Cancer research communications最新文献

{"title":"Systematic Evaluation of Tyrosine Kinase Inhibitors as OATP1B1 Substrates Using a Competitive Counterflow Screen.","authors":"Thomas Drabison, Mike Boeckman, Yan Yang, Kevin M Huang, Peter de Bruijn, Mahesh R Nepal, Josie A Silvaroli, Anika T Chowdhury, Eric D Eisenmann, Xiaolin Cheng, Navjotsingh Pabla, Ron H J Mathijssen, Sharyn D Baker, Shuiying Hu, Alex Sparreboom, Zahra Talebi","doi":"10.1158/2767-9764.CRC-24-0332","DOIUrl":"10.1158/2767-9764.CRC-24-0332","url":null,"abstract":"<p><p>Although the primary elimination pathway for most tyrosine kinase inhibitors (TKI) involves CYP3A4-mediated metabolism, the mechanism by which these agents are brought into hepatocytes remains unclear. In this study, we optimized and validated a competitive counterflow (CCF) assay to examine TKIs as substrates of the hepatic uptake transporter OATP1B1. The CCF method was based on the stimulated efflux of radiolabeled estradiol-17β-glucuronide under steady-state conditions in HEK293 cells engineered to overexpress OATP1B1. Of the 62 approved TKIs examined, 13 agents were identified as putative substrates of OATP1B1, and pazopanib was selected as a representative hit for further validation studies. The transport of pazopanib by OATP1B1 was confirmed by decreased activity of its target VEGFR2 in OATP1B1-overexpressing cells, but not cells lacking OATP1B1, consistent with molecular docking analyses indicating an overlapping binding orientation on OATP1B1 with the known substrate estrone-3-sulfate. In addition, the liver-to-plasma ratio of pazopanib in vivo was decreased in mice with a deficiency of the orthologous transporters, and this was accompanied by diminished pazopanib-induced hepatotoxicity, as determined by changes in the levels of liver transaminases. Our study supports the utility of CCF assays to assess substrate affinity for OATP1B1 within a large set of agents in the class of TKIs and sheds light on the mechanism by which these agents are taken up into hepatocytes in advance of metabolism.</p><p><strong>Significance: </strong>Despite the established exposure-pharmacodynamic relationships for many TKIs, the mechanisms underlying the agents' unpredictable pharmacokinetic profiles remain poorly understood. We report here that the disposition of many TKIs depends on hepatic transport by OATP1B1, a process that has toxicologic ramifications for agents that are associated with hepatotoxicity.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2489-2497"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115574","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":"Anti-HDGF Antibody Targets EGFR Tyrosine Kinase Inhibitor-Tolerant Cells in NSCLC Patient-Derived Xenografts.","authors":"Cindy Q Zhou, Ariel Li, Kaoru Ri, Ahmed S Sultan, Hening Ren","doi":"10.1158/2767-9764.CRC-24-0020","DOIUrl":"10.1158/2767-9764.CRC-24-0020","url":null,"abstract":"<p><p>Constitutively active mutant EGFR is one of the major oncogenic drivers in non-small cell lung cancer (NSCLC). Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a first-line option in patients that have metastatic or recurring disease. However, despite the high response rate to TKI, most patients have a partial response, and the disease eventually progresses in 10 to 19 months. It is believed that drug-tolerant cells that survive TKI exposure during the progression-free period facilitate the emergence of acquired resistance. Thus, targeting the drug-tolerant cells could improve the treatment of NSCLC with EGFR mutations. We demonstrated here that EGFR-mutant patient-derived xenograft tumors responded partially to osimertinib despite near-complete inhibition of EGFR activation. Signaling in AKT/mTOR and MAPK pathways could be reactivated shortly after initial inhibition. As a result, many tumor cells escaped drug killing and regained growth following about 35 days of continuous osimertinib dosing. However, when an antibody to hepatoma-derived growth factor (HDGF) was given concurrently with osimertinib, tumors showed complete or near-complete responses. There was significant prolongation of progression-free survival of tumor-bearing mice as well. IHC and Western blot analysis of tumors collected in the early stages of treatment suggest that increased suppression of the AKT/mTOR and MAPK pathways could be a mechanism that results in enhanced efficacy of osimertinib when it is combined with an anti-HDGF antibody.</p><p><strong>Significance: </strong>These results suggest that HDGF could be critically involved in promoting tolerance to TKI in patient-derived xenografts of NSCLC tumors. Blocking HDGF signaling could be a potential means to enhance EGFR-targeted therapy of NSCLC that warrants further advanced preclinical and clinical studies.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2308-2319"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749902","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":"Long-Lasting Response to Lorlatinib in Patients with ALK-Driven Relapsed or Refractory Neuroblastoma Monitored with Circulating Tumor DNA Analysis.","authors":"Torben Ek, Raghda R Ibrahim, Hartmut Vogt, Kleopatra Georgantzi, Catarina Träger, Jennie Gaarder, Anna Djos, Ida Rahmqvist, Elisabeth Mellström, Fani Pujol-Calderón, Christoffer Vannas, Lina Hansson, Henrik Fagman, Diana Treis, Susanne Fransson, Tobias Österlund, Tzu-Po Chuang, Bronte Manouk Verhoeven, Anders Ståhlberg, Ruth H Palmer, Bengt Hallberg, Tommy Martinsson, Per Kogner, Martin Dalin","doi":"10.1158/2767-9764.CRC-24-0338","DOIUrl":"10.1158/2767-9764.CRC-24-0338","url":null,"abstract":"<p><p>Patients with anaplastic lymphoma kinase (ALK)-driven neuroblastoma may respond to tyrosine kinase inhibitors, but resistance to treatment occurs and methods currently used for detection of residual disease have limited sensitivity. Here, we present a national unselected cohort of five patients with relapsed or refractory ALK-driven neuroblastoma treated with lorlatinib as monotherapy and test the potential of targeted circulating tumor DNA (ctDNA) analysis as a guide for treatment decisions in these patients. We developed a sequencing panel for ultrasensitive detection of ALK mutations associated with neuroblastoma or resistance to tyrosine kinase inhibitors and used it for ctDNA analysis in 83 plasma samples collected longitudinally from the four patients who harbored somatic ALK mutations. All four patients with ALK p.R1275Q experienced major responses and were alive 35 to 61 months after starting lorlatinib. A fifth patient with ALK p.F1174L initially had a partial response but relapsed after 10 months of treatment. In all cases, ctDNA was detected at the start of lorlatinib single-agent treatment and declined gradually, correlating with clinical responses. In the two patients exhibiting relapse, ctDNA increased 9 and 3 months, respectively, before clinical detection of disease progression. In one patient harboring HRAS p.Q61L in the relapsed tumor, retrospective ctDNA analysis showed that the mutation appeared de novo after 8 months of lorlatinib treatment. We conclude that some patients with relapsed or refractory high-risk neuroblastoma show durable responses to lorlatinib as monotherapy, and targeted ctDNA analysis is effective for evaluation of treatment and early detection of relapse in ALK-driven neuroblastoma.</p><p><strong>Significance: </strong>We present five patients with ALK-driven relapsed or refractory neuroblastoma treated with lorlatinib as monotherapy. All patients responded to treatment, and four of them were alive after 3 to 5 years of follow-up. We performed longitudinal ctDNA analysis with ultra-deep sequencing of the ALK tyrosine kinase domain. We conclude that ctDNA analysis may guide treatment decisions in ALK-driven neuroblastoma, also when the disease is undetectable using standard clinical methods.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2553-2564"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11440348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037904","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":"Therapeutic Efficacy of IL7/CCL19-Expressing CAR-T Cells in Intractable Solid Tumor Models of Glioblastoma and Pancreatic Cancer.","authors":"Keisuke Ohta, Yukimi Sakoda, Keishi Adachi, Taro Shinozaki, Masao Nakajima, Hiroyuki Yasuda, Hiroaki Nagano, Koji Tamada","doi":"10.1158/2767-9764.CRC-24-0226","DOIUrl":"10.1158/2767-9764.CRC-24-0226","url":null,"abstract":"<p><p>Cancer immunotherapy using immune checkpoint inhibitors and its combination with other anticancer therapies has emerged as a new standard of care because of the encouraging therapeutic effects in various solid cancers. Nonetheless, glioblastoma and pancreatic cancer remain resistant to immunotherapy and represent intractable cancers with the poorest prognosis. We investigated the therapeutic effects of next-generation chimeric antigen receptor (CAR) T cells producing IL7 and chemokine (C-C motif) ligand 19 (CCL19; referred to as 7 × 19 CAR-T) in these intractable cancers. Cytotoxic activities and therapeutic effects of 7 × 19 CAR-T were evaluated in vitro and in vivo, in a model using EGFR variant III (EGFRvIII)-positive glioblastoma and anti-EGFRvIII CAR-T generated from healthy donor peripheral blood mononuclear cells (PBMC), or a model using HER2-positive pancreatic cancer organoids and anti-HER2 CAR-T generated from the same patient's PBMC. Anti-EGFRvIII 7 × 19 CAR-T exhibited cytotoxic activity specific to EGFRvIII-positive tumor, induced complete rejection of glioblastoma with massive T-cell infiltration and tumor cell death in the tumor tissues, and consequently prolonged mouse survival. Anti-HER2 7 × 19 CAR-T demonstrated a potent cytotoxic activity against autologous HER2-positive pancreatic cancer organoids and induced complete rejection of autologous tumor along with prolonged mouse survival. Our results suggest that 7 × 19 CAR-T could become a therapeutic option for glioblastoma and pancreatic cancer. To the best of our knowledge, this is the first study to demonstrate the therapeutic efficacy of next-generation CAR-T in an autologous model using patient-derived tumor organoids and CAR-T generated from the same patient's PBMC, in which unwanted allogeneic immune responses are fully excluded.</p><p><strong>Significance: </strong>Despite the clinical development of CAR T-cell therapy, its efficacy in solid cancers has yet to be established. This study explored the therapeutic potential and immunologic mechanisms of IL7/CCL19-producing CAR-T therapy in preclinical solid cancer models of glioblastoma and pancreatic cancer. We found that IL7/CCL19-producing CAR-T cells generated from the patient's PBMC showed potent therapeutic effects against the solid cancer model established by inoculating organoids from the autologous tumor tissue.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2514-2524"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141903","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":"Engineering Oncogenic Hotspot Mutations on SF3B1 via CRISPR-Directed PRECIS Mutagenesis.","authors":"Mike M Fernandez, Lei Yu, Qiong Jia, Xuesong Wang, Kevyn L Hart, Zhenyu Jia, Ren-Jang Lin, Lili Wang","doi":"10.1158/2767-9764.CRC-24-0145","DOIUrl":"10.1158/2767-9764.CRC-24-0145","url":null,"abstract":"<p><p>SF3B1 is the most recurrently mutated RNA splicing gene in cancer. However, research of its pathogenic role has been hindered by a lack of disease-relevant cell line models. Here, our study compared four genome engineering platforms to establish SF3B1 mutant cell lines: CRISPR-Cas9 editing, AAV homology-directed repair editing, base editing (ABEmax, ABE8e), and prime editing (PE2, PE3, PE5max). We showed that prime editing via PE5max achieved the most efficient SF3B1 K700E editing across a wide range of cell lines. Our approach was further refined by coupling prime editing with a fluorescent reporter that leverages a SF3B1 mutation-responsive synthetic intron to mark successfully edited cells. By applying this approach, called prime editing coupled intron-assisted selection (PRECIS), we introduced the K700E hotspot mutation into two chronic lymphocytic leukemia cell lines, HG-3 and MEC-1. We demonstrated that our PRECIS-engineered cells faithfully recapitulate known mutant SF3B1 phenotypes, including altered splicing, copy number variations, and cell-growth defect. Moreover, we discovered that the SF3B1 mutation can cause the loss of Y chromosome in chronic lymphocytic leukemia. Our results showcase that PRECIS is an efficient and generalizable method for engineering genetically faithful SF3B1 mutant models. Our approach provides new insights on the role of SF3B1 mutation in cancer and enables the generation of SF3B1 mutant cell lines in relevant cellular context.</p><p><strong>Significance: </strong>This study developed an approach that can reliably and efficiently engineer SF3B1 mutation into different cellular contexts, thereby revealing novel roles of SF3B1 mutation in driving aberrant splicing, clonal evolution, and genome instability.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2498-2513"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11421219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082741","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":"NCI's Proteomic Data Commons: A Cloud-Based Proteomics Repository Empowering Comprehensive Cancer Analysis through Cross-Referencing with Genomic and Imaging Data.","authors":"Ratna R Thangudu, Michael Holck, Deepak Singhal, Alexander Pilozzi, Nathan Edwards, Paul A Rudnick, Marcin J Domagalski, Padmini Chilappagari, Lei Ma, Yi Xin, Toan Le, Kristen Nyce, Rekha Chaudhary, Karen A Ketchum, Aaron Maurais, Brian Connolly, Michael Riffle, Matthew C Chambers, Brendan MacLean, Michael J MacCoss, Peter B McGarvey, Anand Basu, John Otridge, Esmeralda Casas-Silva, Sudha Venkatachari, Henry Rodriguez, Xu Zhang","doi":"10.1158/2767-9764.CRC-24-0243","DOIUrl":"10.1158/2767-9764.CRC-24-0243","url":null,"abstract":"<p><p>Proteomics has emerged as a powerful tool for studying cancer biology, developing diagnostics, and therapies. With the continuous improvement and widespread availability of high-throughput proteomic technologies, the generation of large-scale proteomic data has become more common in cancer research, and there is a growing need for resources that support the sharing and integration of multi-omics datasets. Such datasets require extensive metadata including clinical, biospecimen, and experimental and workflow annotations that are crucial for data interpretation and reanalysis. The need to integrate, analyze, and share these data has led to the development of NCI's Proteomic Data Commons (PDC), accessible at https://pdc.cancer.gov. As a specialized repository within the NCI Cancer Research Data Commons (CRDC), PDC enables researchers to locate and analyze proteomic data from various cancer types and connect with genomic and imaging data available for the same samples in other CRDC nodes. Presently, PDC houses annotated data from more than 160 datasets across 19 cancer types, generated by several large-scale cancer research programs with cohort sizes exceeding 100 samples (tumor and associated normal when available). In this article, we review the current state of PDC in cancer research, discuss the opportunities and challenges associated with data sharing in proteomics, and propose future directions for the resource.</p><p><strong>Significance: </strong>The Proteomic Data Commons (PDC) plays a crucial role in advancing cancer research by providing a centralized repository of high-quality cancer proteomic data, enriched with extensive clinical annotations. By integrating and cross-referencing with complementary genomic and imaging data, the PDC facilitates multi-omics analyses, driving comprehensive insights, and accelerating discoveries across various cancer types.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2480-2488"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121258","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":"Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis.","authors":"Joel D Pearson, Katherine Huang, Louis G Dela Pena, Benjamin Ducarouge, Patrick Mehlen, Rod Bremner","doi":"10.1158/2767-9764.CRC-24-0101","DOIUrl":"10.1158/2767-9764.CRC-24-0101","url":null,"abstract":"<p><p>Opposite expression and pro- or anti-cancer function of YAP and its paralog TAZ/WWTR1 stratify cancers into binary YAPon and YAPoff classes. These transcriptional coactivators are oncogenic in YAPon cancers. In contrast, YAP/TAZ are silenced epigenetically along with their integrin and extracellular matrix adhesion target genes in neural and neuroendocrine YAPoff cancers (e.g., small cell lung cancer, retinoblastoma). Forced YAP/TAZ expression induces these targets, causing cytostasis in part through Integrin-αV/β5, independent of the integrin-binding RGD ligand. Other effectors of this anticancer YAP function are unknown. Here, using clustered regularly interspaced short palindromic repeats (CRISPR) screens, we link the Netrin receptor UNC5B to YAP-induced cytostasis in YAPoff cancers. Forced YAP expression induces UNC5B through TEAD DNA-binding partners, as either TEAD1/4-loss or a YAP mutation that disrupts TEAD-binding (S94A) blocks, whereas a TEAD-activator fusion (TEAD(DBD)-VP64) promotes UNC5B induction. Ectopic YAP expression also upregulates UNC5B relatives and their netrin ligands in YAPoff cancers. Netrins are considered protumorigenic, but knockout and peptide/decoy receptor blocking assays reveal that in YAPoff cancers, UNC5B and Netrin-1 can cooperate with integrin-αV/β5 to mediate YAP-induced cytostasis. These data pinpoint an unsuspected Netrin-1/UNC5B/integrin-αV/β5 axis as a critical effector of YAP tumor suppressor activity.</p><p><strong>Significance: </strong>Netrins are widely perceived as procancer proteins; however, we uncover an anticancer function for Netrin-1 and its receptor UNC5B.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2374-2383"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11384508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019717","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":"MYBL2 Drives Prostate Cancer Plasticity: Inhibiting Its Transcriptional Target CDK2 for RB1-Deficient Neuroendocrine Prostate Cancer.","authors":"Beatriz German, Sarah A Alaiwi, Kun-Lin Ho, Jagpreet S Nanda, Marcos A Fonseca, Deborah L Burkhart, Anjali V Sheahan, Hannah E Bergom, Katherine L Morel, Himisha Beltran, Justin H Hwang, Matthew L Freedman, Kate Lawrenson, Leigh Ellis","doi":"10.1158/2767-9764.CRC-24-0069","DOIUrl":"10.1158/2767-9764.CRC-24-0069","url":null,"abstract":"<p><p>Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in patients with prostate cancer. Although underlying molecular causations driving phenotypic plasticity have been identified, therapeutic success is yet to be achieved. To identify putative master regulator transcription factors (MR-TF) driving phenotypic plasticity in prostate cancer, this work utilized a multiomic approach using genetically engineered mouse models of prostate cancer combined with patient data to identify MYB proto-oncogene like 2 (MYBL2) as a significantly enriched transcription factor in prostate cancer exhibiting phenotypic plasticity. Genetic inhibition of Mybl2 using independent murine prostate cancer cell lines representing phenotypic plasticity demonstrated Mybl2 loss significantly decreased in vivo growth as well as cell fitness and repressed gene expression signatures involved in pluripotency and stemness. Because MYBL2 is currently not druggable, a MYBL2 gene signature was employed to identify cyclin-dependent kinase-2 (CDK2) as a potential therapeutic target. CDK2 inhibition phenocopied genetic loss of Mybl2 and significantly decreased in vivo tumor growth associated with enrichment of DNA damage. Together, this work demonstrates MYBL2 as an important MR-TF driving phenotypic plasticity in prostate cancer. Furthermore, high MYBL2 activity identifies prostate cancer that would be responsive to CDK2 inhibition.</p><p><strong>Significance: </strong>Prostate cancers that escape therapy targeting the androgen receptor signaling pathways via phenotypic plasticity are currently untreatable. Our study identifies MYBL2 as a MR-TF in phenotypic plastic prostate cancer and implicates CDK2 inhibition as a novel therapeutic target for this most lethal subtype of prostate cancer.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2295-2307"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903812","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":"Activation of Cell-Intrinsic Signaling in CAR-T Cells via a Chimeric IL7R Domain.","authors":"Stamatia C Vorri, Natalie J Holl, Michael Leeming, Petya Apostolova, Andrew Marple, Jonas W Ravich, Ata Canbaz, Ruyan Rahnama, Jun Choe, Arjun Modi, Adam D Fearnow, Scott T R Walsh, Erika L Pearce, Ravi Varadhan, Challice L Bonifant","doi":"10.1158/2767-9764.CRC-24-0286","DOIUrl":"10.1158/2767-9764.CRC-24-0286","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cells can effectively treat leukemias, but sustained antitumor responses can be hindered by a lack of CAR T-cell persistence. Cytotoxic effector T cells are short-lived, and establishment of CAR-T cells with memory to ensure immune surveillance is important. Memory T cells depend on cytokine support, with IL7 activation of the IL7 receptor (IL7R) being critical. However, IL7R surface expression is negatively regulated by exposure to IL7. We aimed to support CAR T-cell persistence by equipping CAR-T cells with a sustained IL7Rα signal. We engineered T cells to constitutively secrete IL7 or to express an anti-acute myeloid leukemia-targeted IL7Rα-chimeric cytokine receptor (CCR) and characterized the phenotype of these cell types. Canonical downstream signaling was activated in CCR-T cells with IL7R activation. When coexpressed with a cytotoxic CAR, functionality of both the CCR and CAR was maintained. We designed hybrid CAR-CCR and noted membrane proximity of the intracellular domains as vital for signaling. These data show cell-intrinsic cytokine support with canonical signaling, and functionality can be provided via expression of an IL7Rα domain whether independently expressed or incorporated into a cytotoxic CAR for use in anticancer therapy.</p><p><strong>Significance: </strong>To improve the phenotype of tumor-directed T-cell therapy, we show that provision of cell-intrinsic IL7R-mediated signaling is preferable to activation of cells with exogenous IL7. We engineer this signaling via independent receptor engineering and incorporation into a CAR and validate maintained antigen-specific cytotoxic activity.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2359-2373"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11382189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057479","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":"Synergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation.","authors":"Anna Rutkowska, H Christian Eberl, Thilo Werner, Marco L Hennrich, Daniel C Sévin, Massimo Petretich, James P Reddington, Shirin Pocha, Stephan Gade, Amalia Martinez-Segura, Dmytro Dvornikov, Joel Karpiak, Gavain M A Sweetman, Christian Fufezan, Birgit Duempelfeld, Florian Braun, Christopher Schofield, Hakan Keles, David Alvarado, Zhuo Wang, Keith H Jansson, Maria Faelth-Savitski, Edward Curry, Katja Remlinger, Euan A Stronach, Bin Feng, Geeta Sharma, Kevin Coleman, Paola Grandi, Marcus Bantscheff, Giovanna Bergamini","doi":"10.1158/2767-9764.CRC-23-0549","DOIUrl":"10.1158/2767-9764.CRC-23-0549","url":null,"abstract":"<p><p>An in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signaling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of an LSS inhibitor with a PARP inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing cancer cells to levels comparable with niraparib as a single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme catalyzing the rate-limiting step in the mevalonate pathway, had a synergistic effect on tumor cell killing in cell lines and patient-derived ovarian tumor organoids. These observations suggest that concomitant inhibition of the cholesterol biosynthesis pathway and PARP activity might result in stronger efficacy of these inhibitors against tumor types highly dependent on cholesterol metabolism.</p><p><strong>Significance: </strong>The presented data indicate, to our knowledge, for the first time, the potential benefit of concomitant modulation of cholesterol biosynthesis pathway and PARP inhibition and highlight the need for further investigation to assess its translational relevance.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"2427-2443"},"PeriodicalIF":2.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11403291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141728384","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}