WHO5 genomic classification identified subtype-defining abnormalities in 81.2% of 533 pediatric B-ALL patients treated on the ICiCLe-ALL-14 protocol, and a three-tier genomic risk model separated outcomes: 3-year EFS of 80.4%, 59.3%, and 45.8% for standard, intermediate, and high genomic risk (P < .0001). Genomic risk independently predicted EFS alongside postinduction MRD and ICiCLe risk on multivariable analysis, showing genomics can complement MRD-directed risk stratification.
A pivotal trial of Bristol Myers Squibb's GPRC5D-directed CAR-T cell therapy in multiple myeloma has met its primary endpoint. The result advances Bristol Myers Squibb's effort to compete with Johnson & Johnson for the post-BCMA multiple myeloma market. No outcome figures were disclosed in the announcement.
FDA approval of Rasonque, Revolution Medicines' pancreatic cancer drug that nearly doubles median overall survival, closed the company's expanded access program, leaving patients mid-process without coverage. Commercial insurers like Aetna and Medicare Part D plans take weeks or months to set up coverage, with one Medicare denial reversed only after OptumRx approved prior authorization. Patients such as Juan Solano, who has metastatic disease, remain caught in the gap.
Thioredoxin reductase 1 (TXNRD1), expressed about 2-fold higher in advanced-stage NSCLC, drives epithelial-mesenchymal transition, migration, invasion, and stemness through an autocrine TGF-β1 loop. Knockdown of TXNRD1 reduced EMT-associated genes and TGF-β1 production in A549 and H226 cells, while overexpression raised EMT and stemness markers in H1299 cells. In an orthotopic mouse model, TXNRD1 deficiency or inhibition with TRi-1 suppressed metastatic tumor growth.
BrainChild Bio has completed a $116 million series A round to advance its CAR-T cell therapy for pediatric brain tumors into pivotal trials. The company was spun out of Seattle Children's Hospital and focuses on developing cell therapies for deadly childhood brain tumors.
Why it matters: A large series A for CAR-T in pediatric brain tumors, comparable with Seattle Children's early clinical data and similar pediatric cell therapy programs, helps gauge the pace of further development.
First-line osimertinib plus chemotherapy extended median progression-free survival to 34.0 months versus 15.6 months with osimertinib alone in treatment-naive advanced NSCLC patients with EGFR-sensitizing mutations and concurrent TP53 mutations, cutting the risk of progression or death by 56% (HR=0.44). The randomized phase 3 trial, led by researchers at Sun Yat-sen University Cancer Center and published in JAMA, is described as the first prospective trial dedicated to this co-mutated population, giving clinicians a biomarker-defined basis for adding chemotherapy to osimertinib.
The FDA granted accelerated approval to AstraZeneca's Etcamah (camizestrant) combined with a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) for adults with HR-positive, HER2-negative locally advanced or metastatic breast cancer whose ESR1 mutations were detected during aromatase inhibitor and CDK4/6 inhibitor therapy. The FDA also approved a companion diagnostic for detecting emerging ESR1 resistance mutations in ctDNA. The approval rests on positive results from the pivotal Phase III SERENA-6 study.
p53 loss causes hypertranscription that drains nucleotide pools, and the resulting nucleotide shortage induces replication stress, telomere dysfunction, micronuclei formation, and chromothripsis in p53-depleted epithelial cells and fibroblasts, including patient-derived fibroblasts with germline p53 variants. Nucleoside supplementation or normalization of transcription levels rescued these effects, establishing a causal link between transcription, nucleotide availability, and genome stability, and identifying nucleotide pool homeostasis as a critical p53 function protecting against early tumorigenesis.
Adding induction and consolidation atezolizumab to stereotactic body radiation therapy did not improve overall survival in patients with high-risk, inoperable, early-stage non-small-cell lung cancer in the SWOG/NRG S1914 phase 3 randomised trial. This was the first fully reported phase 3 cooperative group trial of immunotherapy in this setting, and the combination produced more grade 3 or higher adverse events than radiation alone. The results argue against adding atezolizumab to SBRT in this population.
CD55, classically a complement regulator, acts as an immune activator in NK cells: after tumor recognition NK cells upregulate CD55, which binds CD97 on tumor cells, promotes lipid raft clustering and activates LCK signaling to strengthen antitumor killing. The work, published in Cell Research by a team from the First Hospital of Jilin University, also shows sustained loss of CD55 in the tumor microenvironment drives NK cell exhaustion, and restoring CD55 markedly enhances antitumor activity of NK and CAR-NK cells.
A single 2 Gy fraction of carbon ion irradiation provokes antitumor immunity by switching cell death from apoptosis to MLKL-dependent necroptosis, surpassing 8 Gy x-rays in immunogenicity despite lower direct tumor cell killing. Multi-omics analyses trace the switch to clustered DNA damage-driven super-enhancer remodeling that suppresses cIAP1/2-caspase-8-mediated apoptosis and licenses an NF-κB inflammatory cascade (IL1A/B, CXCL1/2/3). In vivo, 2 Gy CIRT drives an abscopal response with increased CD8+ T cell infiltration and function, and MLKL inhibition abolishes these effects.
Why it matters: A clinically used 2 Gy carbon ion dose converts local irradiation into systemic antitumor immunity, informing radio-immunotherapy design.
Pyroptosis-associated long non-coding RNAs can stratify breast cancer patients into risk groups with significantly different survival outcomes, based on transcriptomic analyses. Low-risk tumors show increased infiltration of CD8+ T cells, NK cells, and B cells with elevated immune checkpoint expression, while high-risk tumors show M2 macrophage enrichment and higher tumor mutation burden. Mechanistically, these lncRNAs act through inflammasome activation, gasdermin-mediated signaling, and epigenetic modulation, marking them as candidate prognostic biomarkers and therapeutic targets.
The complete biosynthetic pathways of cephalotaxinone and homoerythratine, alkaloids from endangered Cephalotaxus species related to the leukemia drug homoharringtonine, have been identified using multi-omics analysis and synthetic standards. Two highly homologous P450 enzymes, CfCYP2 and CfCYP3, catalyze a rare divergent oxidation yielding two structurally distinct alkaloids, and key residues controlling this divergence were pinpointed. Both pathways were reconstituted in N. benthamiana, opening a route to production independent of limited natural resources.
A 22-year-old woman's approximately 10 cm fungating, ulcerated breast mass, complicated by methicillin-resistant Staphylococcus aureus infection, was confirmed after enucleation to be a giant fibroadenoma with multiple epidermal inclusion cysts, not malignancy. Multiple core biopsies had shown fibroadenoma despite rapid progression. The breast-preserving surgery spared the nipple-areolar complex, and at six months there was no clinical or ultrasonographic recurrence.
Benchmarking of methods for computing UV-Vis absorption spectra of a Pt(II) pincer complex, alone and intercalated in a small DNA model, shows that the Tamm-Dancoff approximation and resolution-of-identity approximations speed up TD-DFT considerably at only a modest accuracy cost. PBEh-3c geometry optimization matches conventional DFT efficiency gains with errors comparable to TDA, while GFN-xTB is faster but less accurate; the exchange-correlation functional, with PBE0 performing well, is the largest uncertainty. The work supplies a computational protocol for screening luminescent transition metal probes that target DNA abnormalities.
Excess intracellular lactate represses mRNA translation because alanyl-tRNA synthetase 1 charges tRNAs with lactate instead of amino acids; slower lactyl transfer than alanine transfer modifies non-cognate tRNAs and broadly compromises elongation fidelity. Aggressive tumors elevate lactate transporters to limit intracellular lactate and evade this repression. Pharmacological blockade of monocarboxylate transporters restored lactate accumulation, re-established translational repression, and impaired tumor progression in mice.
Liver resection after response to atezolizumab plus bevacizumab prolonged time to treatment failure in advanced hepatocellular carcinoma with macrovascular invasion and no extrahepatic metastasis. In the phase 3 TALENTOP trial, 201 responders were randomised to surgery plus 12 months of the combination or maintenance therapy; median time to treatment failure was 20·4 versus 11·8 months (hazard ratio 0·60, p=0·015). Grade 3 or 4 treatment-related adverse events were more frequent with surgery (39% vs 21%).
The FDA granted accelerated approval to AstraZeneca's Etcamah (camizestrant), an oral tablet, combined with a CDK4/6 inhibitor (abemaciclib, palbociclib or ribociclib) for adults with HR-positive, HER2-negative locally advanced or metastatic breast cancer whose tumors show an ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor therapy, detected by the FDA-authorized Guardant360 CDx companion diagnostic. In the pivotal trial, estimated median progression-free survival was 16 months versus 9.2 months for continuing an aromatase inhibitor plus a CDK4/6 inhibitor. The label carries a boxed warning for irregular heart rhythm, and confirmatory trials are required to verify clinical benefit.
A UC Berkeley team led by Ziyang Zhang reports a strategy to reactivate GTP hydrolysis in KRAS-Q61 mutants rather than inhibit KRAS. Brønsted-basic small molecules deliver a basic group to the catalytic site to substitute for the mutated glutamine 61 residue, restoring hydrolysis and driving KRAS inactivation. The work appears in Nature Chemical Biology.
Ivonescimab, Akeso's PD-1/VEGF bispecific antibody, has beaten pembrolizumab on overall survival in the phase 3 HARMONi-2 trial, according to a company announcement on September 3. The predefined OS interim analysis passed review by the independent data monitoring committee, showing statistical significance and clinical benefit. Ivonescimab is the first bispecific antibody to outperform a PD-1 monoclonal antibody on OS in a phase 3 trial, in first-line PD-L1-positive (TPS ≥1%) locally advanced or metastatic NSCLC.
