Related Experiment Video

Updated: Jun 3, 2025

Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube SWCNT-delivered MALAT1 Antisense Oligos
07:24

Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube SWCNT-delivered MALAT1 Antisense Oligos

Published on: December 13, 2018

6.4K

MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial

Mrinal Gounder1, Melissa Johnson2, Rebecca S Heist3

  • 1Memorial Sloan Kettering Cancer Center; Weill Cornell Medical College, New York, NY, USA.

Nature Communications
|January 6, 2025
PubMed

Insights

This Phase 1 trial investigated AG-270/S095033, a methionine adenosyltransferase 2A (MAT2A) inhibitor, in advanced cancers with MTAP deletion. The drug showed a manageable safety profile and preliminary clinical activity, supporting MAT2A inhibition as a therapeutic strategy.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Homozygous MTAP deletion in ~15% of cancers creates vulnerability to S-adenosylmethionine (SAM) depletion.
  • Methionine adenosyltransferase 2A (MAT2A) is the primary enzyme for SAM synthesis.
  • Targeting MAT2A offers a potential therapeutic strategy for MTAP-deleted cancers.

Purpose of the Study:

  • To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of AG-270/S095033.
  • To determine the maximum tolerated dose (MTD) of AG-270/S095033 in patients with advanced malignancies.
  • To evaluate the proof-of-mechanism for MAT2A inhibition in a clinical setting.

Main Methods:

  • Phase 1, first-in-human trial of AG-270/S095033 monotherapy.
  • Eligible patients had advanced tumors with homozygous CDKN2A/MTAP deletion or MTAP protein loss.
  • Patients received AG-270/S095033 orally, once or twice daily, in 28-day cycles.

Main Results:

  • Forty patients were treated; AG-270/S095033 plasma concentrations increased with dose.
  • Maximal reductions in plasma SAM concentrations ranged from 54% to 70%.
  • Decreases in tumor SDMA levels observed; common toxicities included reversible liver function test elevations, thrombocytopenia, anemia, and fatigue. Two partial responses and five cases of stable disease ≥16 weeks were noted.

Conclusions:

  • AG-270/S095033 demonstrates a manageable safety profile in patients with advanced malignancies.
  • Preliminary clinical activity and proof-of-mechanism for MAT2A inhibition were observed.
  • Targeting MAT2A warrants further investigation in MTAP-deleted cancers.

More Related Videos

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts10:27

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Published on: July 25, 2020

7.2K
Robot-Assisted Radical Antegrade Modular Pancreatosplenectomy Including Resection and Reconstruction of the Spleno-Mesenteric Junction12:34

Robot-Assisted Radical Antegrade Modular Pancreatosplenectomy Including Resection and Reconstruction of the Spleno-Mesenteric Junction

Published on: January 3, 2020

16.5K

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.7K