayne State University School of Medicine, Detroit, MI
(2010-Present)   Director, Cancer Biology Graduate Program, Department of Oncology, Wayne State University School of Medicine, Detroit, MI
(2005-Present)  Member, Institute of Environment Health Sciences, Wayne State, University, Detroit, MI.
(2000-Present)  Professor, Department of Pharmacology, Wayne State University, School of Medicine, Detroit, MI
(1989-Present)  Faculty, Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI
(2006-2010)  Associate Director, Graduate Program in Cancer Biology, Wayne State University School of Medicine, Detroit, MI
(1994-2000)  Associate Professor, Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI
(1989-1994)  Adjunct Faculty, Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI
(1981-1984)  Instructor, Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, VA

Hospital and Other Professional Appointments
(2012-Present)  Program Leader, Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI
(1999-Present)  Member: Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI
(1994-1999)  Associate Member: Karmanos Cancer Institute, Wayne State University, Detroit, MI
(1991-1994)  Associate Member: Developmental Therapeutics Program, Michigan Cancer Foundation, Detroit, MI
(1987‑1991)  Assistant Member: Developmental Therapeutics Program, Michigan Cancer Foundation, Detroit, MI

MAJOR PROFESSIONAL SOCIETIES

American Association for the Advancement of Science
American Association for Cancer Research
American Society of Hematology
American Society of Biochemistry and Molecular Biology
American Society of Pharmacology and Experimental Therapeutics
Children's Oncology Group
Folate Receptor Society (Member, Board of Directors) 

HONORS AND AWARDS

(2016) Eunice and Milt Ring Endowed Chair for Cancer Research
(2015) Wayne State University School of Medicine Teaching Award
(2012) Wayne State University School of Medicine Teaching Award
(2012) Kale's Award in Oncology, Karmanos Cancer Institute
(2009) Wayne State University School of Medicine Teaching Award
(2009) Center Director's Quarterly Research Award, Karmanos Cancer
(2008) Center Director's Quarterly Research Award, Karmanos Cancer Institute
(2006) Wayne State University School of Medicine Teaching Award
(2005) Wayne State University School of Medicine Research Excellence Award
(2005) Wayne State University Service Award
(2001) President's Exceptional Service Award, Wayne State University
(2000) Karmanos Cancer Institute President's Achievement Award for Basic Research
(1999) Wayne State University School of Medicine Research Excellence Award
(1998) Karmanos Recognition Award
(1992) Leukemia Society of America Scholar Award
(1985) American Cancer Society Junior Faculty Award
(1985) Awardee, Leukemia Society of America Special Fellow
(1981) Sigma Xi
(1976) Phi Kappa Phi

COURSES TAUGHT

CB 7210/PHC 7210: Fundamentals of Cancer Biology
CB 7240: Cancer Chemotherapy
PHC 7010: Introduction to Graduate Pharmacology

RESEARCH INTERESTS

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 and drug discovery, and on 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 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. 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 folate analogs 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 ranged from characterizing (anti)folate transporter levels in malignant mesotheliomas from patients treated with pemetrexed, to identifying molecularly-based prognostic markers for methotrexate or new drug targets for treating pediatric leukemias. A recent focus has involved 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.  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 significance to T-ALL biology and therapy. They 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.

PUBLICATIONS

1. Wilson, M.R., Hou, Z., Yang, S., Polin, L., Kushner, J., White, K., Huang, J., Ratnam, M., Gangjee, A., Matherly, L.H. Targeting non-squamous non-small cell lung cancer via the proton-coupled folate transporter with 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates. Mol. Pharmacol. 89(4):425-34, 2016.


2. Wilson, M.R., Kugel, S., Huang, J., Wilson, L.J., Wloszczynski, P.A., Ye, J., Matherly, L.H., 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. 469(1):33-44, 2015.

3. Wang, L., Wallace, A., Raghavan, S., Deis, S.M., Wilson, M.R., Yang, S., Polin, L., White, K., Kushner, J., Orr, S., George, C., O’Connor, C., Hou, S., Mitchell-Ryan, S., Dann, C.E., Matherly, L.H., 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. 58(17):6938-59, 2015.

4. Wilson, M. R., Hou, Z. and Matherly, L. H., Substituted cysteine accessibility reveals a novel transmembrane 2-3 reentrant loop and functional role for transmembrane domain 2 in the human proton-coupled folate transporter. J. Biol. Chem. 289: 25287-95, 2014.

5. Golani, L.K., George, C., Zhao, S., Raghavan, S., Orr, S., Wallace, A., Wilson, M.R., Hou, Z., Matherly, L.H., Gangjee, A.: 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. 57: 8152-66, 2014.

6. Matherly LH, Wilson MR, Hou Z. The Major Facilitative Folate Transporters SLC19A1 and SLC46A1: Biology and Role in Antifolate Chemotherapy of Cancer, Drug Distribution and Metabolism 2014; 42: 632-49.

7. Wang Y, Cherian C, Orr S, Mitchell-Ryan S, Hou Z, Raghavan S, Matherly LH, Gangjee A.Tumor-Targeting with Novel Non-Benzoyl 6-Substituted Straight Chain Pyrrolo[2,3-d]pyrimidine Antifolates via Cellular Uptake by Folate Receptor α and Inhibition of de novo Purine Nucleotide Biosynthesis. J Med Chem. 2013; 56: 8684-95.

8. Hales EC, Orr SM, Larson Gedman A, Taub JW, Matherly LH. Notch1 regulates AKT activation loop (T308) dephosphorylation through modulation of the PP2A phosphatase in PTEN-null T-cell acute lymphoblastic leukemia cells. J Biol Chem. 2013; 288: 22836-48.

9. Cherian C, Kugel Desmoulin S, Wang L, Polin L, White K, Kushner J, Stout M, Hou Z, Gangjee A, Matherly LH. Therapeutic targeting malignant mesothelioma with a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate via its selective uptake by the proton-coupled folate transporter. Cancer Chemother Pharmacol. 2013;71: 999-1011.

10. Kugel Desmoulin S, Hou Z, Gangjee A, Matherly LH. The human proton-coupled folate tranporter: biology and therapeutic applications to cancer. Cancer Biol Ther. 2012;13:1355-73

 

http://www.ncbi.nlm.nih.gov/pubmed/?term=larry+matherly