Intrathecal Administration of Double Checkpoint Inhibition in Combination with Pemetrexed in Patients with Leptomeningeal Metastasis: a Monocentric Phase I/II

The objective of the present study is to evaluate the tolerability, feasibility, safety and therapeutic response of intrathecal administration of double checkpoint inhibition(QL1706) in combination with pemetrexed in patients with leptomeningeal metastasis.

Start Date01 Sep 2025

Sponsor / Collaborator

Guangzhou Medical University

NCT06809517

/ RecruitingPhase 1/2IIT

A Phase I/II Clinical Study of an Intrathecal Combination of PD-1/VEGF Bispecific Antibody and Pemetrexed for Leptomeningeal Metastasis.

Leptomeningeal metastasis, characterized by tumor cells infiltrating and proliferating in the subarachnoid space, represents a distinct pattern of central nervous system involvement and is a fatal complication of malignant tumors. This study is a prospective, single-arm phase I/II clinical trial aimed at evaluating the safety and efficacy of intrathecal PD-1/VEGF bispecific antibodies combined with pemetrexed in treating leptomeningeal metastases from solid tumors, with the goal of identifying more effective treatment options.

Start Date01 Sep 2025

Sponsor / Collaborator

Guangzhou Medical University

100 Clinical Results associated with DHFR x TYMS

100 Translational Medicine associated with DHFR x TYMS

0 Patents (Medical) associated with DHFR x TYMS

778

Literatures (Medical) associated with DHFR x TYMS

28 Feb 2025·The FASEB Journal

DHFR2 RNA directly regulates dihydrofolate reductase and its expression level impacts folate one carbon metabolism

Article

Author: Drago, Paola ; Bookey, Niamh ; Greene, Nicholas D. E. ; Leung, Kit‐Yi ; Henry, Michael ; Parle‐McDermott, Anne ; Meleady, Paula

AbstractDihydrofolate reductase activity is required in One Carbon Metabolism to ensure that the biologically active form of folate, tetrahydrofolate, is replenished and available as an enzyme cofactor for numerous cellular reactions, including purine and pyrimidine synthesis. Most cellular enzyme activity was thought to arise from the product of the DHFR gene on chromosome 5, with its paralogue DHFR2 (formerly known as DHFRL1; [chromosome 3]), believed to be responsible for mitochondrial dihydrofolate activity based on recombinant versions of the enzyme. In this paper, we confirm our earlier findings that dihydrofolate reductase activity in mitochondria is derived from the DHFR gene rather than DHFR2 and that endogenous DHFR2 protein is not detectable in most cells and tissues. Using HepG2 cell lines with modulated expression of either DHFR or DHFR2, we observed an impact of DHFR2 RNA on One Carbon Metabolism mediated through an influence on DHFR expression and activity. Knockout of DHFR2 results in a drop in dihydrofolate reductase activity, lowered 10‐formyltetrahydrofolate abundance, downregulation of DHFR mRNA, and diminished DHFR protein abundance. We also observed downregulation of Serine Hydroxymethyltransferase and Thymidylate Synthase, two One Carbon Metabolism enzymes that work with DHFR to support de novo thymidylate synthesis. The expression of recombinant DHFR2 resulted in restoration of DHFR mRNA and protein levels while a DHFR knockdown cell line showed upregulation of DHFR2 RNA. We propose that the DHFR2 gene encodes an RNA molecule that regulates cellular dihydrofolate reductase activity through its impact on DHFR mRNA and protein.

01 Jan 2025·Indian Journal of Clinical Biochemistry

Assessment of Erythrocytes Methotrexate Polyglutamate Three Levels in Psoriatic Patients Treated with Methotrexate Monotherapy and Their Association with Disease Response

Article

Author: Ramassamy, Sivaranjini ; Goud, Veera Krishna ; Goud, Alladi Charanraj ; Medha, R ; Chandrashekar, Laxmisha ; Jayanthi, M

Methotrexate is used to manage moderate to severe psoriasis and psoriatic arthritis. Methotrexate acts by inhibiting the enzymes involved in nucleotide synthesis. Methotrexate polyglutamates (MTXPGs) have a higher potency to inhibit Dihydrofolate reductase (DHFR), 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC), and thymidylate synthase (TS), compared to naïve methotrexate. Among all the MTXPGs, methotrexate polyglutamate three (MTXPG-3) is a more potent inhibitor of DHFR, ATIC, and TS enzymes. MTXPG-3 is anticipated to allow therapeutic drug monitoring in immune-mediated inflammatory diseases. We aim to study MTXPG-3 levels as a biomarker for both efficacy and adverse events among psoriatic patients treated with methotrexate monotherapy. We used the LC-MS/MS (Liquid Chromatography Mass Spectrophotometry) system for measuring erythrocyte MTXPG-3. We recruited 106 patients with psoriasis who were treated with methotrexate. Sixty-one of them had psoriatic arthritis (concomitant or in the past). The mean age was 45.08 ± 13.04 years. After twenty-four weeks of methotrexate treatment, 73(69%) were responders, and 33(31%) were non-responders. Thirty-nine (36%) experienced adverse effects, and 67(64%) did not experience any adverse effects. We observed a significant positive correlation between erythrocyte MTXPG-3 and methotrexate dose per week at weeks 12 and 16 but not at week 24. Erythrocyte MTXPG-3 did not correlate with response or adverse effects. It can be used as a marker of compliance.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12291-024-01269-x.

01 Oct 2024·Trends in Biochemical Sciences

Enzoology: understanding enzyme interactions and epistasis in the cell

Article

Author: Savinov, Andrew

Recent work from Nguyen et al. unveils massively parallel measurements of epistatic interactions between two enzymes, dihydrofolate reductase and thymidylate synthase, in their natural cellular context. Almost 3000 mutations of DHFR in three TYMS backgrounds reveal a complex interaction network. The authors capture much of this complexity using a simple model.

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