Cancer research communications最新文献

{"title":"A Phase 1 Study of PF-07062119, an Anti-GUCY2C/Anti-CD3 Bispecific Fc Antibody, in Patients With Advanced Gastrointestinal Cancers.","authors":"Marwan Fakih, Toshihiko Doi, Anthony Tolcher, David Hong, Jeanne Tie, Wells Messersmith, Takafumi Koyama, Lee Rosen, Joana Borlido, Michael A Damore, Maria Delioukina, Ioanna Cheronis, Lee Noel Clark, Marzieh Golmakani, Amy Jackson-Fisher, Szu-Yu Tang, Cathy C Guo, Edmund J Keliher, Kevin Maresca, Neil H Segal","doi":"10.1158/2767-9764.CRC-26-0101","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0101","url":null,"abstract":"<p><strong>Purpose: </strong>PF-07062119 is an anti-GUCY2C/anti-CD3ε bispecific Fc antibody designed to elicit systemic anti-tumor immunity. This phase 1, first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, immunogenicity, and anti-tumor activity of PF-07062119 as monotherapy and in combination with sasanlimab or bevacizumab in patients with advanced gastrointestinal cancers expressing GUCY2C.</p><p><strong>Patients and methods: </strong>Patients received escalating doses of PF-07062119 (45-3700 μg subcutaneously [SC]) in Part 1A. In Part 1B, PF-07062119 was administered with either sasanlimab (300 mg SC) or bevacizumab (5 mg/kg intravenously). Primary endpoints were safety and tolerability; secondary endpoints included PK, immunogenicity and efficacy.</p><p><strong>Results: </strong>A total of 79 patients were enrolled. In Part 1A, maximum tolerated dose without a priming dose was 800 μg. Dose-limiting toxicities observed at this level were grade 3 cytokine release syndrome (CRS), colitis, and diarrhea. A 400 μg priming dose with premedication reduced CRS incidence and recommended dose for expansion was 2100 μg. Treatment-related grade 3/4 treatment-emergent adverse events (TEAEs) were observed in 27 (34.2%) patients, with no grade 5 treatment-related TEAEs. Diarrhea remained the most clinically significant toxicity in Part 1A. Combination therapy in Part 1B did not result in significant additional toxicity. PK analyses demonstrated dose-proportional increases in exposure. The overall response rate was 2.5% across all cohorts.</p><p><strong>Conclusions: </strong>PF-07062119 monotherapy demonstrated a generally tolerable safety profile within the context of this early-phase study with evidence of clinical activity in patients with advanced/metastatic gastrointestinal cancers.</p><p><strong>Clinical trial information: </strong>NCT04171141.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving long-read somatic structural variant calling with pangenome and de novo personal genome assembly.","authors":"Qian Qin, Jakob M Heinz, Heng Li","doi":"10.1158/2767-9764.CRC-25-0769","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0769","url":null,"abstract":"<p><p>Accurate detection of mosaic and somatic structural variants (SVs) provides early diagnostic and therapeutic evidence for cancers. While long-read whole-genome sequencing leads to more accurate SV detection than short read sequencing, existing long-read SV callers only look at alignment against a single reference genome and are susceptible to systematic false discovery caused by germline differences between the individual genome and the reference genome. Here we develop a new SV filtering method that jointly considers the alignment against a pangenome and the de novo assembly of the germline genome. It dramatically reduces false positive mosaic and somatic SVs in cancer cell lines with little loss in sensitivity for existing long read SV callers. Our study highlights the essential need for pangenome or personal genome assembly to integrate SV calls for both SV discoveries and clinical diagnostics.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome-based synthetic lethality predictions to improve targeted therapy/immunotherapy treatment prioritization in non-metastatic breast cancer: BC-SELECT.","authors":"Yewon Kim, Matthew Nagy, Rebecca Pollard, Padma Sheila Rajagopal","doi":"10.1158/2767-9764.CRC-26-0401","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0401","url":null,"abstract":"<p><p>Patients with non-metastatic triple-negative (TNBC) or HER2-positive (HER2+) breast cancer do not have tools to predict treatment response or prioritize options prior to starting therapy. Pathologic complete response (pCR) is a proxy that requires neoadjuvant treatment. BC-SELECT leverages genetic interactions (e.g. synthetic lethality (SL)/rescue (SR)) to predict treatment response via pCR from breast cancer gene expression data. BC-SELECT involves (1) \"Training: Gene-pair identification\" that identifies clinically relevant partner genes from large-scale datasets for a given targeted therapy or immunotherapy target, and (2) \"Training: Parameter tuning\" using clinical trials to predict treatment response. We evaluated BC-SELECT's ability to predict pCR for trastuzumab, poly (ADP-ribose) polymerase (PARP) inhibitors, and immunotherapy, with tuning supported by three trials (n=86) and validation on nine unseen trials (n=722). BC-SELECT significantly predicted pCR in 6/9 trials, including all PARP inhibitors (ROC-AUCs 0.6-0.8; Odds Ratio (OR): 1.9-3.5) and immunotherapy (ROC-AUCs 0.7-0.8; OR: 3.2-7.1). BC-SELECT significantly distinguished between pCR and residual disease in 8/9 trials. No current standard-of-care, pre-treatment approaches predict benefit in non-metastatic TNBC and HER2+ breast cancer. BC-SELECT leverages genetic interactions to predict treatment response from gene expression data. Our findings support development of BC-SELECT towards studying how to prioritize PARP inhibitors and immunotherapy in non-metastatic breast cancer.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Window-of-Opportunity Study Utilizing Preoperative Cetuximab in Patients with Head and Neck Cancer.","authors":"Justine Y Bruce, Tiffany A Glazer, Liliana L Berube, Colin A Longhurst, Menggang Yu, Rong Hu, Aaron M Wieland, Paul M Harari, Gregory K Hartig, Mari Iida, Ranjit K Mehta, Theodore S Lawrence, Mukesh K Nyati, Michael J Poellmann, Jiyoon Bu, Kwangok P Nickel, Seungpyo Hong, Deric L Wheeler, Randall J Kimple","doi":"10.1158/2767-9764.CRC-26-0258","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0258","url":null,"abstract":"<p><strong>Purpose: </strong>AXL, is a receptor tyrosine kinase implicated in EGFR resistance. The primary objective of this study was to test the hypothesis, generated in preclinical studies, that low AXL correlates with clinical response to cetuximab in patients with head and neck cancer (HNC). The secondary objectives were to further describe the feasibility and safety of preoperative administration of cetuximab.</p><p><strong>Methods: </strong>We performed a single-site, single arm, open label, window-of-opportunity study utilizing preoperative cetuximab in 15 patients with HNC. Patients received two doses of cetuximab and underwent resection of their tumor. Biopsies were used to assess AXL expression, change in Ki67 staining, and to establish patient-derived xenografts. scRNA-seq of treated xenograft tissue was used to assess differences between sensitive and resistant tumors.</p><p><strong>Results: </strong>Fifteen subjects were registered for treatment on the study and fourteen completed treatment with cetuximab prior to surgical resection. No correlation between AXL expression at baseline and change in tumor size in response to cetuximab was seen. Preoperative cetuximab did not delay surgical resection and no unexpected treatment-related adverse events were seen. scRNA-seq identified that cetuximab sensitivity is marked by transcriptional remodeling, while resistance is associated with stable HER signaling and elevated TAM activity.</p><p><strong>Conclusion: </strong>Delivery of preoperative cetuximab is safe, and a short course can be utilized to identify patients with HNC responding to single-agent cetuximab treatment.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of germline transposable element insertions in pediatric cancer predisposition.","authors":"Corinne E Sexton, Kayla V Hamilton, Chong Chu, David T Ting, Judy E Garber, Peter J Park, Junne Kamihara","doi":"10.1158/2767-9764.CRC-26-0229","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0229","url":null,"abstract":"<p><p>At least 15% of children with cancer have a pathogenic germline variant in a cancer predisposition gene. Studies of germline cancer predisposition, however, have focused primarily on single nucleotide and copy number variants, leaving other classes such as transposable elements (TEs) largely unexplored. Although rare pathogenic TE insertions have been implicated in inherited cancer, their contribution to pediatric cancer predisposition remains unknown, partly because these repetitive sequences often require whole-genome sequencing for detection. We characterized the germline TE insertion landscape using non-tumor whole genome sequencing data from 2,334 pediatric cancer and 3,447 controls. Across 5,781 genomes, we identified 96,484 TE insertions, most of which were rare and located in intergenic or intronic regions. While global TE burden did not differ between cases and controls, rare TE insertions were significantly enriched in cancer genes in patients with solid tumors, particularly within 3' untranslated regions (p<0.02). Gene-phenotype concordance analysis identified 19 insertions in genes with established dominant cancer predisposition, representing ~0.8% of cases. Integration of RNA-seq data revealed transcriptional impact for a subset of insertions. Notably, a 3' UTR L1 insertion in the tumor suppressor PTEN disrupted alternative polyadenylation, whereas an SVA insertion in a STIM1 intron induced exonization, generating a novel transcript containing SVA sequence. These findings demonstrate that rare germline TE insertions in cancer predisposition genes can have functional consequences at the RNA level. Incorporating TE detection into genomic workflows may improve identification of cancer predisposition syndromes and expand understanding of noncoding contributions to pediatric cancer susceptibility.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antitumor Activity of Novel Transcriptional Inhibitors Ecubectedin and PM54 in Soft Tissue Sarcoma Patient-Derived Xenografts.","authors":"Daniël Gorgels, Chao-Chi Wang, Lore De Cock, Luna De Sutter, Karo Wyns, Kimberly Verbeeck, Ulla Vanleeuw, Daphne Hompes, Friedl Sinnaeve, Hazem Wafa, Maria Jose Guillén, Pablo Avilés, Raf Sciot, Agnieszka Wozniak, Patrick Schöffski","doi":"10.1158/2767-9764.CRC-26-0377","DOIUrl":"10.1158/2767-9764.CRC-26-0377","url":null,"abstract":"<p><p>Trabectedin, prototype of the ecteinascidin class of drugs, is a known second- or later-line therapeutic option for advanced soft tissue sarcoma (STS). We evaluated the antitumor activity of two novel synthetic trabectedin derivatives, ecubectedin and PM54, in selected patient-derived xenograft (PDX) STS models. In total, 364 Naval Medical Research Institutenu/nu mice were transplanted bilaterally with two leiomyosarcoma (LMS), two dedifferentiated liposarcoma (DDLPS), one synovial sarcoma (SynSa), and one CIC-rearranged sarcoma (CRS) PDX models. Mice were randomized to six groups and treated via tail vein injection with (i) vehicle, (ii) doxorubicin, (iii) trabectedin, (iv) lurbinectedin, (v) ecubectedin, or (vi) PM54. Treatment was given on days 1, 8, and 15, and mice were sacrificed on day 16. The SynSa experiment included extra mice to investigate posttreatment xenograft evolution. Antitumor activity was assessed by tumor volume measurement, histopathologic, and immunohistochemical analyses. In all LMS and DDLPS models, ecubectedin and PM54 led to tumor growth delay compared with trabectedin. Histopathologic evaluation of treated tumors showed moderately increased antitumor activity of novel ecteinascidins compared with trabectedin. The CRS model showed tumor shrinkage in response to ecubectedin (63% regression from baseline) and PM54 (24% regression from baseline), while the SynSa model showed tumor volume stabilization. Both translocation-related models showed significant antitumor effect on histopathologic evaluation in response to the novel drugs compared with trabectedin. Ecubectedin and PM54 have modest antitumor activity in STS PDX models, with the strongest effects seen in the translocation-related sarcoma models, showing the potential of this class of drugs in the treatment of STS.</p><p><strong>Significance: </strong>Advanced STS remains without truly effective therapeutic options. Translocation-related sarcomas demonstrate higher vulnerability to next-generation ecteinascidin treatment compared with more complex sarcoma subtypes. This vulnerability builds upon known literature and could be exploited in future clinical trials using the next-generation ecteinascidins.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2056-2066"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148766064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Prostate Cancer Survivorship through Transatlantic Consortium Science: The iCCaRE Initiative.","authors":"Folakemi T Odedina, Roxana Dronca, Kimlin Tam Ashing, Ernest Kaninjing, Solomon Rotimi, Che Ngufor, Arnold Merriweather, Vinessa Gordon, Emelina Asto-Flores","doi":"10.1158/2767-9764.CRC-26-0165","DOIUrl":"10.1158/2767-9764.CRC-26-0165","url":null,"abstract":"<p><p>Black/African American populations, globally, bear the greatest prostate cancer burden compared with other racial/ethnic groups. Addressing prostate cancer disparities in Black men is complex, requiring a patient-centered, community-centric, and comprehensive approach. This study integrates Inclusive Cancer Care Research Equity (iCCaRE) Consortium findings and broader literature to address unmet needs in survivorship care. The iCCaRE Consortium implemented five complementary pilot studies using mixed-methods designs, including feasibility trials, qualitative research, and observational analyses across the United States and sub-Saharan Africa. Descriptive statistics, subgroup analyses, and qualitative thematic analyses were performed across these studies. Collectively, projects addressed multilevel determinants, including social, behavioral, and biological drivers of disparities. Project 1 implemented a Virtual Realty Assistant across clinical and community settings, with ongoing evaluation in pragmatic trials. Project 2 showed strong patient preference for home-based cancer care. Project 3 demonstrated trends toward improved health-related quality of life. Project 4 identified key themes influencing survivorship experiences. Project 5 identified biological mechanisms linking stress, immune modulation, and symptom burden. The iCCaRE pilot projects demonstrate the feasibility and early impact of a consortium-based, transdisciplinary approach to addressing prostate cancer disparities in Black men. These findings highlight the importance of integrating patient-centered interventions, community engagement, and biological insights to inform scalable strategies aimed at improving survivorship outcomes and advancing health equity. The iCCaRE Consortium demonstrates that a transatlantic, patient-centered, and multidisciplinary approach integrating social, clinical, and biological factors can generate scalable strategies to improve survivorship outcomes and advance equity in prostate cancer care for Black men.</p><p><strong>Significance: </strong>Black men experience the highest global burden of prostate cancer, yet disparities persist due to fragmented research and limited infrastructure. The iCCaRE Consortium demonstrates how coordinated, community-engaged consortium science can accelerate equity-driven research, expand minority investigator leadership, and generate sustained funding and scholarly productivity. By integrating survivors, advocates, scientists, and clinicians across continents, iCCaRE establishes a scalable model to reduce prostate cancer disparities and advance health equity worldwide.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2067-2078"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148586112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neighborhood Factors and Treatment Outcomes in Pediatric Acute Lymphoblastic Leukemia: A REDIAL Consortium Report.","authors":"Rutu A Rathod, Amy E Hughes, Pagna Sok, Karen R Rabin, Sandi L Pruitt, Philip J Lupo, Michael E Scheurer, Jeremy M Schraw","doi":"10.1158/2767-9764.CRC-26-0134","DOIUrl":"10.1158/2767-9764.CRC-26-0134","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) shows persistent outcome disparities among socioeconomically disadvantaged and Hispanic children. Neighborhood socioeconomic status (nSES) and residence in Hispanic enclaves may contribute to these disparities, yet their impact on pediatric ALL is unclear. We examined associations of nSES and Hispanic enclave residence with ALL treatment outcomes. We analyzed children (0-24 years) diagnosed with ALL between 2005 and 2017 and treated at REducing Disparities In Acute Leukemia (REDIAL) Consortium centers in Texas. Census-tract nSES (Yost) and Hispanic enclave indices were computed from US Census and American Community Survey (ACS) data, classifying tracts into low/high nSES and enclave/no enclave residence. Outcomes included end-of-induction (EOI) minimal residual disease (MRD) positivity (MRD ≥ 0.01%), relapse, event-free survival (EFS), and overall survival (OS). Associations were evaluated using multivariable logistic and Cox regression models adjusting for sex, age at diagnosis, race/ethnicity, EOI MRD, cytogenetic features, National Cancer Institute (NCI) risk group at diagnosis, ALL immunophenotype, and treating institutions. Among 1,348 patients, 41% resided in low-nSES tracts and 42% in Hispanic enclaves. Neither enclave residence nor low nSES was associated with EOI MRD positivity; similar null associations were observed for relapse, EFS, and OS. Although unadjusted analyses indicated slightly poorer 5-year EFS for low-nSES areas (81% vs. 85%, P = 0.04), this difference attenuated after adjustment. In this large, multicenter, and diverse cohort of children with ALL, neighborhood socioeconomic disadvantage and Hispanic enclave residence were not independently associated with treatment outcomes after accounting for clinical and cytogenetic features. Future studies should examine other social determinants and neighborhood influences on disease characteristics, survivorship, and late effects.</p><p><strong>Significance: </strong>In this multicenter study, neither neighborhood socioeconomic disadvantage nor residence in a Hispanic/Latino enclave was associated with inferior outcomes among children with ALL after controlling for clinical and cytogenetic disease features. Disparities affecting economically disadvantaged or minoritized populations may be mediated by other factors.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2079-2089"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting PRMT5 Inhibitor-Induced Adaptation in Pancreatic Cancer with the RBM39 Degrader Indisulam.","authors":"Valentina Spielmann, Jonas Buchloh, Selen Selcen, Carolin Schneider, Shaishavi Jansari, Xin Fang, Ningjun Duan, Engin Demirdizen, Lukas Krauß, Jessica Eggert, Geraldine Siegfried, Sandrine Fedou, Christof Lenz, Lena Wieland, Lena-Christin Conradi, Maximilian Reichert, Volker Ellenrieder, Michael Ghadimi, Marian Grade, Elisabeth Hessmann, Abdel-Majid Khatib, Christian J Braun, Florian Wegwitz, Dieter Saur, Matthias Wirth, Günter Schneider","doi":"10.1158/2767-9764.CRC-25-0670","DOIUrl":"10.1158/2767-9764.CRC-25-0670","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge. Next-generation protein arginine methyltransferase 5 (PRMT5) inhibitors show promising clinical results in a subset of PDACs with codeletion of the tumor-suppressor CDKN2A and the methylthioadenosine phosphorylase (MTAP) gene, but resistance limits their efficacy. Our study suggests that compensatory spliceosomal reprogramming contributes to adaptation to PRMT5 inhibition. Through comprehensive molecular profiling, we demonstrate that PRMT5 inhibitors induce upregulation of RNA-binding proteins, including RNA-binding protein 39 (RBM39). We investigated whether this response could be therapeutically leveraged by combining PRMT5 inhibition with indisulam-mediated RBM39 degradation, which yielded synergistic activity in cellular model systems. The combination strategy significantly enhanced apoptotic cell death and suppressed tumor outgrowth in resistance assays compared with single-agent treatments. Multiomics analysis revealed concomitant suppression of DNA repair and metabolic pathways. Collectively, our work support spliceosomal rewiring as a candidate adaptive response to PRMT5 inhibition and nominates RBM39 as a candidate therapeutic vulnerability, thereby supporting further evaluation of dual targeting of the splicing machinery.</p><p><strong>Significance: </strong>Our study suggests that compensatory spliceosomal reprogramming occurs in response to PRMT5 inhibition. We investigated this vulnerability by combining PRMT5 inhibition with indisulam-mediated RBM39 degradation, which yielded synergistic antitumor activity in selected cellular PDAC models.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2039-2055"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148723482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitronectin enrichment in prostate cancer liver metastases promotes adhesion and survival.","authors":"Jacob Egelberg, Rebecca Kim, Min J Kim, Jeanne Maria Dsouza, Alice Bernard-Tessier, Ramyar Molania, Varadha B Venkadakrishnan, Jingjing Chen, Martin K Bakht, Himisha Beltran","doi":"10.1158/2767-9764.CRC-26-0305","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0305","url":null,"abstract":"<p><p>The development of liver metastases in prostate cancer is associated with aggressive disease and poor prognosis. Because hepatocytes exhibit high metabolic activity with unique secretory profiles, we hypothesized that hepatocyte-to-tumor cell signaling plays a role in promoting liver metastasis. We evaluated single-cell transcriptomic data and metastatic tissue from patients with castration-resistant prostate cancer spanning androgen receptor (AR)-positive and AR-negative pathologies. Despite extensive intra- and inter-sample heterogeneity, communication analysis predicted vitronectin engagement of tumor integrins as a common feature. Vitronectin-positive hepatocytes were observed in prostate tumors with vitronectin accumulation in sinusoidal patches. Consistent with integrin activation, vitronectin treatment of AR-positive and AR-negative prostate cancer cells significantly promoted tumor cell adhesion, inhibited hypodiploid accumulation consistent with survival effects, and stimulated FAK-dependent phosphorylation of ERK and AKT. FAK inhibition with defactinib abrogated vitronectin- and serum-mediated adhesion in a cell-specific manner and mitigated VTN-driven depletion of hypodiploid populations. These findings support a model where dense intra-sinusoidal vitronectin deposits might capture metastatic prostate tumor cells in the liver and biochemically activate tumorigenic signaling, promoting tumor aggressiveness.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148868137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}