Phase I trial findings indicate that two different personalized vaccine strategies, DNA-based GNOS-PV01 and peptide-based NeoVax, may be promising strategies for patients with glioblastoma. Notably, the former is effecti...Phase I trial findings indicate that two different personalized vaccine strategies, DNA-based GNOS-PV01 and peptide-based NeoVax, may be promising strategies for patients with glioblastoma. Notably, the former is effective against MGMT-unmethylated glioblastoma, a subtype for which the prognosis is particularly poor.
Tolmeijer SH, Maurice-Dror C, Sandhu S
… +30 more, de la Calle CM, Kollmannsberger C, Adil M, Wang CK, Murtha AJ, Donnellan G, van Erp NP, Mehra N, Hofman MS, Azad AA, Davis ID, Bergman AM, Zwart W, van der Zande K, Seymour L, Black PC, Akbari V, Cordova L, Lansdorp PM, Jones SJ, Nelson PS, Castro E, Schrader KA, Ha G, Cheng HH, Ost P, Olmos D, Chi KN, Pritchard CC, Wyatt AW
CDK12 mutations occur in 2-7% of metastatic prostate cancers (mPCa) and are considered to be exclusively somatic. Here, we identified five patients with mPCa (ages 44-62) harboring germline CDK12 truncating variants amon...CDK12 mutations occur in 2-7% of metastatic prostate cancers (mPCa) and are considered to be exclusively somatic. Here, we identified five patients with mPCa (ages 44-62) harboring germline CDK12 truncating variants among 4,535 tested (0.1%). All had CDK12-driven cancers defined by an additional somatic CDK12 variant and the CDK12-specific hallmark genomic instability signature characterized by hundreds of tandem duplications. Two patients had multiple independent CDK12-driven tumors with distinct secondary somatic CDK12 variants. Germline CDK12 truncating variants were enriched in mPCa compared to gnomAD V4.1.0 controls (n=807,162; odds ratio 11.4, 95% CI 3.6-27.8) and V2.1.1 non-cancer controls (n=134,187; odds ratio 29.6; 95% CI 6.8-28.6). Family history revealed multiple related individuals with prostate or ovarian cancer, and germline variant inheritance was confirmed in the two tested pedigrees. Our data suggest that germline CDK12 truncating variants are a rare driver of lethal mPCa.
AJ1-11095, a type II JAK2 inhibitor being developed for myelofibrosis, led to impressive clinical responses in a recent phase I study, suggesting that the drug, and perhaps the rest of its still-investigational class, co...AJ1-11095, a type II JAK2 inhibitor being developed for myelofibrosis, led to impressive clinical responses in a recent phase I study, suggesting that the drug, and perhaps the rest of its still-investigational class, could prove better than currently approved type I JAK2 inhibitors.
Balogun FO, Sherman MH, Park W
… +6 more, Soares KC, Reyngold M, Schoenfeld JD, Singhal A, Iacobuzio-Donahue CA, O'Reilly EM
Cancer Discov
· 2026 Jul · PMID 42381464
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UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers and has a very poor prognosis. Ten to 15% are staged as resectable at diagnosis, and 5% to 15% downstaged with therapy to where s...UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers and has a very poor prognosis. Ten to 15% are staged as resectable at diagnosis, and 5% to 15% downstaged with therapy to where surgery is feasible. Chemotherapy is a mainstay for all stages of PDAC. Targeted therapies are available for patients with select but expanding actionable genomic alterations. The tumor microenvironment provides a dense stroma with an immunosuppressive milieu that contributes to inherent treatment resistance of PDAC. Herein, we review current management of PDAC with a focus on emerging treatment paradigms, including targeted and immunomodulatory agents. SIGNIFICANCE: PDAC is a complex disease with unique genomic, immunologic, and clinical features. Recent developments in understanding of the pathobiology of this disease are translating into targeted and immunomodulatory therapies that will alter treatment paradigms and improve outcomes for this recalcitrant malignancy.
Biomolecular condensates formed via phase separation are emerging targets for pharmacologic or genetic manipulation for cancer therapy. In this commentary, we envisage that further deciphering the composition and the phy...Biomolecular condensates formed via phase separation are emerging targets for pharmacologic or genetic manipulation for cancer therapy. In this commentary, we envisage that further deciphering the composition and the physicochemical properties of oncogenic condensates will provide unprecedented opportunities to develop novel strategies for cancer chemotherapy and immunotherapy.
Clusmann and colleagues developed PRE-Screen-HCC, an interpretable machine learning framework that leverages multimodal clinical data from 2 population-scale cohorts to stratify hepatocellular carcinoma risk, significant...Clusmann and colleagues developed PRE-Screen-HCC, an interpretable machine learning framework that leverages multimodal clinical data from 2 population-scale cohorts to stratify hepatocellular carcinoma risk, significantly outperforming existing risk scores and demonstrating robustness across diverse ethnic subgroups. See related article by Clusmann et al., p. 1304.
Min, Schweizer, and colleagues use artificial intelligence-powered deep visual proteomics to generate a spatial proteomic atlas of pancreatic cancer precursor evolution, revealing that major metabolic and inflammatory re...Min, Schweizer, and colleagues use artificial intelligence-powered deep visual proteomics to generate a spatial proteomic atlas of pancreatic cancer precursor evolution, revealing that major metabolic and inflammatory reprogramming occurs long before overt histologic transformation. More broadly, the study highlights the emerging potential of spatial proteomics and multiomics to bridge histopathology with molecular pathology and precision oncology. See related article by Min et al., p. 1323.
Cancer Discov
· 2026 Jun · PMID 42363683
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According to two phase I/II trials, ASCERTAIN-V and SAVE, the all-oral regimen of decitabine-cedazuridine and venetoclax, with revumenib added in the latter study, could be an effective option for patients with acute mye...According to two phase I/II trials, ASCERTAIN-V and SAVE, the all-oral regimen of decitabine-cedazuridine and venetoclax, with revumenib added in the latter study, could be an effective option for patients with acute myeloid leukemia who would otherwise receive intravenous or subcutaneous chemotherapy.
Liu H, Jang JH, Peng F
… +29 more, Rajaei H, Chandra V, Li L, Rupani DN, Taghinezhadsaroukalaei S, Zhao Y, Faraoni EY, Bartelli TF, Le Roux O, Tahan V, Jimenez-Arancon F, Baydogan S, Mohseni AH, Gomez JA, Patel M, Burks JK, Miño Galvez B, Carvajal-Hausdorf DE, Ruiz-García E, Fernandez-Figueroa EA, Kopetz S, Maron SB, Cercek A, Riquelme EM, Navin NE, White JR, Wang L, Diaz LA, McAllister F
Cancer Discov
· 2026 Jun · PMID 42360233
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Tumor microbes are increasingly recognized for modulating tumor behavior and therapy responses. Intratumoral microbial burden (ITMB) analysis across cancers revealed regulation of immune pathways, and activated mast cell...Tumor microbes are increasingly recognized for modulating tumor behavior and therapy responses. Intratumoral microbial burden (ITMB) analysis across cancers revealed regulation of immune pathways, and activated mast cells, mostly in colorectal (CRC) and gastric (STAD) cancers. High ITMB CRC leads to interferon regulation and is associated with improved outcomes in advanced disease. Single-cell sequencing revealed induction of interferon-related genes (IRGs) within microbes-containing human CRC. GI-luminal mismatch repair deficiency (MMRd) tumors had higher ITMB than proficient tumors (MMRp). In a rectal MMRd cohort with 100% remission after immune checkpoint blockade (ICB), tumor microbes and microbes-containing mast cells increased. In ICB-sensitive syngeneic murine MMRd tumor models, local tumor microbial depletion, impaired ICB efficacy while downregulating IFN signaling. Forced upregulation of IRGs in ADAR1-deficient cancer cells restored immunotherapy responses during microbial ablation. These data highlight dynamic interplay between ITMB, host defense, and immunogenicity which seems key to determine therapy responses.
Huang J, Chen Y, Deng P
… +14 more, Kong Q, Lin K, Li Y, Li Y, Fu C, Deng W, Xv J, Wei B, Kuang DM, Cai J, Jin J, Tian R, Lu Y, Su S
Cancer Discov
· 2026 Jun · PMID 42339989
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Tertiary lymphoid structures (TLSs) are associated with the efficacy of various oncological therapies. However, the comprehensive spatial TLS pharmacodynamics are largely unclear. Here, we performed multifaceted spatial...Tertiary lymphoid structures (TLSs) are associated with the efficacy of various oncological therapies. However, the comprehensive spatial TLS pharmacodynamics are largely unclear. Here, we performed multifaceted spatial transcriptomic analysis with whole-transcriptome coverage and single-cell resolution, complemented by the high-throughput spatial proteomics, to thoroughly characterize TLSs in clinical breast cancer samples after neoadjuvant therapy. Notably, spatial multi-omics data identified that precursors of exhausted T cells (Tpex cells) preferentially reside within TLSs. Spatial transcriptomics with TCR-seq revealed the presence of tumor-specific Tpex cells inside TLSs and their clonally related terminally differentiated effector T cells outside TLSs. B cells are nearest neighbors of Tpex cells in TLSs and B cells promote invigoration of Tpex cells via ICOSL-ICOS and CD86-CD28 interactions within TLSs. These findings extend the current understanding of TLS spatial architecture and highlight a therapy-induced evolution of anti-tumor immune responses driven by the interaction between Tpex cells and B cells within TLSs.
Cancer Discov
· 2026 Jun · PMID 42333443
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RNA-triggered chromatin shredding may offer a new way to attack cancers driven by mutations that have resisted conventional drugs, two new studies show. In mouse models, upon activation by a target transcript, the CRISPR...RNA-triggered chromatin shredding may offer a new way to attack cancers driven by mutations that have resisted conventional drugs, two new studies show. In mouse models, upon activation by a target transcript, the CRISPR enzyme Cas12a2 can selectively eliminate tumor cells carrying mutations in TP53, MYC, and other hard-to-drug cancer genes.
Jee J, Zhang J, Lavery JA
… +7 more, Waters M, Fong CJ, Minn AJ, Glickman MS, Panageas KS, Sawyers CL, Schultz N
Cancer Discov
· 2026 Jun · PMID 42330421
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Real-world data suggest that SARS-CoV-2 mRNA vaccines, administered within 100 days of immune checkpoint inhibitor (ICI) treatment ("peri-ICI vaccination"), may improve ICI effectiveness through synergistic immune primin...Real-world data suggest that SARS-CoV-2 mRNA vaccines, administered within 100 days of immune checkpoint inhibitor (ICI) treatment ("peri-ICI vaccination"), may improve ICI effectiveness through synergistic immune priming. In an independent real-world cohort and re-analysis of a published cohort, both from tertiary cancer centers in the USA, multiple analyses did not support a treatment-synergy hypothesis. Applying a prior analytic framework, although longer survival with peri-ICI vaccination was observed at the start of the pandemic, this association was not seen in periods when vaccination was broadly available. Longer survival with vaccination in the early pandemic was also not specific to ICI therapies. Progression-free survival during periods of high vaccine uptake was not longer than in pre-vaccination periods. Together, these findings indicate that the previously reported vaccination survival advantage is largely explained by selection bias, with patients who had more favorable prognoses more likely to receive SARS-CoV-2 vaccination, particularly in the early pandemic.
McDaid WJ, Adderley H, d'Arienzo PD
… +30 more, Parreira AS, Woodhouse LC, Zhuang Y, Castillo-Lluva S, Tinsley KL, Cooksedge J, Baker MJ, Searle J, Brown KD, Carter M, Aldea M, Marinello A, Aredo JV, Gomez Serra N, Bisbe M, East P, de Carné Trécesson S, Barlesi F, Wislez M, Besse B, Wakelee HA, Nadal E, Blackhall F, Wedge DC, Holderfield M, Smith JAM, Singh M, Seamon KJ, Malliri A, Lindsay CR
Cancer Discov
· 2026 Jun · PMID 42329102
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Direct inhibitors of KRASG12C are now used as standard-of-care therapy in KRASG12C-mutant non-small cell lung cancer (NSCLC), but less is understood about the molecular mechanisms and consequent treatment vulnerabilities...Direct inhibitors of KRASG12C are now used as standard-of-care therapy in KRASG12C-mutant non-small cell lung cancer (NSCLC), but less is understood about the molecular mechanisms and consequent treatment vulnerabilities of KRAS codon 13 mutations in this setting. Here we characterized tumorigenic properties of NSCLC harboring KRASG13X in a large multi-national cohort of NSCLC patients and in preclinical models of KRASG13X NSCLC. Induction of KRASG13C or KRASG13D expression confers reduced oncopotency compared to allele-specific controls affecting KRAS codon 12, particularly KRASG13C. We identified functionally relevant co-mutations in KRASG13X NSCLC, including KEAP1, STK11, BRAF and NF1. The novel RAS(ON) G13C-selective inhibitor, RMC-8839, reduces viability in a panel of KRASG13C NSCLC cell models. To determine combination partners that enhance RAS(ON) mutant-selective inhibition, a drug repurposing screen revealed that KRASG13C models are selectively vulnerable to chemotherapy. Combination of docetaxel with RMC-8839 demonstrated robust anti-proliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo.
Scaparone P, Mira A, Cheong TC
… +19 more, Patrucco E, Ricciuti B, Gribaudo R, Garbo E, Scardaci R, Savinelli I, Vietti Michelina S, Odintsov I, Brea EJ, Mignacco R, Blasco RB, Santamaría D, Voena C, Hofmann MH, Nadal E, Novello S, Awad MM, Chiarle R, Ambrogio C
Cancer Discov
· 2026 Jun · PMID 42329099
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KRAS mutations are common oncogenic drivers in human cancers, with the KRASG12C variant being a key target in lung adenocarcinoma (LUAD). Despite the FDA approval of KRASG12C-selective inhibitors, their clinical efficacy...KRAS mutations are common oncogenic drivers in human cancers, with the KRASG12C variant being a key target in lung adenocarcinoma (LUAD). Despite the FDA approval of KRASG12C-selective inhibitors, their clinical efficacy has been limited, as evidenced by trials showing modest response rates and resistance development through the selection of acquired genomic alterations. Our study explores the mechanisms underlying acquired EML4-ALK fusion in KRASG12C-driven tumors developing resistance to KRASG12C inhibitors and potential therapeutic strategies to overcome it. Our findings reveal that combined ALK/KRASG12C inhibition is an effective therapeutic approach in this context. Moreover, we observed that KRASG12C/EML4-ALK tumor cells kept under constant pressure with KRASG12C inhibitors exhibit sensitivity to single-agent ALK inhibitors, suggesting a potential for rationally designed sequential treatments. Mechanistically, EML4-ALK bypasses KRASG12C inhibition by activating wild-type RAS, highlighting an additional therapeutic opportunity for multi-selective RAS inhibitors under clinical investigation.
Seamon KJ, Zhuang Y, Yang YC
… +19 more, Chakraborty S, Cregg J, Tomlinson ACA, Gould A, Ahler E, Maldonato BJ, Spradlin JN, Pota K, Weller C, Marquez A, Wang Z, Koltun ES, Knox JE, Gill AL, Smith JAM, Singh M, Jiang J, Wildes D, Holderfield M
Cancer Discov
· 2026 Jun · PMID 42329095
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Covalent KRAS G12C inhibitors have changed the treatment landscape for NSCLC and CRC patients, but numerous RAS-mutant cancers lack approved targeted therapies. Here we describe RMC-8839, an oral RAS(ON) G13C-selective,...Covalent KRAS G12C inhibitors have changed the treatment landscape for NSCLC and CRC patients, but numerous RAS-mutant cancers lack approved targeted therapies. Here we describe RMC-8839, an oral RAS(ON) G13C-selective, covalent, tri-complex inhibitor that induced tumor regressions in selected KRAS G13C-mutant xenograft models. However, one-third of KRAS G13C-mutant human cancer cell lines in vitro showed incomplete RAS pathway suppression despite near-complete KRAS G13C engagement, suggesting a role for wild-type RAS(ON). We find that codon 13-mutant RAS differs from other KRAS mutations, exhibiting decreased stability, increased nucleotide exchange, and substantial intrinsic and GAP-stimulated GTP hydrolysis, which decreases oncogenicity. Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13 mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, combination of RMC-8839 with a RAS(ON) multi-selective inhibitor resulted in deeper inhibition of KRAS G13C-mutant xenograft tumor growth than either inhibitor alone.
Arbet J, Yamaguchi TN, Shiah YJ
… +28 more, Hugh-White R, Wiggins A, Oh J, Zeltser N, Gebo T, Foucal A, Lesurf R, Jung CH, Dang RMA, Agrawal R, Livingstone J, Salcedo A, Yao CQ, Espiritu SMG, Houlahan K, Yousif F, Heisler LE, Papenfuss AT, Fraser M, Pope BJ, Kishan AU, Berlin A, Chua MLK, Corcoran NM, van der Kwast T, Hovens CM, Bristow RG, Boutros PC
Cancer Discov
· 2026 Jun · PMID 42307031
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Prostate cancer is characterized by profound clinical and molecular heterogeneity. While its genomic heterogeneity is well-characterized, its epigenomic heterogeneity remains less understood. We therefore created a compe...Prostate cancer is characterized by profound clinical and molecular heterogeneity. While its genomic heterogeneity is well-characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multi-ancestry prostate methylomes spanning normal tissue through localized disease of all grades to poly-metastatic disease. A subset of 884 samples had multi-omic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA copy number and methylation, with transcriptional consequences that vary across genes and disease stages. We define epigenetic dysregulation signatures for 15 important clinico-molecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and are synergistic with clinical prognostic features. These results define a complex interplay between tumour genetics and epigenetics that converges to modify gene-expression programs and clinical presentation, in part through modulation of epigenetic aging.
Cancer Discov
· 2026 Jun · PMID 42305094
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The FDA has launched a pilot program to establish real-time clinical trials that includes two proof-of-concept clinical trials that will report endpoints and data signals in real time. AstraZeneca is conducting TrAVeRse,...The FDA has launched a pilot program to establish real-time clinical trials that includes two proof-of-concept clinical trials that will report endpoints and data signals in real time. AstraZeneca is conducting TrAVeRse, a phase II trial in treatment-naïve mantle cell lymphoma, and Amgen is planning the phase Ib STREAM-SCLC study in limited-stage small cell lung carcinoma.
Cancer Discov
· 2026 Jun · PMID 42299111
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At this year's ASCO Annual Meeting, investigators also presented encouraging early clinical data for several KRASG12D-selective inhibitors, including RNK08594, GFH375, and DN022150, suggesting that this type of drug coul...At this year's ASCO Annual Meeting, investigators also presented encouraging early clinical data for several KRASG12D-selective inhibitors, including RNK08594, GFH375, and DN022150, suggesting that this type of drug could play a role in the treatment of several solid tumors, such as pancreatic ductal adenocarcinoma and non-small cell lung cancer.