MTAP deletion

CDKN2A homozygous deletions were confirmed in all 5 tested cases by sequencing, whereas MTAP deletions were detected in only 2 cases. In conclusion, p16 expression loss and CDKN2A deletions can be frequently seen in invasive/metastatic cases of EMPD.

Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.

We show that MTAP IHC and molecular assays are complementary in detecting 9p21 homozygous deletion. MTAP IHC may be particularly useful for low tumor purity samples and in low-resource settings.

Fibroblasts exposed to MTA exhibit: i) molecular reprogramming compatible with cancer aggressiveness, ii) a significant production of purine derivatives that could be readily recycled by cancer cells, and iii) the capacity to secrete purine derivatives that induce macrophage polarization. Our study supports the potential of SERS for cancer metabolism research and reveals an unprecedented paracrine crosstalk that explains TME reprogramming in MTAP-deleted cancers.

The selected compound 30 exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile. Furthermore, in an HCT-116 MTAP-deleted xenograft model, compound 30 showed better in vivo potency than current clinical compound AG-270.

P1, N=130, Recruiting, IDEAYA Biosciences | N=382 --> 130

Two patients had deletion of SMARCA4 at diagnosis, that confers resistance to the BCL-2 inhibitor venetoclax (Agarwal et al...Mutations in the NF-κB alternative pathway, responsible for resistance to ibrutinib, are found in both LR and HR patients. ConclusionIn this small cohort of MCL patients included in a trial, complex structural alterations were identified by OGM at the time of diagnosis. OGM is a very promising technology that demonstrated its potential in the cytogenetic prognostic staging of MCL.

Combination MTDIA and AG-270 treatment differs from direct inhibition of PRMT5 by GSK3326595 by avoiding toxicity caused by cell death in the normal gut epithelium induced by the PRMT5 inhibitor. The combination of MTAP and MAT2a inhibitors expands this synthetic lethal approach to include MTAP cancers, especially the remaining 98% of CRCs without the MTAP genotype.

The proliferation effects of MTA-cooperative PRMT5 inhibitors, TNG908 or TNG462, and a SAM-cooperative PRMT5 inhibitor, GSK3326595, on MTAP-deleted and MTAP-intact MPNST cell lines were determined using CellTiter-Glo (CTG) assays. The clinical stage MTA-cooperative PRMT5 inhibitors TNG908 (NCT05275478) and TNG462 (NCT05732831) are efficacious in MPNST models in vitro and in vivo and are therefore promising therapeutic agents for patients with MTAP-deleted MPNST.

In summary, TNG908 is a potent, brain-penetrant, MTA-cooperative PRMT5 inhibitor that drives strong antitumor activity in preclinical models of MTAP-deleted GBM. TNG908 is currently enrolling patients with MTAP-deleted tumors including glioblastoma in a Phase I/II clinical trial (NCT05275478).

In this issue of Cancer Discovery, Engstrom and colleagues report an MTA-cooperative PRMT5 methyltransferase inhibitor MRTX1719 that selectively kills CDKN2A/MTAP-codeleted cancers and demonstrates early efficacy in clinical trials for solid tumors harboring the CDKN2A/MTAP codeletion. See related article by Engstrom et al., p. 2412 (1).

MRTX1719 demonstrated marked anti-tumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and MPNST from the Phase 1/2 study.

Both p16 and MTAP IHC showed high concordance with Oncoscan CNV arrays (kappa = 0.952, p < 0.0001, and kappa = 0.787, p < 0.0001 respectively). We recommend combined MTAP and p16 immunohistochemistry to confirm the diagnosis of PM.

In a phase I trial of the MTA-cooperative PRMT5 inhibitor AMG 193, five of 39 patients with advanced MTAP-deleted solid tumors who had scans following initial treatment experienced partial responses. The responses occurred in five tumor types-esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancer.

P1/2, N=184, Recruiting, Amgen | Not yet recruiting --> Recruiting

No abstract available

P1/2, N=184, Not yet recruiting, Amgen

The most common tyrosine kinase inhibitors used to treat LM were lorlatinib (n=7), alectinib (n=6), and selpercatinib (n=5). We found leptomeningeal metastases in 8% of patients with fusion+ lung cancers, of which the majority developed on treatment. Responses occurred with a switch to another targeted therapy and proton craniospinal irradiation. Median survivals from LM detections ranged from 8 months (ROS1) to 30 months (ALK).

P1, N=123, Terminated, Institut de Recherches Internationales Servier | Completed --> Terminated; Strategic reasons

By binding to and inhibiting PRMT5 cooperatively with MTA, TNG462 leverages the synthetic lethal relationship between MTAP deletion and PRMT5 to selectively kill MTAP-deleted cells with a mean 45-fold selectivity over MTAP-proficient cells. Herein we report on the discovery of TNG462, a potential best-in-class, potent, and selective MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted cancer.

We also show that replication stress is induced upon MAT2A inhibition in 3KO cells, and it is exacerbated when the treatments are combined.ConclusionOur data suggest promising therapeutic strategies for the management of bladder cancer patients with 9p21 loss. Specifically, the 3KO cells are selectively sensitive to multiple agents that could be combined to maximally exploit the vulnerabilities exposed by 9p21 loss.

We indeed present a comprehensive atlas of CRC extreme gene expression outliers which includes events with diagnostic or therapeutic relevance. This resource could also serve as a reference for further discoveries in CRC and other tumour types.

Additionally, we have also tested our system for the monitoring of MTAP deleted tumor dynamics. Finally, to upscale our metabolomics studies to high-throughput modalities, we devised ad hoc microfluidic chips, to readily conduct SERS measurements through a prototype relying on capillary pumps made of filter paper, which eventually would function as the SERS substrates.ConclusionThe developed strategy may pave the way towards a faster implementation of SERS into cell secretome classification, which could be extended even to laboratories lacking highly specialized facilities.

P1/2, N=159, Recruiting, Tango Therapeutics, Inc. | Not yet recruiting --> Recruiting

P1, N=123, Completed, Institut de Recherches Internationales Servier | Active, not recruiting --> Completed

More importantly, introducing an amide motif (28) to the core structure raised the plasma drug exposure from 11 718 to 41 192 ng·h·mL. 28 displayed a significantly better in vivo potency than AG-270, which is being evaluated in clinical trails, and induced -52% tumor regression in a xenograft MTAP-depleted colon tumor model.

MTAP loss in MBC has distinct clinical features with genomic alterations (GA) affecting both targeted and immunotherapies. Further efforts are necessary to identify alternative means of targeting PRMT5 and MTA2 in MTAP-ve cancers to benefit from the high-MTA environment of MTAP-deficient cancers.

MTAP (methyl-adenosine phosphorylase) is an enzyme involved in salvage purine biosynthesis and its deletion confers sensitivity to pemetrexed and taxanes, but resistance to immune checkpoint inhibitors...MTAP wild-type patients had a higher frequency of TERT alterations (p=0.012), but not ERBB2, (p=0.453) than patients with MTAP-deleted type tumors. Ongoing evaluation of timing and location of pathogenic variants will inform where (primary tumor, metastatic site) and when (after chemotherapy, immune checkpoint inhibitors, antibody drug conjugates) to biopsy patients on progression after cancer therapies.

The median overall survival (OS) of GBM patients is poor (1-2 years) on standard of care therapies, which include surgery, radiotherapy, and the alkylating agent temozolomide. As such, TNG908 may provide a novel treatment strategy for MTAP-deleted GBM patients. *MZ and AT contributed equally to the work.

Prioritized strategies were tested in vivo where MRTX1719, in combination with agents inhibiting complementary mechanisms of action, demonstrated enhanced tumor growth inhibition compared to either agent alone, including but not limited to palbociclib (CDK4/6), olaparib (PARP), and Type I PRMT and Bcl-xL inhibitors. Further investigation into potential biomarkers conferring sensitivity or resistance to PRMT5 inhibition was also performed using orthogonal datasets including molecular characterization, differential expression, differential splicing and proteomic analysis. These data suggest MRTX1719, an MTA cooperative PRMT5 inhibitor currently in a Phase I clinical trial (NCT05245500), has the potential to be a synthetically lethal precision medicine for multiple indications harboring MTAP del with high unmet medical need either as a single agent or in combination with clinically feasible rational combination partners.

Synergy between IDE397 and pemetrexed was of particular interest given mechanistic convergence of the methionine salvage and folate cycle pathways on nucleotide synthesis in the context of MTAP-/-. Collectively, these observations indicate that MAT2A inhibition can generate cell states in MTAP-/- tumor cells that are selectively vulnerable to approved chemotherapies and targeted therapies. These synergistic relationships may provide a predictive biomarker strategy for multiple IDE397 synthetic lethal combination therapies.

We noted synergistic antiproliferative effects when the potent and selective MAT2A inhibitor IDE397 was combined with any of multiple MTA-cooperative PRMT5 inhibitors in MTAPdel cell lines that exhibit sensitivity to each single agent...The potentiation of the antitumor response with the combination did not occur in the MTAPWT setting. Thus, combined inhibition of MAT2A and PRMT5 potentially offers a compelling dual synthetic lethal opportunity to address unmet need for the many patients afflicted with MTAPdel cancers.

P1/2, N=159, Not yet recruiting, Tango Therapeutics, Inc.

We describe herein the clinical and pathologic features of patients with an emerging subtype of bladder cancer characterized by deletion of the gene MTAP encoding the enzyme S-Methyl-5'-thioadenosine phosphatase, a potential biomarker of response to pemetrexed...Covariates did not impact significantly overall survival on propensity score matching. In conclusion, MTAP -del occurs in approximately 30% of patients with advanced urothelial carcinoma and defines a subgroup of patients with aggressive features, such as squamous differentiation, frequent bone metastases, poor response to chemotherapy, and shorter time to progression to metastatic disease.

P1/2, N=0, Withdrawn, Institut de Recherches Internationales Servier | N=105 --> 0 | Initiation date: Aug 2022 --> May 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2025 --> Jun 2026

In recent years, several PRMT5 inhibitors have entered clinical trials for the treatment of various cancers, such as advanced or recurrent solid tumors with MTAP deletion. Herein, we reviewed the binding modes and structure-activity relationships of novel PRMT5 inhibitors and discussed prospects of PRMT5 inhibitors in cancer therapy, aiming to provide insights on drug development of PRMT5 inhibitors.