Larry H. Matherly (ad6348)

421 East Canfield
Detroit, MI 48201-1976

Mathew Schneider

 Oncology

• Cancer metabolism
• Mitochondrial metabolism
• Folates and one-carbon metabolism
• Drug discovery
• Translational studies of chemotherapy response and resistance
 

Metabolic reprogramming is a hallmark of cancer. Of the altered metabolic pathways in cancer, one-carbon (C1) metabolism is notable. C1 metabolism encompasses folate-mediated C1 transfer reactions and related processes, including nucleotide and amino acid biosynthesis, anti-oxidant regeneration, and epigenetic regulation. Uptake of folates into tissues is mediated by the major facilitative transporters, the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), and by folate receptors (FRs) α and β. C1 pathways are compartmentalized in the cytosol, mitochondria and nucleus. Current studies in the Matherly laboratory focus on understanding the biology of C1 metabolism and related processes in relation to therapy of cancer, as well as other diseases.

1. Based on patterns of tumor-selective expression and/or function of FRs and PCFT, our studies focus on discovery of novel cytotoxic drugs that target tumors via their selective membrane transport. For instance, solid tumors such as ovarian cancer express high levels of FRs, and tumors such as pancreatic ductal adenocarcinoma, lung adenocarcinoma, and malignant mesothelioma express high levels of PCFT. For PCFT, transport occurs under acidic pH conditions that characterize the tumor microenvironment. We are working to advance our most optimal agents with the best balance of FR and PCFT transport specificity and potent antitumor efficacy to the clinic.
2. Ongoing studies explore the transcriptional and posttranscriptional regulation of PCFT- and RFC-mediated transport in the context of targeted therapies with the goal of further harnessing these systems for tumor-selective delivery of PCFT-targeted therapies.
3. Recent insights into C1 metabolism in cancer cells, including the critical role of the mitochondrial C1 metabolism from serine as a major source of C1 units, glycine, reducing equivalents and ATP, suggests that key metabolic enzymes including serine hydroxymethyltransferase 2 (SHMT2) could be independent prognostic factors and important therapeutic targets for cancer. Based on our discovery of powerful inhibitors of SHMT2 with broad-based anti-tumor efficacy, we are now exploring the broader biological role of mitochondrial C1 metabolism in cancer cells with the goal of developing new therapies.
4. There is growing interest in the role of immune populations as critical determinants of anti-tumor responses to standard and targeted therapies for many cancers. Ongoing studies explore the potential of targeting FRβ-expressing tumor-associated macrophages (TAMs) for therapy of ovarian cancer. TAMs are the most abundant immune population in ovarian cancer and contribute to an immunosuppressive environment, permitting these tumors to evade immune detection.
 

Wallace-Povirk A, O'Connor C, Dekhne AS, Bao X, Nayeen MJ, Schneider M, Katinas JM, Wong-Roushar J, Kim S, Polin L, Li J, Back JB, Dann CE 3rd, Gangjee A, Hou Z, Matherly LH. Mitochondrial and Cytosolic One-Carbon Metabolism Is a Targetable Metabolic Vulnerability in Cisplatin-Resistant Ovarian Cancer. Mol Cancer Ther. 2024;23:809-22.

Katinas JM, Nayeen MJ, Schneider M, Shah K, Fifer AN, Klapper LM, Sharma A, Thalluri K, Van Nieuwenhze MS, Hou Z, Gangjee A, Matherly LH, Dann CE 3rd. Structural Characterization of 5-Substituted Pyrrolo[3,2-d]pyrimidine Antifolate Inhibitors in Complex with Human Serine Hydroxymethyl Transferase 2. Biochemistry. 2024 Feb 7. Online ahead of print.

Kaku K, Ravindra MP, Tong N, Choudhary S, Li X, Yu J, Karim M, Brzezinski M, O'Connor C, Hou Z, Matherly LH, Gangjee A. Discovery of Tumor-Targeted 6-Methyl Substituted Pemetrexed and Related Antifolates with Selective Loss of RFC Transport. ACS Med Chem Lett. 2023;14:1682-91.

Nayeen MJ, Katinas JM, Magdum T, Shah K, Wong JE, O'Connor CE, Fifer AN, Wallace-Povirk A, Hou Z, Matherly LH, Dann CE 3rd, Gangjee A. Structure-Based Design of Transport-Specific Multitargeted One-Carbon Metabolism Inhibitors in Cytosol and Mitochondria. J Med Chem. 2023;66:11294-323.

Tong N, Wong-Roushar J, Wallace-Povirk A, Shah Y, Nyman MC, Katinas JM, Schneider M, O'Connor C, Bao X, Kim S, Li J, Hou Z, Matherly LH, Dann CE 3rd, Gangjee A. Multitargeted 6-Substituted Thieno[2,3-d]pyrimidines as Folate Receptor-Selective Anticancer Agents that Inhibit Cytosolic and Mitochondrial One-Carbon Metabolism. ACS Pharmacol Transl Sci. 2023;6:748-70.

Dekhne AS, Shah K, Ducker GS, Katinas JM, Wong-Roushar J, Nayeen MJ, Doshi A, Ning C, Bao X, Frühauf J, Liu J, Wallace-Povirk A, O'Connor C, Dzinic SH, White K, Kushner J, Kim S, Hüttemann M, Polin L, Rabinowitz JD, Li J, Hou Z, Dann CE, Gangjee A, Matherly LH. Novel Pyrrolo[3,2-d]Pyrimidine Compounds Target Mitochondrial and Cytosolic One-Carbon Metabolism with Broad-spectrum Antitumor Efficacy. Mol Cancer Ther. 2023;22:287.

Matherly LH, Hou Z. Folate transporter offers clues for anticancer drugs. Nature. 2022;612:39-41.

Hou Z, Gangjee A, Matherly LH. The evolving biology of the proton-coupled folate transporter: New insights into regulation, structure, and mechanism. FASEB J. 2022;36:e22164.

Wallace-Povirk A, Hou Z, Nayeen MJ, Gangjee A, Matherly LH. Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer. Cancers (Basel). 2021;14:191.

O'Connor C, Wallace-Povirk A, Ning C, Frühauf J, Tong N, Gangjee A, Matherly LH, Hou Z. Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer. Sci Rep. 2021;11:6389.

Dekhne AS, Hou Z, Gangjee A, Matherly LH. Therapeutic Targeting of Mitochondrial One-Carbon Metabolism in Cancer. Mol Cancer Ther.
2020;19:2245-55.

Dekhne AS, Ning C, Nayeen MJ, Shah K, Kalpage H, Frühauf J, Wallace-Povirk A, O'Connor C, Hou Z, Kim S, Hüttemann M, Gangjee A, Matherly LH. Cellular pharmacodynamics of a novel pyrrolo[3,2-d]pyrimidine inhibitor targeting mitochondrial and cytosolic one-carbon metabolism. Mol Pharmacol. 2020;97:9-22.

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

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

Professor and Associate Center
Director for Basic Science
Basic Science

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

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

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) 

(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

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

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.

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

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

421 East Canfield
Detroit, MI 48201-1976

313-578-4280

Metabolic reprogramming is a hallmark of cancer. Of the altered metabolic pathways in cancer, one-carbon (C1) metabolism is notable. C1 metabolism encompasses folate-mediated C1 transfer reactions and related processes, including nucleotide and amino acid biosynthesis, anti-oxidant regeneration, and epigenetic regulation. Uptake of folates into tissues is mediated by the major facilitative transporters, the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), and by folate receptors (FRs) α and β. C1 pathways are compartmentalized in the cytosol, mitochondria and nucleus. Current studies in the Matherly laboratory focus on understanding the biology of C1 metabolism and related processes in relation to therapy of cancer, as well as other diseases.

1. Based on patterns of tumor-selective expression and/or function of FRs and PCFT, our studies focus on discovery of novel cytotoxic drugs that target tumors via their selective membrane transport. For instance, solid tumors such as ovarian cancer express high levels of FRs, and tumors such as pancreatic ductal adenocarcinoma, lung adenocarcinoma, and malignant mesothelioma express high levels of PCFT. For PCFT, transport occurs under acidic pH conditions that characterize the tumor microenvironment. We are working to advance our most optimal agents with the best balance of FR and PCFT transport specificity and potent antitumor efficacy to the clinic.

2. Ongoing studies explore the transcriptional and posttranscriptional regulation of PCFT- and RFC-mediated transport in the context of targeted therapies with the goal of further harnessing these systems for tumor-selective delivery of PCFT-targeted therapies.

3. Recent insights into C1 metabolism in cancer cells, including the critical role of the mitochondrial C1 metabolism from serine as a major source of C1 units, glycine, reducing equivalents and ATP, suggests that key metabolic enzymes including serine hydroxymethyltransferase 2 (SHMT2) could be independent prognostic factors and important therapeutic targets for cancer. Based on our discovery of powerful inhibitors of SHMT2 with broad-based anti-tumor efficacy, we are now exploring the broader biological role of mitochondrial C1 metabolism in cancer cells with the goal of developing new therapies.

4. There is growing interest in the role of immune populations as critical determinants of anti-tumor responses to standard and targeted therapies for many cancers. Ongoing studies explore the potential of targeting FRβ-expressing tumor-associated macrophages (TAMs) for therapy of ovarian cancer. TAMs are the most abundant immune population in ovarian cancer and contribute to an immunosuppressive environment, permitting these tumors to evade immune detection.

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

Mentoring: 

• Mathew Schneider
• Adrianne Wallace-Povirk (Graduated 9/1/2021)
• Aamod Dekhne (Graduate 4/29/2019)

Search PubMed for publications from the Matherly Lab

• Cancer metabolism
• Mitochondrial metabolism
• Folates and one-carbon metabolism
• Drug discovery
• Translational studies of chemotherapy response and resistance