Abstract Homozygous deletion of MTAP frequently co-occurs with the adjacent CDKN2A tumor suppressor on chromosome 9p21.3 in human cancers. Loss of MTAP activity creates an acute dependency on MAT2A, the rate-limiting enzyme for SAM synthesis, to produce sufficient SAM to overcome MTA suppression of PRMT5 and to support the folate cycle via 1-carbon metabolism. Proof-of-concept therapeutic targeting of this vulnerability has been achieved by allosteric inhibition of MAT2A or by MTA-cooperative inhibition of PRMT5. However, variability of response highlights the opportunity to continue to improve outcomes with combination therapy strategies. Preclinical profiling has indicated the extent of MTA accumulation in tumor cells and intrinsic or acquired resistance mechanisms are key determinants of antitumor activity. Notably, co-administration of appropriately designed MAT2A and PRMT5 inhibitors can deliver durable tumor regressions and complete responses in multiple MTAPdel PDX models recalcitrant to either monotherapy. Here we describe the biochemical, cell biological, and in vivo efficacy profiles of IDE892, an MTA-cooperative PRMT5 inhibitor purposely designed to exploit the therapeutic opportunity associated with combined inhibition of PRMT5 and MAT2A. Extensive biophysical and biochemical characterization of the IDE397 mode-of-inhibition of MAT2A yielded a mechanistic model that accounts for MTAPdel tumor-specific activity of IDE397 due to allostery-dependent preservation of basal MAT2A activity, maintaining SAM levels above the threshold required to sustain function in normal tissues. In addition, extensive evaluation of the kinetic and equilibrium binding parameters of metabolite and inhibitor exchange on PRMT5 revealed key relationships that specify MTA-cooperativity as well as slow on-rate binding kinetics to the SAM-bound state (negative cooperativity) relative to the apo state. These findings informed the design of IDE892 that optimized efficacy and tolerability in combination with allosteric inhibition of MAT2A. IDE892 demonstrated at least 1,400-fold selective binding to MTA-PRMT5 versus SAM-PRMT5 complexes (by SPR) and robust MTAPdel-specific PRMT5 pathway inhibition in vitro and in vivo. Whole transcriptome, proteome, and mRNA/tRNA methylome analyses indicated both shared and distinct contributions of IDE397 and IDE892 to perturbation of MTAPdel cellular systems which translated to robust combination benefit in MTAPdel CDX and PDX models. These preclinical studies indicate that the combination of IDE892/IDE397 has the potential to deliver durable therapeutic activity for patients harboring MTAPdel tumors; an opportunity that is currently under evaluation in phase 1 clinical trials. Citation Format: Arjun A. Rao, Marcus M. Fischer, Rebeca M. Choy, Angelica M. Gonzalez-Sanchez, Natalie Bresnahan, Zhipeng Fang, Mason J. Appel, Atul Rathore, Oscar Aubi, Shannon Faris, Parker Y. Jameson, Zabrisky Roland, David Trinh, Kelly Trego, John Vivian, Michael E. Dalziel, Christian R. Frey, Yuchen Bai, Jasgit Sachdev, Claire L. Neilan, Jay Prakash Jain, Michael A. White, Paul A. Barsanti, Peter Teriete, Melissa Fleury. IDE892 is a highly potent and selective PRMT5 inhibitor, with MTA-positive and SAM-negative cooperativity, optimized for development in MTAPdel cancers in combination with the allosteric MAT2A inhibitor IDE397 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4505.

This paper provides a comprehensive review of the TRANSP code, a sophisticated tool for interpretive and predictive analysis of tokamak plasmas, detailing its major capabilities and features. It describes the equations for particle, power, and momentum balance analysis, as well as the poloidal field diffusion equations. The paper outlines the spatial and time grids used in TRANSP and details the equilibrium assumptions and solvers. Various models for heating and current drive and radiation, including updates to the NUBEAM model, are discussed. The handling of large-scale events such as sawtooth crashes and pellet injections is examined, along with the predictive capabilities for advancing plasma profiles. The integration of TRANSP with the ITER Integrated Modeling and Analysis Suite (IMAS) is highlighted, demonstrating enhanced data access and analysis capabilities. Additionally, the paper discusses best practices and continuous integration techniques to enhance TRANSP's robustness. The suite of TRANSP tools, designed for efficient data analysis and simulation, further supports the optimization of tokamak operations and coupling with other tokamak codes. Continuous development and support ensure that TRANSP remains a major code for the analysis of experimental data for controlled thermonuclear fusion, maintaining its critical role in supporting the optimization of tokamak operations and advancing fusion research.

Figure S1, Figure S2, Table S1, Table S2, Table S3, Table S4

Abstract Methylthioadenosine phosphorylase (MTAP) loss, due to focal homozygous deletions in chromosome 9 (9p21.3), occurs in over 25% of urothelial carcinoma and is an adverse prognostic factor for overall survival. Furthermore, MTAP-deleted tumors are associated with a “cold” tumor immune microenvironment and are resistant to immune checkpoint inhibitor therapy. Loss of MTAP confers a dependency on methionine adenosyltransferase 2A (MAT2A), which catalyzes the production of the primary methyl donor for all cellular methyltransferase reactions, S-adenosyl methionine (SAM). IDE397, a potent small molecule inhibitor of MAT2A, was developed to selectively exploit this synthetic lethal vulnerability in MTAP −/− tumors. The accumulation of the metabolite MTA in MTAP −/− tumors combined with a reduction of SAM by MAT2A inhibition results in selective inhibition of PRMT5, a methyltransferase that governs spliceosome fidelity. This triggers pre-mRNA splicing defects that may induce RNA polymerase stalling and can cause R-loop accumulation. Furthermore, due to essential roles in 1-carbon metabolism, MAT2A inhibition together with MTAP loss leads to depletion of metabolites required for both de novo and salvage nucleotide biosynthesis, thus preventing effective management of DNA replication and DNA damage repair. Notably, R-loops must be resolved by topoisomerase activity (TOP1) to prevent replication conflict and mitotic catastrophe. These combinatorial mechanistic relationships underpin a hypothesis that dual inhibition of MAT2A and TOP1 will fully capitalize on the synthetic lethal vulnerabilities associated with MTAP loss in urothelial cancers (replication stress, genomic instability). Consistent with this, IDE397 in combination with TOP1 inhibitors demonstrated synergistic combination benefit in MTAP −/− bladder cancer cell lines in vitro and in cell-line derived xenograft (CDX) models in vivo. IDE397 exposure was associated with heavily disordered methionine metabolism and accumulation of DNA damage response intermediates. In the ongoing Phase 1 dose escalation/expansion study of IDE397 in MTAP −/− solid tumors (NCT04794699), measurable tumor shrinkage has been observed in urothelial cancers (including a CR per RECIST 1.1) along with molecular responses on serial ctDNA measurements. Supported by our preclinical data, and the clinical observation that MTAP −/− urothelial cancers may be more sensitive to sacituzumab govitecan (SG); a TROP-2-targeting TOP1 ADC (UNITE study; JCO.2023.41.16_suppl.4572), a combination of SG+IDE397 could represent a novel early-line therapy for these patients with high unmet need. We plan to evaluate the combination of SG+IDE397 in MTAP-/- urothelial cancers in the next stage of the ongoing IDE397 trial (NCT04794699). Citation Format: Claire L. Neilan, Marcus M. Fischer, Damien Garbett, Arjun A. Rao, Mili Mandal, Michael A. White, Jasgit C. Sachdev. The MAT2A inhibitor IDE397: a novel combination backbone for urothelial cancer subjects with MTAP deficiency [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B027.

Abstract It is well appreciated that the integrity of both pluripotent and terminally differentiated cellular genomes is under constant pressure from damage provoked by cell-intrinsic and environmental factors. As such, defects in the cellular machinery preserving genomic integrity lead to the accumulation of variants that can promote cancer, but they also confer tumor-cell specific vulnerabilities that present synthetic-lethal therapeutic opportunities. The deepening mechanistic appreciation of tumor-selective pressure on DNA replication-fork fidelity, namely oncogene-induced replication stress, has provoked great interest in the prosecution of drug targets within the cellular machinery that otherwise supports replication fork stability. Poly (ADP-Ribose) glycohydrolase (PARG) is an enzyme with a unique role in the resolution of DNA damage repair and DNA replication fork restart through hydrolysis of Poly (ADP-ribose) (PAR) chains. IDE161 is a potent, selective small molecule inhibitor of PARG that is being developed as an anti-cancer therapeutic for patients with advanced or metastatic cancer harboring defects in homologous recombination repair. In culture, the accumulation of PAR chains upon PARG inhibition causes delayed repair of DNA breaks, replication stress and mitotic catastrophe in settings with collateral liabilities in DNA damage repair and/or replication fork stability. Genome-wide CRISPR-mediated fitness screens across multiple genetic backgrounds revealed strong synthetic lethal interactions of IDE161 with otherwise non-essential components of cellular machinery supporting base excision repair, homologous recombination repair and replication fork stability. In addition, evaluation of IDE161 antiproliferative activity across a panel of 350 molecularly characterized cancer cell lines returned a response profile that was only partially overlapping with that observed with PARPi and was enriched for models harboring vulnerabilities associated with replication stress and/or defects in DNA repair. Notably, many homologous recombination deficient (HRD) cell models display differential dependency on PARG activity vs PARP1/2 activity, suggesting PARG inhibition as a potential therapeutic strategy distinct from PARP inhibitors. In vivo assessment of IDE161 anti-tumor activity in CDX and PDX models mirrored these mechanistic relationships. A number of HRD PDX models displayed a superior response to IDE161 versus PARPi, including robust regressions selectively observed with IDE161 versus niraparib in BRCA2 altered ER+, HER2-breast cancers. Thus, IDE161 has potential as novel targeted therapy that exploits the synthetic lethal relationship between PARG and genomic instability, leading to selective anti-proliferative activity in tumors harboring defects in DNA repair and replication fidelity. Citation Format: Reeja Maskey, Diana Munoz, Megan Conway, Arjun Rao, Vidhya Nagarajan, Ivan Shabalin, Kelly Trego, Jonathan Ryan, Peter Teriete, Christian Frey, Josh Taygerly, Paul Barsanti, Claire Neilan, Jasgit Sachdev, Michael White. Exploiting tumor selective vulnerabilities with structure based drug design [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA008.

R * 2 and the apparent concentration of FMX in the tumor (FMX C ) are considered biomarkers of liposomal irinotecan (nal-IRI) drug uptake into that tumor lesion, which in turn would determine response of that tumor to nal-IRI. Historically, quantification of R * 2 and FMX C had been implemented by using a calibration phantom and acquiring patient scans both pre-FMX and post-FMX. Here we have demonstrated a pre-treatment FMX-enhanced MRI companion biomarker of response to nal-IRI in mBC patients that can be computed from a single16-24 h post-FMX MRI scan without the need for calibration phantoms or pre-FMX scans.

Supplemental Methods, Figures S1-S5, Tables S1-S7

Example patient (patient 009) with widespread hepatic metastasis who demonstrated a treatment response following therapy. (A) Selected axial images from FMX-MRI acquired from the FSPGR Fat-Sat breath-hold images (TE = 13.2 milliseconds). The lesion outlined by the red box highlights one of the target lesions that underwent biopsy analysis and subsequent response assessment by RECIST v1.1. The values above each of the axial images are the estimated iron concentrations. (B) Axial contrast-enhanced CT images demonstrating tumor shrinkage (red boxes with reduction in lesion size by 67.3% at cycle 8).

Correlation between FMX 72-hour signals and binding constant. (A) Mechanistic PK model for tumor deposition of FMX driven by permeability and binding parameters; example for lesion fits for low permeability/low signal retention is shown. (B) Correlation for tissue binding parameter B to FMX signal measured at 72 hours. The normalized FMX ratio between tumor and plasma values is shown to account for plasma FMX PK variability.

Additional Prussian blue and CD68 staining in a tumor core biopsy after FMX dosing. (A, B) Serial tumor sections from formalin-fixed, paraffin-embedded biopsies of liver lesions were stained for (A) FMX (Prussian blue) and (B) macrophages (CD68). FMX deposition is detectable primarily in vascular-accessible macrophages in stromal areas surrounding tumor lesions.

Supplementary Methods includes additional details on these topics: tumors eligible for dose escalation phase; tumors eligible for dose expansion phase; patients enrolled using a local laboratory; study design and participants; additional inclusion criteria; full list of exclusion criteria; study treatment; study procedures; pharmacodynamic (PD) analysis; inhibition of PBMC PARP activity.

This Supplementary Methods section provides details for assays that allowed elucidation of the pharmacokinetic and pharmacodynamic results described in the Results and Discussion sections of the article. These supplemental methods descriptions are to be published with the manuscript

Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy, determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients with advanced solid tumors. Patients received oral adavosertib qd or bid on a 5/9 schedule (5 days on treatment, 9 days off) in 14-day cycles, or qd on one of two 5/2 schedules (weekly, or for 2 of 3 weeks) in 21-day cycles. Safety, efficacy, and pharmacokinetic analyses were performed. Sixty-two patients (female, 64.5%; median age, 61.5 years; most common primary tumors: lung [24.2%], ovary [21.0%]) received treatment (qd schedules, n = 50; bid schedules, n = 12) for 1.8 months (median). Median time to maximum adavosertib concentration was 2.2–4.1 h; mean half-life was 5–12 h. Adverse events (AEs) caused dose reductions, interruptions and discontinuations in 17 (27.4%), 25 (40.3%) and 4 (6.5%) patients, respectively. Most common grade ≥ 3 AEs were anemia, neutropenia (each n = 9, 14.5%) and diarrhea (n = 8, 12.9%). Seven (11.3%) patients experienced 10 treatment-related serious AEs (pneumonia n = 2 [3.2%], dehydration n = 2 [3.2%], anemia n = 1 [1.6%], febrile neutropenia n = 1 [1.6%], and thrombocytopenia n = 1 [1.6%]). Overall objective response rate was 3.4% (2/58); disease control rate was 48.4% (30/62); median progression-free survival was 2.7 months. MTDs were 125 mg (bid 5/9) and 300 mg (qd 5/9 and 5/2 for 2 of 3 weeks); RP2D was 300 mg (qd 5/2 for 2 of 3 weeks). The safety profile was manageable, acceptable, and generally concordant with the known safety profile.

Supplementary Figure S1. Talazoparib inhibition of PBMC PARP activity.

Supplemental Section for Resubmission - Clean Version