Tazemetostat for tumors harboring SMARCB1/SMARCA4 or EZH2 alterations: results from NCI-COG pediatric MATCH APEC1621C

JNCI Journal of the National Cancer Institute, Journal Year: 2023, Volume and Issue: 115(11), P. 1355 - 1363

Published: May 25, 2023

Abstract Background National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors, brain lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss SMARCB1 SMARCA4 by immunohistochemistry were treated inhibitor tazemetostat. Methods received tazemetostat 28-day cycles until disease progression intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival tolerability Results Twenty (median age = 5 years) enrolled, all evaluable toxicities. most frequent diagnoses atypical teratoid rhabdoid tumor (n 8) malignant 4). Actionable alterations consisted 16), mutation 3), 1). One observed in a patient non-Langerhans cell histiocytosis (26 cycles, 1200 mg/m2/dose twice daily). Four had best stable disease: epithelioid sarcoma 2), 1), renal medullary carcinoma Six-month 35% (95% confidence interval [CI] 15.7% 55.2%) 6-month overall 45% CI 23.1% 64.7%). Treatment-related adverse events consistent prior reports. Conclusions Although did not meet its efficacy this population pediatric (objective rate 5%, 90% 1% 20%), 25% multiple histologic experienced prolonged 6 months over (range 9-26 cycles), suggesting potential effect stabilization.

Language: Английский

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Novel clinical trial designs emerging from the molecular reclassification of cancer

CA A Cancer Journal for Clinicians, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Abstract Next‐generation sequencing has revealed the disruptive reality that advanced/metastatic cancers have complex and individually distinct genomic landscapes, necessitating a rethinking of treatment strategies clinical trial designs. Indeed, molecular reclassification cancer suggests it is underpinnings disease, rather than tissue origin, mostly drives outcomes. Consequently, oncology trials evolved from standard phase 1, 2, 3 tissue‐specific studies; to tissue‐specific, biomarker‐driven trials; tissue‐agnostic untethered histology (all drug‐centered designs ); and, ultimately, patient‐centered , N‐of‐1 precision medicine studies in which each patient receives personalized, biomarker‐matched therapy/combination drugs. Innovative technologies beyond genomics, including those address transcriptomics, immunomics, proteomics, functional impact, epigenetic changes, metabolomics, are enabling further refinement customization therapy. Decentralized potential improve access approaches for underserved minorities. Evaluation real‐world data, assessment patient‐reported outcomes, use registry protocols, interrogation exceptional responders, exploitation synthetic arms all contributed personalized therapeutic approaches. With greater 1 × 10 12 patterns alterations 4.5 million possible three‐drug combinations, deployment artificial intelligence/machine learning may be necessary optimization individual therapy near future, also permit discovery new treatments real time.

Language: Английский

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Successful treatment of non-Langerhans cell histiocytosis with the MEK inhibitor trametinib: a multicenter analysis

Blood Advances, Journal Year: 2023, Volume and Issue: 7(15), P. 3984 - 3992

Published: March 1, 2023

Abstract Erdheim-Chester disease (ECD) and Rosai-Dorfman (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark correlates with favorable response to BRAF inhibitors the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative inhibitors. To assess efficacy safety trametinib, we retrospectively analyzed outcomes 26 adult patients (17 ECD, 5 ECD/RDD, 3 RDD, 1 ECD/LCH) treated orally administered trametinib at 4 major US care centers. The most common treatment-related toxicity was rash (27% patients). In patients, effectively managed low doses (0.5-1.0 mg daily). rate 17 evaluable 71% (73% [8/11] without detectable achieving response). At median follow-up 23 months, treatment effects were durable, time-to-treatment failure 37 whereas progression-free overall survival not reached (at years, 90.1% alive). Most harbored mutations in (either classic alterations) genes involved pathway, eg, MAP2K, NF1, GNAS, RAS. required lower than standard but responsive doses. Our data suggest that an effective ECD including those mutation.

Language: Английский

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Discovering potential ERK1 inhibitors from natural products for therapeutic targeting of Alzheimer's disease

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Background Extracellular signal-regulated kinase 1 (ERK1) belongs to mitogen-activated protein kinases, which are essential for memory formation, cognitive function, and synaptic plasticity. During Alzheimer's disease (AD), ERK1 phosphorylates tau at 15 phosphorylation sites, leading the formation of neurofibrillary tangles. The overactivation in microglia promotes release pro-inflammatory cytokines, results neuroinflammation. Additionally, elevated oxidative stress during AD stimulates pathway, neuronal loss. Objective Because signaling plays a significant role phosphorylation, targeting may be therapeutically beneficial by either preventing excessive activation pathway or altering its enhance neuroprotective effects AD. Methods This study employed structure-based virtual screening phytoconstituents from IMPPAT library. Subsequently, in-depth docking molecular dynamics (MD) simulation studies were implemented identify potential inhibitors with desirable pharmacological properties. Results Silandrin Hydroxytuberosone found higher affinity specificity than control molecule Tizaterkib. These compounds specifically bind substrate binding pocket interact crucial residues. Finally, elucidated evaluated using an all-atom MD analyze structural dynamics, compactness, hydrogen bond principal component analysis, free energy landscape. Conclusions suggested that can further exploited as lead molecules therapeutic development against ERK1-mediated

Language: Английский

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MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 27, 2023

Abstract Pediatric low-grade gliomas (pLGG) show heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. Thus, more complex stratification biomarkers are needed identify patients likely benefit from MAPKi therapy. Here, we MAPK-related genes enriched MAPKi-sensitive cell lines using the GDSC dataset and apply them calculate class-specific sensitivity scores (MSSs) via single-sample gene set enrichment analysis. The MSSs discriminate non-sensitive cells significantly correlate with response an independent PDX dataset. discern varying alterations higher pLGG compared other pediatric CNS tumors. Heterogenous within pLGGs same alteration proportions of potentially sensitive patients. MEKi MSS predicts treatment a small treated trametinib. High immune infiltration, high expression microglia compartment single-cell RNA sequencing data, while low infiltration increased neuronal score. represent predictive tools for should be prospectively validated Our data supports role MAPKi.

Language: Английский

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Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial

Genome Medicine, Journal Year: 2024, Volume and Issue: 16(1)

Published: Feb. 12, 2024

Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic transcriptomic profiling tumor samples a molecular board (MTB) approach to make real‑time treatment decisions for children relapsed/refractory tumors. Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; 2-relapsed/refractory CNS tumors; 3-relapsed/refractory Tumor sent tumor/normal whole-exome (WES) whole-transcriptome (WTS) sequencing, data used in multi-institutional MTB decisions. The recommended plan allowed combination up 4 agents. Feasibility was measured by time completion review initiation treatment. Response assessed after every two cycles using Evaluation Criteria Solid Tumors (RECIST). Patient benefit calculated sum CR, PR, SD, NED subjects complete response (CR), partial (PR), stable disease (SD), no evidence (NED), progressive (PD) subjects. Grade 3 higher related unexpected adverse events (AEs) tabulated safety evaluation. A total 186 eligible patients enrolled 144 evaluable 124 response. average number days from biopsy MTB-recommended therapy 38 days. exhibited 65% all subjects, 67% neuroblastoma 73% 60% There little associated toxicity above that expected MGT drugs during this trial, suggestive utilizing method selecting targeted therapy. demonstrated feasibility, safety, efficacy comprehensive sequencing model guide personalized any malignancy. Personalized well tolerated, rate these heavily pretreated populations suggests strategy could be an effective option refractory pediatric cancers. ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.

Language: Английский

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Outcome of Children and Adolescents With Relapsed/Refractory/Progressive Malignancies Treated With Molecularly Informed Targeted Drugs in the Pediatric Precision Oncology Registry INFORM

JCO Precision Oncology, Journal Year: 2023, Volume and Issue: 7

Published: June 26, 2023

INFORM is an international pediatric precision oncology registry, prospectively collecting molecular and clinical data of children with recurrent, progressive, or very high-risk malignancies. We have previously identified a subgroup patients improved outcomes on the basis profiling. The present analysis systematically investigates progression-free survival (PFS) overall (OS) receiving matching targeted treatment (MTT) most frequently applied drug classes its correlation underlying alterations.A cohort 519 relapsed refractory malignancies who had completed follow-up at least 2 years shorter in case death loss to was analyzed. Survival times were compared using log-rank test.MTT anaplastic lymphoma kinase (ALK), neurotrophic tyrosine receptor (NTRK), B-RAF (BRAF) inhibitors showed significantly PFS (P = .012) OS .036) comparison conventional no treatment. However, four commonly MTT groups, mitogen-activated protein (MEK- n 19), cyclin-dependent (CDK- 23), other (n 62), mammalian-target rapamycin (mTOR- 20) inhibitors, did not reveal differences similar pathway alterations. observe type alterations (eg, copy number alterations, single-nucleotide variants, InDels, gene fusions) addressed by MTT.Patients respective benefit from ALK, NTRK, BRAF as described. No observed for mutations MEK, CDK, kinase, mTOR signaling pathways. noninterventional character registry has be taken into account when interpreting these underlines need innovative interventional biomarker-driven trials oncology.

Language: Английский

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Neuroblastoma in the Era of Precision Medicine: A Clinical Review

Cancers, Journal Year: 2023, Volume and Issue: 15(19), P. 4722 - 4722

Published: Sept. 26, 2023

The latest advances in treatment for patients with neuroblastoma are constantly being incorporated into clinical trials and practice standards, resulting incremental improvements the survival of over time. Survivors high-risk (HRNBL), however, continue to develop treatment-related late effects. Additionally, majority nearly 50% HRNBL who experience relapse, no curative therapy currently exists. As technologies diagnostic molecular profiling techniques rapidly advance, so does discovery potential targets. Here, we discuss current landscape therapies era precision medicine.

Language: Английский

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Heterogeneity in precision oncology

Cambridge Prisms Precision Medicine, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 37

Published: Oct. 5, 2023

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Language: Английский

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Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents

Journal of Clinical Oncology, Journal Year: 2023, Volume and Issue: 41(18), P. 3408 - 3422

Published: April 4, 2023

There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy most diseases may overcome resistance mechanisms increase synergy. The process these trials needs maximize efficiency should agreed by all stakeholders.

Language: Английский

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