MTAP deletion

Drugs targeting MTAP-deficiency may be useful in urothelial bladder carcinoma. MTAP IHC is a near perfect surrogate for MTAP deficiency in this tumor type.

P1/2, N=225, Recruiting, Tango Therapeutics, Inc. | N=159 --> 225

No abstract available

P1/2, N=192, Active, not recruiting, Tango Therapeutics, Inc. | Recruiting --> Active, not recruiting

Conclusion : We showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.

MTAP deletions are common in the MoST/CaSP population, most frequently in CNS, pancreas, lung and melanoma patients. Detection of MTAP deletion was higher with the FM1&A paltform. MTAP deletions co-existed with CDKN2A deletions in >80% of the cohort.

P1/2, N=184, Recruiting, Amgen | Trial completion date: Dec 2026 --> Sep 2027

P1/2, N=184, Recruiting, Amgen | Trial completion date: Aug 2026 --> Dec 2026 | Trial primary completion date: Nov 2025 --> Mar 2026

Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of MTAP-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.

AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on ORR and ctDNA clearance.

AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.

We showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible in clinical practice. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.

We infer that these pathway-wide perturbations represent adaptive responses to SAM depletion and confer a risk of oxidative stress, hepatic steatosis and an associated disturbance in plasma and cellular lipid homeostasis. The alterations also explain the dramatic increase in plasma and tissue methionine, which could be used as a safety and PD biomarker going forward to the clinic.

P1, N=180, Recruiting, IDEAYA Biosciences | N=130 --> 180 | Trial completion date: Jun 2024 --> Mar 2027 | Trial primary completion date: Dec 2023 --> Dec 2026

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.