Objective:We aimed to directly compare the estimated effects of adherence to a healthy lifestyle with those of risk predisposition according to known genetic variants affecting colorectal cancer(CRC)risk,to support ef...Objective:We aimed to directly compare the estimated effects of adherence to a healthy lifestyle with those of risk predisposition according to known genetic variants affecting colorectal cancer(CRC)risk,to support effective risk communication for cancer prevention.Methods:A healthy lifestyle score(HLS)was derived from 5 lifestyle factors:smoking,alcohol consumption,diet,physical activity,and body adiposity.The association of lifestyle and polygenic risk score(PRS)(based on 140 CRC-associated risk loci)with CRC risk was assessed with multiple logistic regression and compared through the genetic risk equivalent(GRE),a novel approach providing an estimate of the effects of adherence to a healthy lifestyle in terms of percentile differences in PRS.Results:A higher HLS was associated with lower CRC risk(4,844 cases,3,964 controls).Those adhering to all 5 healthy lifestyle factors had a 62%(95%CI 54%-68%)lower CRC risk than those adhering to≤2 healthy lifestyle factors.The estimated effect of adherence to all 5 compared with≤2 healthy lifestyle factors was as strong as the effect of having a 79 percentile(GRE 79,95%CI 61-97)lower PRS.The association between a healthy lifestyle and CRC risk was independent of PRS level but was particularly pronounced among those with a family history of CRC in≥1 first-degree relative(P-interaction=0.0013).Conclusions:A healthy lifestyle was strongly inversely associated with CRC risk.The large GRE indicated that CRC risk determined by polygenic risk may be offset to a substantial extent by adherence to a healthy lifestyle.展开更多
Both overall and abdominal obesity are well-established risk factors for various cancer types,including colorectal cancer(CRC)[1].However,how adiposity impacts CRC development has been insufficiently investigated.Thre...Both overall and abdominal obesity are well-established risk factors for various cancer types,including colorectal cancer(CRC)[1].However,how adiposity impacts CRC development has been insufficiently investigated.Three primary hypotheses have been suggested to elucidate the biological pathways that link adiposity and CRC:alterations in insulin signaling,dysregulation of adipose tissue-derived inflammation,and sex hormone metabolism[2,3].展开更多
Screening for colorectal cancer(CRC)is among the mosteffective approaches to cancer prevention,yet achievinghigh adherence to effective screening offers is challenging[1].Blood-based tests that could be easily impleme...Screening for colorectal cancer(CRC)is among the mosteffective approaches to cancer prevention,yet achievinghigh adherence to effective screening offers is challenging[1].Blood-based tests that could be easily implemented inroutine medical practice might be a promising approachto achieve higher adherence rates than with conven-tional stool-based or endoscopic screening[2,3].However,neoplasm detection rates of previously developed and pro-posed blood-based tests have not been competitive tothose of modern stool-based tests[2],in particular fecalimmunochemical tests(FITs)that are meanwhile widelyused for CRC screening in an increasing number of coun-tries[4].Most recently,performance of a novel cell-freeDNA(cfDNA)blood-based test for detecting colorectalneoplasms was validated in the ECLIPSE study,a largescreening population undergoing screening colonoscopy[5],being the first of its kind to achieve FDA approval asa primary screening option for CRC.展开更多
Based on intriguing findings from observational studies[1,2],colonoscopy has since long been recommended for colorectal cancer(CRC)screening,long before evidence on its effectiveness in reducing CRC incidence and mort...Based on intriguing findings from observational studies[1,2],colonoscopy has since long been recommended for colorectal cancer(CRC)screening,long before evidence on its effectiveness in reducing CRC incidence and mortality was demonstrated by a randomized controlled trial(RCT).Such evidence has only recently been provided by the Nordic-European Initiative on Colorectal Cancer(NordICC)trial[3].In this RCT,the risk of CRC was lower among those invited to undergo screening colonoscopy than among those not invited to screening.However,reported CRC risk reduction was smaller than anticipated:The authors derived risk ratios of 0.82(95%confidence interval[CI]=0.70-0.93)and 0.69(95%CI=0.55-0.83)in intention-to-screen analysis and adjusted per-protocol analysis,respectively,suggesting an 18%risk reduction of CRC among those invited for screening and a 31%risk reduction among screening attenders.展开更多
Ovarian cancer,particularly high-grade serous ovariancancer(HGSOC),remains the most lethal gynecologicalmalignancy,with a 5-year survival rate of around 40%due to late diagnosis,recurrence,and the developmentof chemor...Ovarian cancer,particularly high-grade serous ovariancancer(HGSOC),remains the most lethal gynecologicalmalignancy,with a 5-year survival rate of around 40%due to late diagnosis,recurrence,and the developmentof chemoresistance[1,2].Mutations in tumor protein 53(TP53)occur in over 96%of HGSOC cases,impairing itstumor-suppressive functions,including cell cycle control,DNA repair,and apoptosis.Mutant TP53 promotes tumorprogression,genomic instability,and resistance to stan-dard therapies,thereby worsening patient outcomes[3,4].Death-associated protein kinase 1(DAPK1)is a key reg-ulator of apoptosis and autophagy[5,6].展开更多
A recent publication by Geraghty et al.in Cell investigates how chimeric antigen receptor(CAR)T cell therapy can induce cognitive impairment in murine models of both central nervous system(CNS)-and non-CNS-based tumor...A recent publication by Geraghty et al.in Cell investigates how chimeric antigen receptor(CAR)T cell therapy can induce cognitive impairment in murine models of both central nervous system(CNS)-and non-CNS-based tumors.1 The authors identified persistent neuroinflammation as a key mechanism underlying these cognitive deficits and successfully explored novel therapeutic strategies,including microglial depletion and CCR3 blockade(Fig.1).1.展开更多
In their recently published study in Science,Popow and colleagues developed a proteolysis-targeting chimera(PROTAC)for the in vivo degradation of several oncogenic KRAS variants^(1).Leveraging detailed biophysical ana...In their recently published study in Science,Popow and colleagues developed a proteolysis-targeting chimera(PROTAC)for the in vivo degradation of several oncogenic KRAS variants^(1).Leveraging detailed biophysical analyses and crystal structures of ternary complexes of candidate ligands for KRAS and the von Hippei-Lindau(VHL)E3 ubiquitin ligase complex,they designed a small molecule capable of potently and selectively targeting 13 of the 17 most common KRAS mutants.展开更多
In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute...In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute these differential functions.Here,we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions.Experimentally,we show that human neutrophils,which are sequentially stimulated with bacteria and secreted factors from tumor cells,kill a certain proportion of tumor target cells.However,the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional,phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition.This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model.Mechanistically,we identified the antimicrobial neutrophil granule proteins neutrophil elastase(NE)and matrix metalloprotease-9(MMP-9)as the molecular mediators of this functional switch.We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9.Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis.The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.展开更多
Background Circulating cell-free tumor DNA(ctDNA)provides a non-invasive approach for assessing somatic alterations.The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integr...Background Circulating cell-free tumor DNA(ctDNA)provides a non-invasive approach for assessing somatic alterations.The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integration into clinical practice.In this context,ctDNA testing was included to understand the motivations of clinicians to initiate testing,to identify somatic alterations,and to assess the clinical impact of the results obtained.Methods Patients with advanced/metastatic breast cancer were prospectively enrolled in the Prospective Academic Translational Research Network for the Optimization of Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting(PRAEGNANT study;NCT02338167).The FDA-approved and CE-marked GUARDANT360 CDx test was used to assess somatic alterations.A ctDNA-analysis report was provided to the treating physician along with a questionnaire about the intent for testing and the clinical implications of test results.Results ctDNA from 49 patients was analyzed prospectively:37(76%)had at least one somatic alteration in the analyzed geneset;14 patients(29%)harbored alterations in TP53,12(24%)in PIK3CA,and 6(12%)in ESR1.Somatic mutations in BRCA1 or BRCA2 were detected in 3(6%)and 4(8%)patients,respectively,and 59%of patients had hormone receptor-positive,human epidermal growth factor receptor 2-negative breast cancer.Questionnaires regarding test intentions and clinical impact were completed for 48(98%)patients.These showed that ctDNA testing influenced treatment decisions for 35%of patients.Discussion The high prevalence of somatic alterations in TP53,PIK3CA,ESR1,and BRCA1/2 genes,identified by ctDNA genotyping,highlights their potential as biomarkers for targeted therapies.Detection of specific mutations affected treatment decisions,such as eligibility for alpelisib,and might further facilitate treatment with e.g.elacestrant or capiversatib in future treatment lines.展开更多
Background: Inhibition of the lymphoma surface antigen CD40 by the antagonistic CD40 antibody NVP-HCD122 (HCD122) demonstrates activity in various lymphoma subtypes. In this preclinical in vivo study we examined the s...Background: Inhibition of the lymphoma surface antigen CD40 by the antagonistic CD40 antibody NVP-HCD122 (HCD122) demonstrates activity in various lymphoma subtypes. In this preclinical in vivo study we examined the suitability of positron emission tomography (PET) using the thymidine analogue 3’-deoxy-3’-[18F]fluorothymidine (FLT) for early response assessment upon HCD122 treatment in diffuse large B cell lymphoma (DLBCL). Methods: Immunodeficient mice bearing human DLBCL xenografts (SU-DHL-4) received weekly intraperitoneal injections of HCD122. Tumor growth was followed up until Day 14. Molecular imaging with FLT-PET was performed before (Day 0) and after start of therapy (Day 2 and Day 7). On Day 14 lymphoma xenografts were explanted for immunohistochemical analysis to correlate PET findings with CD40 surface expression on tumor tissue. Results: Treatment with HCD122 significantly delayed tumor growth resulting in a tumor growth inhibition of 45% on Day 14. Significant reduction of tumor-to-background ratio (TBR) of FLT-PET was seen in treated animals on Day 7 and preceded change of tumor volume, thus predicting therapy response to HCD122. Immunohistochemical analysis of xenografts revealed significantly higher CD40 expression on treated than on untreated tissue. Moreover, we found a significant correlation between CD40 expression and FLT-PET response for xenograft tumor treated with HCD122. Conclusions: Treatment of DLBCL with the antagonistic CD40 antibody HCD122 can be monitored with FLT-PET as early as seven days after commencement of therapy and seems to increase CD40 expression on tumor tissue.展开更多
Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits t...Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.展开更多
A recent study published in Nature by Roje,Zhang and colleagues highlights the emergent role gut microbiota play in processing environmental carcinogens and raises its potential as a target for reducing cancer risk in...A recent study published in Nature by Roje,Zhang and colleagues highlights the emergent role gut microbiota play in processing environmental carcinogens and raises its potential as a target for reducing cancer risk in humans.1 This study fills yet another piece into the giant jigsaw puzzle that illustrates the central role of the dynamic structure and function of the intestinal microbiome in cancer pathogenesis and therapy efficacy.展开更多
Dear Editor,Colorectal cancer(CRC)is the third most deadly can-cer worldwide[1].The mortality of CRC has remained high due to limited treatment options for metastatic CRC(mCRC)[2].Epithelial-mesenchymal transition(EMT...Dear Editor,Colorectal cancer(CRC)is the third most deadly can-cer worldwide[1].The mortality of CRC has remained high due to limited treatment options for metastatic CRC(mCRC)[2].Epithelial-mesenchymal transition(EMT)is an important contributor to mCRC[2].The c-MYC proto-oncogene(MYC)-induced transcription factor AP4(TFAP4/AP4)isadriverofEMT,therebypresumablyfacil-itates mCRC[3,4].The mitogen-activated protein kinase(MAPK)/c-JunN-terminalkinase(JNK)/activatorprotein-1(AP-1)pathway has been implicated in the regulation of EMT and mCRC[5].展开更多
In a recently published paper in Nature,Yamagishi et al.deliver a comprehensive exploration on the mechanistic basis and subsequent emergence of resistance of targeting histone H3 lysine trimethylation(H3K27me3)using ...In a recently published paper in Nature,Yamagishi et al.deliver a comprehensive exploration on the mechanistic basis and subsequent emergence of resistance of targeting histone H3 lysine trimethylation(H3K27me3)using the EZH1–EZH2 dual inhibitor,valemetostat,in adult T cell leukemia/lymphoma(ATL)patients.展开更多
Preprint:https://doi.org/10.1101/2022.11.22.22282622.Randomized trials,cohort and modeling studies have consistently demonstrated a major impact of screening endoscopies on reducing colorectal cancer(CRC)inci-dence an...Preprint:https://doi.org/10.1101/2022.11.22.22282622.Randomized trials,cohort and modeling studies have consistently demonstrated a major impact of screening endoscopies on reducing colorectal cancer(CRC)inci-dence and mortality[1].Over time,CRC mortality starts to be lower in those who underwent screening compared to those who did not due to earlier detection of prevalent.展开更多
In a recent article in Nature,Dingpeng Zhang and colleagues1 describe a novel approach for the degradation of target proteins.Their newly designed heterobispecific antibody modality hijacks the transferrin receptor in...In a recent article in Nature,Dingpeng Zhang and colleagues1 describe a novel approach for the degradation of target proteins.Their newly designed heterobispecific antibody modality hijacks the transferrin receptor internalization machinery on one hand and simultaneously marks a protein of interest(POI)for lysosomal degradation on the other.This structure therein constitutes a promising innovative addition to the rapidly evolving field of extracellular protein degradation in cancer drug development.展开更多
Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment,but challenges related to resistance and toxicity still remain.Due to the advancement of immuno-oncology,an incr...Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment,but challenges related to resistance and toxicity still remain.Due to the advancement of immuno-oncology,an increasing number of novel immunoregulatory targets and mechanisms are being revealed,with relevant therapies promising to improve clinical immunotherapy in the foreseeable future.Therefore,comprehending the larger picture is important.In this review,we analyze and summarize the current landscape of preclinical and translational mechanistic research,drug development,and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors.Along with further clarification of cancer immunobiology and advances in antibody engineering,agents targeting additional inhibitory immune checkpoints,including LAG-3,TIM-3,TIGIT,CD47,and B7 family members are becoming an important part of cancer immunotherapy research and discovery,as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells.Exemplified by bispecific T cell engagers,newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits.Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics.Cell therapies,cancer vaccines,and oncolytic viruses are not covered in this review.This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.展开更多
The B cell lymphoma 2(BCL2)protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria.In this cutting-edge review,we summarize the basic biology regulating the BCL2 family...The B cell lymphoma 2(BCL2)protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria.In this cutting-edge review,we summarize the basic biology regulating the BCL2 family including canonical and noncanonical functions,and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions.We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras(PROTACs),antibody-drug conjugates(ADCs)and tools targeting the BH4 domain of BCL2.The first BCL2-selective BH3-mimetic,venetoclax,showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies.Following its success,several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation,alone and in combination.Genetic analysis highlights the importance of BCLX,and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins.However,the development of BH3-mimetics targeting BCL-X_(L) or MCL1 has been more challenging,with on-target toxicities including thrombocytopenia for BCL-X_(L) and cardiac toxicities for MCL1 inhibitors precluding clinical development.Tumor-specific BCL-X_(L) or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy.Taken together,we envision that the targeting of BCL2 proteins,while already a success story of translational research,may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.展开更多
Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Dr...Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Drug Administration(FDA)-approved targeted therapy,the enhancer of zeste homology 2(EZH2)inhibitor tazemetostat,achieved transient responses in only 15%of patients[2].展开更多
基金supported by the Guangzhou Elite Project (GEP)supported by grants from the German Research Council (Grant Nos. BR 1704/6-1, BR1704/6-3, BR 1704/6-4, BR 1704/6-6, CH 117/1-1, and BR 1704/17-1, HO 5117/2-1)the German Federal Ministry of Education and Research (Grant Nos. 01KH0404, 01ER0814, 01ER0815, and 01GL1712)
文摘Objective:We aimed to directly compare the estimated effects of adherence to a healthy lifestyle with those of risk predisposition according to known genetic variants affecting colorectal cancer(CRC)risk,to support effective risk communication for cancer prevention.Methods:A healthy lifestyle score(HLS)was derived from 5 lifestyle factors:smoking,alcohol consumption,diet,physical activity,and body adiposity.The association of lifestyle and polygenic risk score(PRS)(based on 140 CRC-associated risk loci)with CRC risk was assessed with multiple logistic regression and compared through the genetic risk equivalent(GRE),a novel approach providing an estimate of the effects of adherence to a healthy lifestyle in terms of percentile differences in PRS.Results:A higher HLS was associated with lower CRC risk(4,844 cases,3,964 controls).Those adhering to all 5 healthy lifestyle factors had a 62%(95%CI 54%-68%)lower CRC risk than those adhering to≤2 healthy lifestyle factors.The estimated effect of adherence to all 5 compared with≤2 healthy lifestyle factors was as strong as the effect of having a 79 percentile(GRE 79,95%CI 61-97)lower PRS.The association between a healthy lifestyle and CRC risk was independent of PRS level but was particularly pronounced among those with a family history of CRC in≥1 first-degree relative(P-interaction=0.0013).Conclusions:A healthy lifestyle was strongly inversely associated with CRC risk.The large GRE indicated that CRC risk determined by polygenic risk may be offset to a substantial extent by adherence to a healthy lifestyle.
基金funding from British Heart Foundation,Cancer Research UK,Diabetes UK,and National Institute for Health Research(NIHR)supported by the National Health Service(NHS).
文摘Both overall and abdominal obesity are well-established risk factors for various cancer types,including colorectal cancer(CRC)[1].However,how adiposity impacts CRC development has been insufficiently investigated.Three primary hypotheses have been suggested to elucidate the biological pathways that link adiposity and CRC:alterations in insulin signaling,dysregulation of adipose tissue-derived inflammation,and sex hormone metabolism[2,3].
基金funded by grants from the GermanResearch Council(DFG,grant No.BR1704/16-1)the Fed-eral Ministry of Education and Research(BMBF,grantno.01GL1712 and 01KD2104A)the German CancerAid(No.70113330).
文摘Screening for colorectal cancer(CRC)is among the mosteffective approaches to cancer prevention,yet achievinghigh adherence to effective screening offers is challenging[1].Blood-based tests that could be easily implemented inroutine medical practice might be a promising approachto achieve higher adherence rates than with conven-tional stool-based or endoscopic screening[2,3].However,neoplasm detection rates of previously developed and pro-posed blood-based tests have not been competitive tothose of modern stool-based tests[2],in particular fecalimmunochemical tests(FITs)that are meanwhile widelyused for CRC screening in an increasing number of coun-tries[4].Most recently,performance of a novel cell-freeDNA(cfDNA)blood-based test for detecting colorectalneoplasms was validated in the ECLIPSE study,a largescreening population undergoing screening colonoscopy[5],being the first of its kind to achieve FDA approval asa primary screening option for CRC.
基金supported in part by grants from the German Federal Ministry of Education and Research(grant no.01KD2104A)the German Cancer Aid(grant no.70114735).
文摘Based on intriguing findings from observational studies[1,2],colonoscopy has since long been recommended for colorectal cancer(CRC)screening,long before evidence on its effectiveness in reducing CRC incidence and mortality was demonstrated by a randomized controlled trial(RCT).Such evidence has only recently been provided by the Nordic-European Initiative on Colorectal Cancer(NordICC)trial[3].In this RCT,the risk of CRC was lower among those invited to undergo screening colonoscopy than among those not invited to screening.However,reported CRC risk reduction was smaller than anticipated:The authors derived risk ratios of 0.82(95%confidence interval[CI]=0.70-0.93)and 0.69(95%CI=0.55-0.83)in intention-to-screen analysis and adjusted per-protocol analysis,respectively,suggesting an 18%risk reduction of CRC among those invited for screening and a 31%risk reduction among screening attenders.
基金supported by grants from Deutsche Kreb-shilfe(70116875)the German Cancer Consortium(DKTK,Heidelberg).
文摘Ovarian cancer,particularly high-grade serous ovariancancer(HGSOC),remains the most lethal gynecologicalmalignancy,with a 5-year survival rate of around 40%due to late diagnosis,recurrence,and the developmentof chemoresistance[1,2].Mutations in tumor protein 53(TP53)occur in over 96%of HGSOC cases,impairing itstumor-suppressive functions,including cell cycle control,DNA repair,and apoptosis.Mutant TP53 promotes tumorprogression,genomic instability,and resistance to stan-dard therapies,thereby worsening patient outcomes[3,4].Death-associated protein kinase 1(DAPK1)is a key reg-ulator of apoptosis and autophagy[5,6].
基金supported by the Deutsche Forschungsgemeinschaft(DFG,grant number:KO5055-2-1,KO5055/3-1 to S.K.)the European Research Council(Starting Grant 756017,PoC Grant 101100460,CoG 101124203)the Bruno and Helene Jöster Foundation(360°CAR).Figures were created in BioRender.G.,K.(2025)https://BioRender.com/695n975.
文摘A recent publication by Geraghty et al.in Cell investigates how chimeric antigen receptor(CAR)T cell therapy can induce cognitive impairment in murine models of both central nervous system(CNS)-and non-CNS-based tumors.1 The authors identified persistent neuroinflammation as a key mechanism underlying these cognitive deficits and successfully explored novel therapeutic strategies,including microglial depletion and CCR3 blockade(Fig.1).1.
基金supported by the German Cancer Consortium(DKTK)Deutsche Krebshilfe(DKH#70115743)+1 种基金Deutsche Forschungsgemeinschaft(DFG SA 1374/8-1,Project-ID 515991405 to D.S.DFG SA 1374/7-1,Project-ID 515571394 to D.S.DGF SCHO 1732/2-1,Project-ID 360394750 to D.S.DFG SA 1374/6-1,Project ID 458890590 to D.S.DFG SA 1374/4-3,Project ID 219542602 to D.S.SFB 1321 Project-ID 329628492 to D.S.)the Wilhelm Sander-Stiftung(2020.174.1 and 2017.091.2 to D.S.).
文摘In their recently published study in Science,Popow and colleagues developed a proteolysis-targeting chimera(PROTAC)for the in vivo degradation of several oncogenic KRAS variants^(1).Leveraging detailed biophysical analyses and crystal structures of ternary complexes of candidate ligands for KRAS and the von Hippei-Lindau(VHL)E3 ubiquitin ligase complex,they designed a small molecule capable of potently and selectively targeting 13 of the 17 most common KRAS mutants.
基金supported by Marga and Walter Boll Stiftung,Deutsche Forschungsgemeinschaft(BR2278/8-1,HU 2795/2-1)TransRegio 332(project A4)Deutsche Krebshilfe and COST Action Mye-Infobank,supported by COST(European Cooperation in Science and Technology).
文摘In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute these differential functions.Here,we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions.Experimentally,we show that human neutrophils,which are sequentially stimulated with bacteria and secreted factors from tumor cells,kill a certain proportion of tumor target cells.However,the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional,phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition.This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model.Mechanistically,we identified the antimicrobial neutrophil granule proteins neutrophil elastase(NE)and matrix metalloprotease-9(MMP-9)as the molecular mediators of this functional switch.We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9.Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis.The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.
文摘Background Circulating cell-free tumor DNA(ctDNA)provides a non-invasive approach for assessing somatic alterations.The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integration into clinical practice.In this context,ctDNA testing was included to understand the motivations of clinicians to initiate testing,to identify somatic alterations,and to assess the clinical impact of the results obtained.Methods Patients with advanced/metastatic breast cancer were prospectively enrolled in the Prospective Academic Translational Research Network for the Optimization of Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting(PRAEGNANT study;NCT02338167).The FDA-approved and CE-marked GUARDANT360 CDx test was used to assess somatic alterations.A ctDNA-analysis report was provided to the treating physician along with a questionnaire about the intent for testing and the clinical implications of test results.Results ctDNA from 49 patients was analyzed prospectively:37(76%)had at least one somatic alteration in the analyzed geneset;14 patients(29%)harbored alterations in TP53,12(24%)in PIK3CA,and 6(12%)in ESR1.Somatic mutations in BRCA1 or BRCA2 were detected in 3(6%)and 4(8%)patients,respectively,and 59%of patients had hormone receptor-positive,human epidermal growth factor receptor 2-negative breast cancer.Questionnaires regarding test intentions and clinical impact were completed for 48(98%)patients.These showed that ctDNA testing influenced treatment decisions for 35%of patients.Discussion The high prevalence of somatic alterations in TP53,PIK3CA,ESR1,and BRCA1/2 genes,identified by ctDNA genotyping,highlights their potential as biomarkers for targeted therapies.Detection of specific mutations affected treatment decisions,such as eligibility for alpelisib,and might further facilitate treatment with e.g.elacestrant or capiversatib in future treatment lines.
文摘Background: Inhibition of the lymphoma surface antigen CD40 by the antagonistic CD40 antibody NVP-HCD122 (HCD122) demonstrates activity in various lymphoma subtypes. In this preclinical in vivo study we examined the suitability of positron emission tomography (PET) using the thymidine analogue 3’-deoxy-3’-[18F]fluorothymidine (FLT) for early response assessment upon HCD122 treatment in diffuse large B cell lymphoma (DLBCL). Methods: Immunodeficient mice bearing human DLBCL xenografts (SU-DHL-4) received weekly intraperitoneal injections of HCD122. Tumor growth was followed up until Day 14. Molecular imaging with FLT-PET was performed before (Day 0) and after start of therapy (Day 2 and Day 7). On Day 14 lymphoma xenografts were explanted for immunohistochemical analysis to correlate PET findings with CD40 surface expression on tumor tissue. Results: Treatment with HCD122 significantly delayed tumor growth resulting in a tumor growth inhibition of 45% on Day 14. Significant reduction of tumor-to-background ratio (TBR) of FLT-PET was seen in treated animals on Day 7 and preceded change of tumor volume, thus predicting therapy response to HCD122. Immunohistochemical analysis of xenografts revealed significantly higher CD40 expression on treated than on untreated tissue. Moreover, we found a significant correlation between CD40 expression and FLT-PET response for xenograft tumor treated with HCD122. Conclusions: Treatment of DLBCL with the antagonistic CD40 antibody HCD122 can be monitored with FLT-PET as early as seven days after commencement of therapy and seems to increase CD40 expression on tumor tissue.
基金This work was supported by grants from the Deutsche Krebshilfe(70114007)Wilhelm Sander Stiftung(Nr.2021.023.1),German Cancer Consortium(DKTK),Heidelberg.
文摘Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.
基金Work in the lab of FRG and MCA is funded by institutional funds from the Georg-Speyer-Haus,the LOEWE Center Frankfurt Cancer Institute(FCI)funded by the Hessen State Ministry for Higher Education,Research and the Arts LOEWE,grants to FRG from the Deutsche Forschungsgemeinschaft(FOR2438:Gr1916/11-1,SFB1292-Project ID:318346496-TP16,SFB1479-Project ID:441891347-P02,GRK2336)the German Federal Ministry of EducationResearch(BMBF,01KD2206Q/SATURN3)the European Research Council(Advanced Grant PLASTICAN-101021078).
文摘A recent study published in Nature by Roje,Zhang and colleagues highlights the emergent role gut microbiota play in processing environmental carcinogens and raises its potential as a target for reducing cancer risk in humans.1 This study fills yet another piece into the giant jigsaw puzzle that illustrates the central role of the dynamic structure and function of the intestinal microbiome in cancer pathogenesis and therapy efficacy.
基金This work was supported by German Cancer Aid/Deutsche Krebshilfe grants(70114235 and 70112245)to Heiko Hermeking.
文摘Dear Editor,Colorectal cancer(CRC)is the third most deadly can-cer worldwide[1].The mortality of CRC has remained high due to limited treatment options for metastatic CRC(mCRC)[2].Epithelial-mesenchymal transition(EMT)is an important contributor to mCRC[2].The c-MYC proto-oncogene(MYC)-induced transcription factor AP4(TFAP4/AP4)isadriverofEMT,therebypresumablyfacil-itates mCRC[3,4].The mitogen-activated protein kinase(MAPK)/c-JunN-terminalkinase(JNK)/activatorprotein-1(AP-1)pathway has been implicated in the regulation of EMT and mCRC[5].
基金supported by grants from the Deutsche Krebshilfe(#70113643)the DKTK awarded to F.D.Funding。
文摘In a recently published paper in Nature,Yamagishi et al.deliver a comprehensive exploration on the mechanistic basis and subsequent emergence of resistance of targeting histone H3 lysine trimethylation(H3K27me3)using the EZH1–EZH2 dual inhibitor,valemetostat,in adult T cell leukemia/lymphoma(ATL)patients.
基金support for this study was provided in part by grants from the German Federal Ministry of Education and Research(grant numbers 01GL1712 and 01KD2104A)the German Cancer Aid(grant number 70114735).
文摘Preprint:https://doi.org/10.1101/2022.11.22.22282622.Randomized trials,cohort and modeling studies have consistently demonstrated a major impact of screening endoscopies on reducing colorectal cancer(CRC)inci-dence and mortality[1].Over time,CRC mortality starts to be lower in those who underwent screening compared to those who did not due to earlier detection of prevalent.
文摘In a recent article in Nature,Dingpeng Zhang and colleagues1 describe a novel approach for the degradation of target proteins.Their newly designed heterobispecific antibody modality hijacks the transferrin receptor internalization machinery on one hand and simultaneously marks a protein of interest(POI)for lysosomal degradation on the other.This structure therein constitutes a promising innovative addition to the rapidly evolving field of extracellular protein degradation in cancer drug development.
基金supported by grants from 1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(No.ZYJC21003)the National Natural Science Foundation of China(Grant Nos.82373021)+2 种基金the National Clinical Research Center for Geriatrics(Z2021JC001)Sichuan Provincial Research Foundation(24NSFSC6862)Outstanding Youth Talent Foundation for Science and Technology of Sichuan Province(2022JDJQ0056).
文摘Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment,but challenges related to resistance and toxicity still remain.Due to the advancement of immuno-oncology,an increasing number of novel immunoregulatory targets and mechanisms are being revealed,with relevant therapies promising to improve clinical immunotherapy in the foreseeable future.Therefore,comprehending the larger picture is important.In this review,we analyze and summarize the current landscape of preclinical and translational mechanistic research,drug development,and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors.Along with further clarification of cancer immunobiology and advances in antibody engineering,agents targeting additional inhibitory immune checkpoints,including LAG-3,TIM-3,TIGIT,CD47,and B7 family members are becoming an important part of cancer immunotherapy research and discovery,as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells.Exemplified by bispecific T cell engagers,newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits.Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics.Cell therapies,cancer vaccines,and oncolytic viruses are not covered in this review.This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.
基金supported by the Deutsche Krebshilfe(to M.V.)the Wilhelm Sander Stiftung(to M.V.)+13 种基金the Deutsche Kinderkrebsstiftung(to M.V)the Deutsche Jose Carreras Leukamie-Stiftung(to M.V and S.M.)research funding from LOxO(to V.M.S)Y.B.is supported by a Junior Clinician Scientist grant of the Goethe-University Frankfurt and by funds of the Rudolf-GeiBendorfer-StiftungWork in MJSD lab is supported by funds from the Scott-Waudby Trustthe Hope Against Cancer charity,Cancer Research UK in conjunction with the UK Department of Health on an Experimental Cancer Medicine Center grant[MRC]by Leicester Drug Discovery and Diagnostics under the University of Leicester Institute for Precision Health[MRC-Impact Acceleration AccountMR/X502777/1]is carried out at the National Institute for Health and Care Research(NIHR)Leicester Biomedical Research Center(BRC).Additional funding was obtained from Beigene and LOXO pharmaWork in the G.B.lab is funded by grants from the Research Foundation Flanders(GOE7520N,G081821N and G094522 N)from the Research Council,KU Leuven(C14/19/099)the Central European Leuven Strategic Alliance(CELSA/23/031and CELSA/23/032)GB is member of the FWO Scientific Research Network CaSign(W0.014.22N)MC(application number 11K7122N)and TV(application number:12ZG121N)were supported by fellowships from the Research Foundation FlandersWork in SM lab is supported by project PI20/00328 from the Instituto de Salud Carlos ll(Spain)and the M.C.AndreuMemorialFund.
文摘The B cell lymphoma 2(BCL2)protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria.In this cutting-edge review,we summarize the basic biology regulating the BCL2 family including canonical and noncanonical functions,and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions.We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras(PROTACs),antibody-drug conjugates(ADCs)and tools targeting the BH4 domain of BCL2.The first BCL2-selective BH3-mimetic,venetoclax,showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies.Following its success,several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation,alone and in combination.Genetic analysis highlights the importance of BCLX,and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins.However,the development of BH3-mimetics targeting BCL-X_(L) or MCL1 has been more challenging,with on-target toxicities including thrombocytopenia for BCL-X_(L) and cardiac toxicities for MCL1 inhibitors precluding clinical development.Tumor-specific BCL-X_(L) or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy.Taken together,we envision that the targeting of BCL2 proteins,while already a success story of translational research,may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.
基金supported by a grant from the SMARCB1 associationsupported by grants from the Dr.Rolf M.Schwiete foundation(2021-007,2022-031)+11 种基金the Matthias-Lackas foundationthe Dr.Leopold und Carmen Ellinger foundationthe Deutsche Forschungsgemeinschaft(DFG 458891500)the Cancer Grand Challenges project PROTECTthe German Cancer Aid(DKH-7011411,DKH-70114278,DKH-70115315,DKH-70115914)the Ministry of Education and Research(BMBF,SMART-CARE and HEROES-AYA)the KiKa foundation(#486)the Fight Kids Cancer foundation(FKC-NEWtargets)the KiTZ-Foundation in memory of Kirstin Diehl,the KiTZPMC twinning programthe German Cancer Consortium(DKTK,PRedictAHR)the Barbara and Wilfried Mohr foundationThe laboratory of Thomas G.P.Grünewald is co-funded by the European Union(ERC,CANCERHARAKIRI,101122595).
文摘Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Drug Administration(FDA)-approved targeted therapy,the enhancer of zeste homology 2(EZH2)inhibitor tazemetostat,achieved transient responses in only 15%of patients[2].
