Peter Clark
· Associate ProfessorVerifiedUniversity of California, Los Angeles · Nuclear Medicine & Theranostics
Active 1981–2026
About
Peter Clark is an Associate Professor in the Department of Pharmacology at the University of California, Los Angeles. His research focuses on developing new therapies for cancer and autoimmune disease by leveraging positron emission tomography (PET) molecular imaging studies to discover critical pathways involved in these diseases. His lab uses high-throughput screening efforts to identify new ways to target these pathways and further studies these pathways and inhibitors in cell culture and animal models. Clark's work aims to translate molecular imaging insights into therapeutic strategies, contributing to advancements in cancer and autoimmune disease treatment.
Research topics
- Medicine
- Internal medicine
- Cell biology
- Cancer research
- Biology
- Chemistry
- Biochemistry
- Endocrinology
- Pharmacology
Selected publications
Deoxycytidine kinase inhibition: Rewiring tumor nucleotide metabolism for therapeutic gain
Figshare · 2026-03-27
datasetOpen access1st authorCorrespondingDeoxycytidine kinase (dCK) is the rate-limiting enzyme of the deoxyribonucleoside salvage pathway, phosphorylating deoxyadenosine, deoxycytidine, and deoxyguanosine to sustain intracellular deoxyribonucleoside triphosphate (dNTP) pools. Replication stress and DNA damage enhance dCK activity, creating tumor dependence on salvage-mediated dNTP supply for DNA repair and survival. Genetic contexts such as BRCA2 loss and mutant p53 further heighten this vulnerability. This review synthesizes mechanistic evidence linking dCK to stress-adaptive nucleotide metabolism, summarizes progress in small-molecule dCK inhibitor development, and highlights dCK inhibitor TRE-515 as the first clinically tested agent, alongside plasma nucleoside profiling and PET imaging as translational pharmacodynamic biomarkers.
Deoxycytidine kinase inhibition: Rewiring tumor nucleotide metabolism for therapeutic gain
Nucleosides Nucleotides & Nucleic Acids · 2026-03-26
articleOpen access1st authorCorrespondingDeoxycytidine kinase (dCK) is the rate-limiting enzyme of the deoxyribonucleoside salvage pathway, phosphorylating deoxyadenosine, deoxycytidine, and deoxyguanosine to sustain intracellular deoxyribonucleoside triphosphate (dNTP) pools. Replication stress and DNA damage enhance dCK activity, creating tumor dependence on salvage-mediated dNTP supply for DNA repair and survival. Genetic contexts such as BRCA2 loss and mutant p53 further heighten this vulnerability. This review synthesizes mechanistic evidence linking dCK to stress-adaptive nucleotide metabolism, summarizes progress in small-molecule dCK inhibitor development, and highlights dCK inhibitor TRE-515 as the first clinically tested agent, alongside plasma nucleoside profiling and PET imaging as translational pharmacodynamic biomarkers.
Deoxycytidine kinase inhibition: Rewiring tumor nucleotide metabolism for therapeutic gain
Figshare · 2026-03-27
datasetOpen access1st authorCorrespondingDeoxycytidine kinase (dCK) is the rate-limiting enzyme of the deoxyribonucleoside salvage pathway, phosphorylating deoxyadenosine, deoxycytidine, and deoxyguanosine to sustain intracellular deoxyribonucleoside triphosphate (dNTP) pools. Replication stress and DNA damage enhance dCK activity, creating tumor dependence on salvage-mediated dNTP supply for DNA repair and survival. Genetic contexts such as BRCA2 loss and mutant p53 further heighten this vulnerability. This review synthesizes mechanistic evidence linking dCK to stress-adaptive nucleotide metabolism, summarizes progress in small-molecule dCK inhibitor development, and highlights dCK inhibitor TRE-515 as the first clinically tested agent, alongside plasma nucleoside profiling and PET imaging as translational pharmacodynamic biomarkers.
Gastroenterology · 2025-02-01
articleOpen access1st authorCorrespondingInflammatory Bowel Diseases · 2025-02-01
article1st authorCorrespondingAbstract Inflammatory bowel disease (IBD) is a challenging disease in need of new treatment options. Current IBD therapies are mostly injectables, broadly immunosuppressive, and rarely obtain long-term disease remission – presenting a significant challenge. Activated and proliferating CD4 T cells are key drivers of IBD with defined roles for TH1, TH2, and TH17 CD4 T cells. Proliferating CD4 T cells require an uninterrupted supply of deoxyribonucleotides (dNTPs) for DNA synthesis. Two complementary pathways can synthesize dNTPs. The de novo pathway converts glucose and amino acids to dNTPs while the faster salvage pathway with rate-limiting enzyme deoxycytidine kinase (dCK) consumes and phosphorylates deoxyribonucleosides from the extracellular space into dNTPs. TRE-515 is an orally taken first-in-human small molecule dCK inhibitor in Phase 1 clinical trials for solid tumors where it has been shown to be well tolerated with on-target antitumor activity. TRE-515 only impacts aberrantly activated immune cells that cause disease, suggesting that it is not strongly immunosuppressive. TRE-515 pharmacodynamics can be monitored by measuring blood levels of the dCK substrate deoxycytidine. We hypothesized that dCK activity is elevated in and required for disease in the adoptive CD4 T cell transfer (ACT) preclinical IBD model, and studied dCK activity and TRE-515 in this model. Mesenteric lymph nodes dCK activity, as measured by PET with the [18F]FAC radiotracer, correlated with IBD disease activity and was significantly elevated at 8 weeks post-cell transfer in the ACT model during severe disease. Treating the ACT mice with TRE-515 starting at disease onset (3 weeks post-cell transfer) led to a significant decrease in the colon weight-to-length ratio, a measure of disease activity, as well as improved histological measures of disease including inflammation, gland loss, and edema. TRE-515-treated mice had lower levels of activated and effector memory CD4+ T cells in the mesenteric lymph nodes. TRE-515 treatments showed significant disease improvement compared to vehicle as well as non-inferiority to the standard-of-care comparator anti-IL-12/IL-23 in all disease scores. To validate our results, we conducted independent testing in another lab. Here, TRE-515 treatment of ACT mice limited weight loss and increased the percent of naïve CD4 T cells in the mesenteric lymph nodes. Our results in a preclinical model suggest that TRE-515 may have efficacy in treating IBD. Figure 1: Graphical abstract. We show that clinical inhibitor TRE-515 can block IBD in a preclinical model by limiting CD4 T cell proliferation. Figure 2: Representative H&E-stained distal colon sections of an adoptive CD4 T cell transfer IBD model show less inflammation in the mice treated with TRE-515.
Immunology · 2024-12-22 · 2 citations
articleOpen accessSenior authorCorrespondingABSTRACT Autoreactive, aberrantly activated lymphocytes that target myelin antigens in the central nervous system (CNS) are primary drivers of the autoimmune disease multiple sclerosis (MS). Proliferating cells including activated lymphocytes require deoxyribonucleoside triphosphates (dNTPs) for DNA replication. dNTPs can be synthesised via the de novo pathway from precursors such as glucose and amino acids or the deoxyribonucleoside salvage pathway from extracellular deoxyribonucleosides. Deoxycytidine kinase (dCK) is the rate‐limiting enzyme in the salvage pathway. In prior work, we showed that targeting dCK with the small molecule inhibitor TRE‐515 limits clinical symptoms in two myelin oligodendrocyte glycoprotein (MOG)‐induced experimental autoimmune encephalomyelitis (EAE) mouse models of MS and decreases the levels of activated CD4 T and B lymphocytes in vivo. However, whether targeting dCK limits disease in additional EAE models and how targeting dCK directly impacts activated and proliferating CD4 T and B cells has yet to be determined. Here, we show that dCK is activated in the lymph nodes and spleen in an EAE model induced by amino acids 139–151 of the proteolipid protein (PLP 139‐151 ) that is driven by CD4 T and B cells and is characterised by acute disease followed by disease remission. Treating this model with TRE‐515 limits clinical symptoms and decreases the levels of activated CD4 T and B cells. In culture, CD4 T and B cells induce deoxyribonucleoside salvage following activation, and TRE‐515 directly blocks CD4 T and B cell activation‐induced proliferation and activation marker expression. TRE‐515 decreases deoxycytidine triphosphate (dCTP) and deoxythymidine triphosphate (dTTP) pools and increases the length of time cells spend in S phase of the cell cycle without inducing a replication stress response in B cells. Our results suggest that dCK activity is required to supply needed dNTPs and to enable rapid cell division following lymphocyte activation against autoantigens in EAE mouse models.
Pacritinib inhibits glucose consumption in squamous cell lung cancer cells by targeting FLT3
Scientific Reports · 2023-01-25 · 6 citations
articleOpen accessSenior authorSquamous cell lung cancer maintains its growth through elevated glucose consumption, but selective glucose consumption inhibitors are lacking. Here, we discovered using a high-throughput screen new compounds that block glucose consumption in three squamous cell lung cancer cell lines and identified 79 compounds that block glucose consumption in one or more of these cell lines. Based on its ability to block glucose consumption in all three cell lines, pacritinib, an inhibitor of FMS Related Receptor Tyrosine Kinase 3 (FLT3) and Janus Kinase 2 (JAK2), was further studied. Pacritinib decreased glucose consumption in squamous cell lung cancer cells in cell culture and in vivo without affecting glucose consumption in healthy tissues. Pacritinib blocked hexokinase activity, and Hexokinase 1 and 2 mRNA and protein expression. Overexpression of Hexokinase 1 blocked the ability of pacritinib to inhibit glucose consumption in squamous cell lung cancer cells. Overexpression of FLT3 but not JAK2 significantly increased glucose consumption and blocked the ability of pacritinib to inhibit glucose consumption in squamous cell lung cancer cells. Additional FLT3 inhibitors blocked glucose consumption in squamous cell lung cancer cells. Our study identifies FLT3 inhibitors as a new class of inhibitors that can block glucose consumption in squamous cell lung cancer.
Molecular Imaging and Biology · 2022-10-25 · 8 citations
articleOpen accessSenior authorTargeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis
Immunology · 2022-08-20 · 12 citations
articleOpen accessSenior authorCorrespondingAbstract Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate‐limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched in lymphocytes and required for early lymphocyte development. However, specific roles for the deoxyribonucleoside salvage pathway and dCK in autoimmune diseases such as MS are unknown. Here we demonstrate that dCK activity is necessary for the development of clinical symptoms in the MOG 35–55 and MOG 1–125 experimental autoimmune encephalomyelitis (EAE) mouse models of MS. During EAE disease, deoxyribonucleoside salvage activity is elevated in the spleen and lymph nodes. Targeting dCK with the small molecule dCK inhibitor TRE‐515 limits disease severity when treatments are started at disease induction or when symptoms first appear. EAE mice treated with TRE‐515 have significantly fewer infiltrating leukocytes in the spinal cord, and TRE‐515 blocks activation‐induced B and T cell proliferation and MOG 35–55 ‐specific T cell expansion without affecting innate immune cells or naïve T and B cell populations. Our results demonstrate that targeting dCK limits symptoms in EAE mice and suggest that dCK activity is required for MOG 35–55 ‐specific lymphocyte activation‐induced proliferation.
Signaling Pathways That Drive<sup>18</sup>F-FDG Accumulation in Cancer
Journal of Nuclear Medicine · 2022 · 35 citations
Senior authorCorresponding- Cancer research
- Chemistry
- Biology
F-FDG PET in the management of cancer. Work over the past 5 years, building on studies from years prior, has identified new proteins and signaling pathways that drive glucose consumption in cancer. Here, we review these recent studies and discuss current limitations to our understanding of glucose consumption in cancer.
Recent grants
Frequent coauthors
- 30 shared
Linda C. Hsieh–Wilson
California Institute of Technology
- 25 shared
Owen N. Witte
- 23 shared
Bao Ying Chen
City of Hope
- 15 shared
Eric C. Peters
- 15 shared
David A. Nathanson
- 14 shared
Daniel E. Mason
- 13 shared
Timothy F. Cloughesy
University of California, Los Angeles
- 13 shared
Haruko Nakano
University of California, Los Angeles
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