Cancer research communications最新文献

{"title":"Diverse ERBB2/ERBB3 Activating Alterations And Co-Alterations Have Implications For HER2/3 Targeted Therapies Across Solid Tumors.","authors":"Dazhi Liu, Justin Jee, Alexander Drilon, Andreas M Heilmann, Justin M Allen, Alexa B Schrock, Rachel B Keller-Evans, Bob T Li","doi":"10.1158/2767-9764.CRC-24-0620","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0620","url":null,"abstract":"<p><p>While ERBB2 (HER2) is an established oncogenic driver and therapeutic biomarker in several cancers, current drug approvals do not reflect the diverse spectrum of activating alterations across indications in which HER2-targeted therapies may yield clinical benefit. In most cancer types, HER2 status is defined by HER2 overexpression/amplification assessed using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), which do not provide genomic context. We sought to define the pan-tumor landscape of activating ERBB2 and ERBB3 genomic alterations detected by comprehensive genomic profiling (CGP). We queried institutional databases of solid tumor CGP, including 429,666 patients who underwent Foundation Medicine testing and 83,332 patients whose tumors were profiled using MSK-IMPACT. We identified activating ERBB2 and ERBB3 alterations across solid tumor types, including many off-label for current HER2 drug approvals. While non-small cell lung cancer (NSCLC) represented the highest proportion of ERBB2 mutated (ERBB2mut, i.e., single nucleotide variants and short insertions/deletions) cancers (19.0%), breast, colorectal, bladder, and gastroesophageal cancers combined accounted for 50.4% of ERBB2mut tumors. Within NSCLC, 26% of activating mutations were not included in clinical trials that led to approval of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). We also present three clinical cases demonstrating clinical benefit from off-label use of HER2-targeted therapies. We identified substantial populations of patients with diverse ERBB2/ERBB3 activating alterations, which represent unmet therapeutic needs. We demonstrate that CGP provides additional genomic information, inclusive of ERBB2 amplification and mutation status together with potential resistance/response-modifying co-alterations, allowing for more nuanced HER2 status interpretation than is possible with IHC/FISH alone.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774722","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":"Branched-Chain Amino Acid Catabolism Promotes Ovarian Cancer Cell Proliferation via Phosphorylation of mTOR.","authors":"Hannah J Lusk, Monica A Haughan, Tova M Bergsten, Joanna E Burdette, Laura M Sanchez","doi":"10.1158/2767-9764.CRC-24-0532","DOIUrl":"10.1158/2767-9764.CRC-24-0532","url":null,"abstract":"<p><strong>Significance: </strong>This study uncovers altered amino acid metabolism, specifically increased BCAA catabolism, at the interface of ovarian cancer cells and omental tissue in a coculture model of HGSOC secondary metastasis. Enhanced BCAA catabolism promotes cancer cell proliferation through mTOR signaling, presenting potential therapeutic value. These findings deepen our understanding of HGSOC pathogenesis and the metastatic tumor microenvironment, offering insights for developing new treatment strategies.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"569-579"},"PeriodicalIF":2.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607367","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":"Age and Sex Differences in the Prevalence of Specific Comorbidities among Patients with Pediatric Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma at Diagnosis.","authors":"Xin Yang, Maua Mosha, Dave Bell, Jennifer Dean, Jennifer Mayer, Ernest K Amankwah","doi":"10.1158/2767-9764.CRC-24-0517","DOIUrl":"10.1158/2767-9764.CRC-24-0517","url":null,"abstract":"<p><strong>Significance: </strong>Among pediatric patients with ALL/LL, significant disparities were found for specific comorbidities, particularly among females and younger patients who had higher rates of digestive tract diseases and infectious diseases. These findings are important as comorbidities can be considered in clinical decision-making in the management and treatment of these patients.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"549-555"},"PeriodicalIF":2.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607358","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":"LNS8801: An Enantiomerically Pure Agonist of the G Protein-Coupled Estrogen Receptor Suitable for Clinical Development.","authors":"Christopher A Natale, Sophia Mercado, Richard Zhuang, Cristina Aguirre-Portolés, Israel Olayide, Christopher K Arnatt, John T Seykora, Tina K Garyantes, Wayne Luke, Todd W Ridky","doi":"10.1158/2767-9764.CRC-24-0632","DOIUrl":"10.1158/2767-9764.CRC-24-0632","url":null,"abstract":"<p><strong>Significance: </strong>GPER is broadly expressed in human tissues and has tumor-suppressive activity. No FDA-approved agents selectively target GPER. LNS8801 is a synthetic, orally bioavailable, enantiomerically pure, GPER agonist with potent anticancer activity in vivo. LNS8801 response is attenuated by a common germline coding variant present in roughly half of humans.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"556-568"},"PeriodicalIF":2.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607383","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":"A Proteomic Signature for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma Predicts Patients at High Risk of Recurrence.","authors":"Christopher C Jackson, Jia Jenny Liu, Howard Y Liu, Steven G Williams, Asim Anees, Zainab Noor, Natasha Lucas, Dylan Xavier, Peter G Hains, Daniel Bucio-Noble, Adel T Aref, Sandro V Porceddu, Rahul Ladwa, Joseph Whitfield, Roger R Reddel, Qing Zhong, Benedict J Panizza, Phillip J Robinson","doi":"10.1158/2767-9764.CRC-23-0460","DOIUrl":"10.1158/2767-9764.CRC-23-0460","url":null,"abstract":"<p><strong>Significance: </strong>HPV+OPSCC incidence is increasing, with heterogeneous treatment outcomes despite favorable prognosis. Current de-escalation strategies show inferior results, highlighting the need for precise risk stratification. Using data-independent acquisition mass spectrometry proteomics, we identified a 26-peptide signature that stratifies patients into risk categories, potentially enabling personalized treatment decisions and optimal patient selection for de-escalation trials.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"580-593"},"PeriodicalIF":2.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525218","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":"Clear cell renal cell carcinoma molecular subtypes differ by African and European genetic similarity groups.","authors":"Roy Elias, Thomas Nirschl, Michael Rezaee, Anirudh Yerrapragada, Shirley Wang, Joseph Cheaib, Ridwan Alam, Sunil Patel, Yuezhou Jing, Mohamad Allaf, David McKean, Alison P Klein, Elana J Fertig, Ezra Baraban, Yasser Ged, Srinivasan Yegnasubramanian, Nirmish Singla","doi":"10.1158/2767-9764.CRC-24-0624","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0624","url":null,"abstract":"<p><p>Self-reported Black (B) individuals remain underrepresented in molecular studies of clear cell renal cell carcinoma (ccRCC) relative to White (W) individuals. We performed whole-exome and transcriptome sequencing on paired tumor and normal samples from 59 matched B and W patients undergoing nephrectomy for localized ccRCC, comparing molecular differences by estimated genetic similarity to African (AFR) and European (EUR) 1000 Genomes groups. We validated our findings with a propensity-matched subset of TCGA, yielding a final cohort of 254 patients (79 AFR, 175 EUR) with similar baseline clinical variables. Significant differences emerged in VHL mutation frequency (AFR: 23.4%, EUR: 57.5%; FDR = 0.0029) and chromosome 3p deletions (AFR: 59.2%, EUR: 82.6%; FDR = 0.086). Transcriptomic analyses identified 34 genes associated with genetic similarity, and gene set enrichment revealed inflammatory (interferon gamma/alpha, allograft rejection), proliferative (E2F targets, G2M checkpoint), and metabolic (bile acid, fatty acid, glycolysis, MTORC1, peroxisome) pathway enrichment in EUR. We also observed differences in ccRCC molecular subtype distribution, with \"Proliferative\" and \"Angio/Stromal\" subtypes more common in AFR (p = 0.018). Importantly, differential subtype membership explained most group-level differences. These results link EUR and AFR genetic similarity to distinct ccRCC molecular subtypes, underscoring the importance of molecular classifiers in disease stratification and the need to include diverse populations in molecular studies to improve our understanding and treatment of ccRCC.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702169","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 Impact of the Tumor Microenvironment on the Effect of IL-1β Blockade in NSCLC: Biomarker Analyses from CANOPY-1 and CANOPY-N Trials.","authors":"Benjamin J Solomon, Daniel S W Tan, Gilberto de Castro Junior, Manuel Cobo, Marina Chiara Garassino, Jun Zhang, Bruce E Johnson, Jay M Lee, Pilar Garrido, Andrew A Buter, Marc R Pelletier, Alexander Savchenko, Lexiang Ji, Jan C Brase, Rafael Caparica, David Demanse, Jincheng Wu, Claudia Bossen, Tony Mok","doi":"10.1158/2767-9764.CRC-24-0490","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0490","url":null,"abstract":"<p><strong>Purpose: </strong>Preclinical studies have shown that interleukin (IL)-1β blockade can modulate the tumor microenvironment (TME) to activate antitumor immunity and, in combination with immune checkpoint inhibitors (ICIs), prevent cancer growth. Our study investigates if immune biomarkers in the TME impact outcomes in patients with non-small cell lung cancer (NSCLC) treated with the IL-1β inhibitor canakinumab plus an ICI-based therapy and describes canakinumab effects on the TMEs of these patients.</p><p><strong>Methods: </strong>Exploratory analyses were conducted in two prospective trials evaluating canakinumab combined with pembrolizumab-based regimens in patients with NSCLC: CANOPY-1 (first-line setting) and CANOPY-N (neoadjuvant setting). Immunohistochemistry and transcriptomic analyses were performed on baseline tumor samples from CANOPY-1 and immunohistochemistry and multiplex immunofluorescence analyses were performed on baseline and post-treatment tumor samples from CANOPY-N. Associations with clinical outcomes were evaluated.</p><p><strong>Results: </strong>In CANOPY-1, in patients with low levels of T-cell infiltration in the tumor, the addition of canakinumab to a pembrolizumab-based regimen was associated with progression-free and overall survival improvements. Low levels of T-cell infiltration were associated with an immunosuppressive gene expression phenotype, supporting the role of low T-cell infiltration as a surrogate of an overall immunosuppressive TME. In CANOPY-N, a reduction in immunosuppressive cells in the TME was observed following canakinumab and pembrolizumab treatment.</p><p><strong>Conclusions: </strong>Our exploratory biomarker analyses from the CANOPY-1 and CANOPY-N trials suggest that IL-1β blockade may shift the TME towards an immune-activated status and that patients with immunosuppressive TME features could benefit from the addition of canakinumab to an ICI-based treatment.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675080","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":"Preclinical activity of the type II RAF inhibitor tovorafenib in tumor models harboring either a BRAF fusion or an NF1-loss of function mutation.","authors":"Shubhra Rastogi, Samantha Perino, Madhu Lal-Nag, Yujin Wang, Samuel C Blackman, Eleni Venetsanakos","doi":"10.1158/2767-9764.CRC-24-0451","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0451","url":null,"abstract":"<p><p>Genomic alterations and dysregulation of the MAPK pathway have been described in many different types of cancers. BRAF V600 mutations and BRAF fusions, found in both pediatric and adult cancers, are oncogenic drivers that drive constitutive activation of the RAF pathway. Neurofibromin 1 (NF1) loss of function (LOF) mutations, which occur in many cancer types, result in decreased neurofibromin GAP function, thus activating RAS. Tovorafenib is an oral selective, central nervous system-penetrant, type II RAF inhibitor which inhibits RAF monomers and dimers. In this study, the impact of tovorafenib alone or in combination with MEK inhibitor, pimasertib, was explored in adult or pediatric tumor models harboring BRAF fusions or NF1-LOF mutations. Tovorafenib resulted in tumor regression in an AGK::BRAF fusion melanoma patient-derived xenograft (PDX) model in vivo, while exhibiting little anti-tumor activity in NF1-LOF tumor models. In vitro anti-proliferative activity of tovorafenib and pathway modulation was evaluated in NF1-LOF tumor cell lines. Little anti-proliferative activity was observed in the NF1-LOF tumor cell lines treated with tovorafenib. In NF1-LOF tumor cells treated with tovorafenib, increase in phosphorylated-ERK (pERK) was observed at low concentrations, with inhibition of pERK at higher concentrations. When tovorafenib was combined with pimasertib in vitro, synergy was observed in a NF1-LOF embryonal rhabdomyosarcoma PDX model ex vivo and a NF1-LOF MPNST cell line in vitro, suggesting that vertical pathway inhibition is needed in the NF1-LOF mutant setting.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665451","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":"PLK1 inhibition induces synthetic lethality in Fanconi anemia pathway-deficient acute myeloid leukemia.","authors":"Aditya S Sheth, Ka-Kui Chan, Sheng Liu, Jun Wan, Steven P Angus, Steven D Rhodes, Dana K Mitchell, Christopher Davis, Maya Ridinger, Peter J Croucher, Amer M Zeidan, Aruna Wijeratne, Shaomin Qian, Ngoc Tung Tran, Elizabeth A Sierra Potchanant","doi":"10.1158/2767-9764.CRC-24-0260","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0260","url":null,"abstract":"<p><p>Overall survival of acute myeloid leukemia (AML) remains limited. Inhibitors of the master mitotic kinase PLK1 have emerged as promising therapeutics, demonstrating efficacy in an undefined subset of AML patients. However, the clinical success of PLK1 inhibitors remains hindered by a lack of predictive biomarkers. The Fanconi anemia (FA) pathway, a tumor-suppressive network comprised of at least 22 genes, is frequently mutated in sporadic AML. Here, we demonstrate that FA pathway disruption sensitizes AML cells to PLK1 inhibition. Mechanistically, we identify novel interactions between PLK1 and both FANCA and FANCD2 at mitotic centromeres. We demonstrate that PLK1 inhibition impairs recruitment of FANCD2 to mitotic centromeres, induces damage to mitotic chromosomes, and triggers mitotic collapse in FANCA-deficient cells. Our findings indicate that PLK1 inhibition targets mitotic vulnerabilities specific to FA pathway-deficient cells and implicate FA pathway mutations as potential biomarkers for the identification of patients likely to benefit from PLK1 inhibitors.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665449","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":"Osteosarcoma exosome priming of primary human lung fibroblasts induces an immune modulatory and pro-tumorigenic phenotype.","authors":"Eric P Palmer, Kathryn E Cronise, Laurel A Haines, Sunetra Das, Aaron Offermann, Carina P Easton, Daniel P Regan","doi":"10.1158/2767-9764.CRC-24-0371","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0371","url":null,"abstract":"<p><p>Osteosarcoma (OS) is the most common malignant bone cancer. 30-40% of all OS patients develop tumor recurrence, almost exclusively in the form of lung metastasis, which is associated with a dismal 20% 5-year survival rate. Cancer-associated fibroblasts are a critical cell type within the lung TME, which promote immune suppression, drug resistance, and tumor cell survival. Prior work shows tumor cells can co-opt fibroblasts to a pro-tumorigenic phenotype via exosome mediated intercellular communication. Currently, the mechanisms by which OS exosomes modulate resident lung fibroblast function has not been evaluated. To investigate this, we isolated exosomes from a panel of 6 OS cell lines. We assessed the uptake and response of human donor-derived primary lung fibroblasts (LF's; n=4) to OS exosome treatment in vitro via flow cytometry, confocal fluorescent microscopy, proliferation assays, phospho-kinase array, multiplex cytokine analysis and RNA-sequencing. We observed that LFs efficiently take up OS exosomes, which is associated with induction of MAPK pathway activation, fibroblast proliferation and significantly enhanced secretion of IL-6, CXCL8 and CCL2 compared to untreated LFs. RNA-seq of exosome treated LFs confirmed these responses and revealed significant enrichment of pathways related to cytokine secretion, proliferation, immune cell chemotaxis, migration, proinflammatory and profibrotic mediators. Finally, in an exosome-educated lung fibroblast-OS co-culture model, exosome educated LFs conferred significantly increased OS cell survival and proliferation as compared to untreated fibroblasts. Together, these data suggest OS-derived exosomes can induce a hallmark, CAF-like inflammatory phenotype in lung fibroblasts providing valuable insights into mechanisms that may promote recurrent OS lung metastasis.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659489","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}