K-ras wild-type carcinoma is a tumour that is sensitive to treatment with anti-cancer and anti-EGFR drugs: the combination of Cetuximab and Panitumumab with chemotherapy (Cetuximab) or as a single therapy (Panitumumab...K-ras wild-type carcinoma is a tumour that is sensitive to treatment with anti-cancer and anti-EGFR drugs: the combination of Cetuximab and Panitumumab with chemotherapy (Cetuximab) or as a single therapy (Panitumumab). Case Report: The clinical case presented here refers to a 68-year-old patient who had been diagnosed with adenocarcinoma of the recto sigmoid with pelvic recurrence three years after surgery. The patient had a severe co-morbidity: correlated B-type liver cirrhosis. First-line chemotherapy was begun with Oxaliplatin plus Capecitabine (CAPOXI) following a relapse, and this continued for six months (six cycles), when the treatment was interrupted because of the disease’s progression and hematological and gastrointestinal toxicity. Following an assessment of the K-ras, diagnosed as wild type, the patient was excluded from second-line chemotherapy treatment because of decompensated cirrhosis and the persistence of thrombocytopenia and leukopenia. The patient was put forward for biological treatment with an anti-EGFR monoclonal antibody (Panitumumab). Panitumumab was administered at a dosage of 6 mg/kg every 2 weeks for 17 months;the treatment was well tolerated, despite the cirrhosis, and the main toxicity was the skin rash. Conclusion: In patients with severe comorbidities such as cirrhosis of the liver and K-ras wild-type carcinomas, therapy with a monoclonal antibody such as Panitumumab is a treatment that is well tolerated, with few serious toxic side-effects;it also offers advantages in terms of survival and clinical benefits.展开更多
BACKGROUND The combination of anti-epidermal growth factor receptor(EGFR)therapy and chemotherapy is currently a preferred first-line treatment for patients with unre-sectable,RAS and BRAF wild-type,left-sided metasta...BACKGROUND The combination of anti-epidermal growth factor receptor(EGFR)therapy and chemotherapy is currently a preferred first-line treatment for patients with unre-sectable,RAS and BRAF wild-type,left-sided metastatic colorectal cancer(mCRC).Several studies have also demonstrated the benefit of anti-EGFR therapy in sub-sequent line settings for this patient population.However,direct evidence com-paring the effectiveness of frontline vs subsequent anti-EGFR therapy remains limited,leaving a crucial gap in guiding optimal treatment strategies.AIM To compare overall survival(OS)between frontline and subsequent anti-EGFR treatment in patients with unresectable,RAS and BRAF wild-type,left-sided mCRC.METHODS We retrospectively reviewed the medical records of mCRC patients treated at The King Chulalongkorn Memorial Hospital and Songklanagarind Hospital,Thailand,between January 2013 and April 2023.Patients were classified into two groups based on the sequence of their anti-EGFR treatment.The primary endpoint was OS.RESULTS Among 222 patients with a median follow-up of 29 months,no significant difference in OS was observed between the frontline and subsequent-line groups(HR 1.03,95%CI:0.73-1.46,P=0.878).The median OS was 35.53 months(95%CI:26.59-44.47)for the frontline group and 31.60 months(95%CI:27.83-35.37)for the subsequent-line group.In the subsequent-line group,71 patients(32.4%)who ultimately never received anti-EGFR therapy had a significantly worse median OS of 19.70 months(95%CI:12.87-26.53).CONCLUSION Frontline and subsequent-line anti-EGFR treatments provide comparable OS in unresectable,RAS/BRAF wild-type,left-sided mCRC patients,but early exposure is vital for those unlikely to receive subsequent therapy.展开更多
目的:评价尼妥珠单抗联合吉西他滨(nimotuzumab plus gemcitabine,NG)一线治疗局部晚期或转移性K-Ras野生型胰腺癌患者的经济性,为相关卫生决策提供参考。方法:基于一项多中心、随机、开放标签的Ⅲ期临床试验(NCT02395016)数据构建分区...目的:评价尼妥珠单抗联合吉西他滨(nimotuzumab plus gemcitabine,NG)一线治疗局部晚期或转移性K-Ras野生型胰腺癌患者的经济性,为相关卫生决策提供参考。方法:基于一项多中心、随机、开放标签的Ⅲ期临床试验(NCT02395016)数据构建分区生存模型,模拟时限为5年,循环周期为28 d。比较NG方案和吉西他滨(gemcitabine,G)方案一线治疗局部晚期或转移性K-Ras野生型胰腺癌的经济性。以质量调整生命年(quality-adjusted life year,QALY)作为产出指标并计算增量成本-效果比(incremental cost-effectiveness ratio,ICER),采用单因素敏感性分析及概率敏感性分析评价模型参数变化对结果稳健性的影响。结果:基础分析结果显示,相较于G方案,NG方案人均成本增加304806.15元,人均效用增加0.16 QALYs,ICER为1865405.26元/QALY,高于本研究设定的268074.00元/QALY的意愿支付(willingness-to-pay,WTP)阈值。单因素敏感性分析结果表明,尼妥珠单抗的成本、肿瘤稳定状态效用和肿瘤进展状态效用对ICER的影响较大。概率敏感性分析结果显示,在WTP阈值为268074.00元/QALY时,NG方案具有经济性的概率为0。结论:与G方案相比,NG方案作为一线药物治疗局部晚期或转移性K-Ras野生型胰腺癌不具有经济性。展开更多
Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community.A classical model is the removal of polarity-deficient clones,such as the p...Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community.A classical model is the removal of polarity-deficient clones,such as the precancerous scribble(scrib)mutant clones,in Drosophila imaginal discs.The activation of Ras,Yki,or Notch signaling robustly reverses the scrib mutant clonal fate from elimination to tumorous growth.Whether these signals converge to adopt a common mechanism to overcome the elimination pressure posed by cell competition remains unclear.Using single-cell transcriptomics,we find that a critical converging point downstream of Ras,Yki,and Notch signals is the upregulation of Upd2,an IL-6 family cytokine.Overexpression of Upd2 is sufficient to rescue the scrib mutant clones from elimination.Depletion of Upd2 blocks the growth of the scrib mutant clones with active Ras,Yki,and Notch signals.Moreover,Upd2 overexpression promotes robust intestinal stem cell(ISC)proliferation,while Upd2 is intrinsically required in ISCs for the growth of the adult intestine.Together,these results identify Upd2 as a crucial cell fitness factor that sustains tissue growth but can potentiate tumorigenesis when deregulated.展开更多
OBJECTIVE To investigate the structural requirements for effective binding of andrographolide(AGP)and its derivatives(SRJ09and SRJ23)to mutant K-ras for inhibition of exchange factor binding viain silico docking simul...OBJECTIVE To investigate the structural requirements for effective binding of andrographolide(AGP)and its derivatives(SRJ09and SRJ23)to mutant K-ras for inhibition of exchange factor binding viain silico docking simulations.METHODS The molecular docking studies were carried out by using SiteMap v3.4andGlide v6.6modules(Schrdinger,Inc.).Surface mapping on the 3-D X-ray crystal structures of three mutant K-ras proteins-K-rasG12V(PDB ID:4EPX),K-rasG12C(PDB ID:4LDJ),and K-rasG12D(PDB ID:4DSU),as well as wild-type K-ras protein(PDB ID:4LPK),was performed to generate possible sites for ligand binding.Thirty conformers were generated for each of the studied compounds,and these conformers were docked into each possible binding site in both wild-type and mutant K-ras proteins.The free energy of binding of the compounds with the wild-type and mutant K-ras proteins was performed using prime molecular mechanics with generalized Born and solvent accessibility(MM-GBSA)approach.RESULTS The conformers of AGP,SRJ09 and SRJ23that were found to form the most stable complex inside each possible binding siteas indicated by the highest binding free energy,both in wild-type and mutant proteins,were selected.A common binding site between switchⅠ and Ⅱregions,where a pocket surrounded by amino acid residues Lys5,Leu6,Val7,Ser39,Asp54,Leu56,Tyr71,Thr74,and Gly75,was found in all K-rasG12 mutants.This site corresponds to the hydrophobic binding pockets having aliphatic side-chain portionsas found previously for other Ras binders,which are located betweenα-helix 2 and the core β-sheets(between switchⅠ and Ⅱregions).This common binding pocket was not observed in the wild-type K-ras.A binding pocket adjacent to switchⅡregion(amino acid 60-72),where all ligands bind well,was found instead.All compoundsanchor well inside the common binding pocket in each of the K-fasG12 mutants and these compounds showed the strongest binding interactions to K-fasG12 C.SRJ09 and SRJ23 showed stronger binding interactions to both wild-type and mutant K-ras proteins as compared with the parent compound.Overall,the compounds displayed higher binding energies toall three mutant proteins as compared to their wild-type counterpart.CONCLUSION AGP,SRJ09,and SRJ23 are potential K-ras-targeting anti-cancer agents.The compounds target both wild-type and mutant K-ras but they bind to a different binding pocket in the wild-type protein.Both binding pockets found in wild-type and mutant K-ras involve switchⅡ region that binds the guanine nucleotide exchange factor(GEF)such as Son of Sevenless.These suggest a possible inhibition of exchange factor binding to both wild-type and mutant K-ras proteins.Lower binding energies of the compounds to wild-type K-ras protein suggest a transient binding and inhibition.Stronger binding of all compounds to mutant K-ras proteins could lead to more targeted and prolonged inhibition.展开更多
文摘K-ras wild-type carcinoma is a tumour that is sensitive to treatment with anti-cancer and anti-EGFR drugs: the combination of Cetuximab and Panitumumab with chemotherapy (Cetuximab) or as a single therapy (Panitumumab). Case Report: The clinical case presented here refers to a 68-year-old patient who had been diagnosed with adenocarcinoma of the recto sigmoid with pelvic recurrence three years after surgery. The patient had a severe co-morbidity: correlated B-type liver cirrhosis. First-line chemotherapy was begun with Oxaliplatin plus Capecitabine (CAPOXI) following a relapse, and this continued for six months (six cycles), when the treatment was interrupted because of the disease’s progression and hematological and gastrointestinal toxicity. Following an assessment of the K-ras, diagnosed as wild type, the patient was excluded from second-line chemotherapy treatment because of decompensated cirrhosis and the persistence of thrombocytopenia and leukopenia. The patient was put forward for biological treatment with an anti-EGFR monoclonal antibody (Panitumumab). Panitumumab was administered at a dosage of 6 mg/kg every 2 weeks for 17 months;the treatment was well tolerated, despite the cirrhosis, and the main toxicity was the skin rash. Conclusion: In patients with severe comorbidities such as cirrhosis of the liver and K-ras wild-type carcinomas, therapy with a monoclonal antibody such as Panitumumab is a treatment that is well tolerated, with few serious toxic side-effects;it also offers advantages in terms of survival and clinical benefits.
文摘BACKGROUND The combination of anti-epidermal growth factor receptor(EGFR)therapy and chemotherapy is currently a preferred first-line treatment for patients with unre-sectable,RAS and BRAF wild-type,left-sided metastatic colorectal cancer(mCRC).Several studies have also demonstrated the benefit of anti-EGFR therapy in sub-sequent line settings for this patient population.However,direct evidence com-paring the effectiveness of frontline vs subsequent anti-EGFR therapy remains limited,leaving a crucial gap in guiding optimal treatment strategies.AIM To compare overall survival(OS)between frontline and subsequent anti-EGFR treatment in patients with unresectable,RAS and BRAF wild-type,left-sided mCRC.METHODS We retrospectively reviewed the medical records of mCRC patients treated at The King Chulalongkorn Memorial Hospital and Songklanagarind Hospital,Thailand,between January 2013 and April 2023.Patients were classified into two groups based on the sequence of their anti-EGFR treatment.The primary endpoint was OS.RESULTS Among 222 patients with a median follow-up of 29 months,no significant difference in OS was observed between the frontline and subsequent-line groups(HR 1.03,95%CI:0.73-1.46,P=0.878).The median OS was 35.53 months(95%CI:26.59-44.47)for the frontline group and 31.60 months(95%CI:27.83-35.37)for the subsequent-line group.In the subsequent-line group,71 patients(32.4%)who ultimately never received anti-EGFR therapy had a significantly worse median OS of 19.70 months(95%CI:12.87-26.53).CONCLUSION Frontline and subsequent-line anti-EGFR treatments provide comparable OS in unresectable,RAS/BRAF wild-type,left-sided mCRC patients,but early exposure is vital for those unlikely to receive subsequent therapy.
文摘目的:评价尼妥珠单抗联合吉西他滨(nimotuzumab plus gemcitabine,NG)一线治疗局部晚期或转移性K-Ras野生型胰腺癌患者的经济性,为相关卫生决策提供参考。方法:基于一项多中心、随机、开放标签的Ⅲ期临床试验(NCT02395016)数据构建分区生存模型,模拟时限为5年,循环周期为28 d。比较NG方案和吉西他滨(gemcitabine,G)方案一线治疗局部晚期或转移性K-Ras野生型胰腺癌的经济性。以质量调整生命年(quality-adjusted life year,QALY)作为产出指标并计算增量成本-效果比(incremental cost-effectiveness ratio,ICER),采用单因素敏感性分析及概率敏感性分析评价模型参数变化对结果稳健性的影响。结果:基础分析结果显示,相较于G方案,NG方案人均成本增加304806.15元,人均效用增加0.16 QALYs,ICER为1865405.26元/QALY,高于本研究设定的268074.00元/QALY的意愿支付(willingness-to-pay,WTP)阈值。单因素敏感性分析结果表明,尼妥珠单抗的成本、肿瘤稳定状态效用和肿瘤进展状态效用对ICER的影响较大。概率敏感性分析结果显示,在WTP阈值为268074.00元/QALY时,NG方案具有经济性的概率为0。结论:与G方案相比,NG方案作为一线药物治疗局部晚期或转移性K-Ras野生型胰腺癌不具有经济性。
基金supported by grants to Yan Yan from the Research Grants Council of the Hong Kong Special Administrative Region(GRF16103620,GRF16104324,T13-602/21N)from Shenzhen Science and Technology Innovation Commission(JCYJ20200109140201722)+1 种基金to Toyotaka Ishibashi from the National Natural Science Foundation of China(32170548)to Zongzhao Zhai from the National Natural Science Foundation of China(32170509 and 31871469).
文摘Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community.A classical model is the removal of polarity-deficient clones,such as the precancerous scribble(scrib)mutant clones,in Drosophila imaginal discs.The activation of Ras,Yki,or Notch signaling robustly reverses the scrib mutant clonal fate from elimination to tumorous growth.Whether these signals converge to adopt a common mechanism to overcome the elimination pressure posed by cell competition remains unclear.Using single-cell transcriptomics,we find that a critical converging point downstream of Ras,Yki,and Notch signals is the upregulation of Upd2,an IL-6 family cytokine.Overexpression of Upd2 is sufficient to rescue the scrib mutant clones from elimination.Depletion of Upd2 blocks the growth of the scrib mutant clones with active Ras,Yki,and Notch signals.Moreover,Upd2 overexpression promotes robust intestinal stem cell(ISC)proliferation,while Upd2 is intrinsically required in ISCs for the growth of the adult intestine.Together,these results identify Upd2 as a crucial cell fitness factor that sustains tissue growth but can potentiate tumorigenesis when deregulated.
基金The project supported by Ministry of Education,Malaysia(Research University Grant Scheme Grant 04-02-12-2017RU)
文摘OBJECTIVE To investigate the structural requirements for effective binding of andrographolide(AGP)and its derivatives(SRJ09and SRJ23)to mutant K-ras for inhibition of exchange factor binding viain silico docking simulations.METHODS The molecular docking studies were carried out by using SiteMap v3.4andGlide v6.6modules(Schrdinger,Inc.).Surface mapping on the 3-D X-ray crystal structures of three mutant K-ras proteins-K-rasG12V(PDB ID:4EPX),K-rasG12C(PDB ID:4LDJ),and K-rasG12D(PDB ID:4DSU),as well as wild-type K-ras protein(PDB ID:4LPK),was performed to generate possible sites for ligand binding.Thirty conformers were generated for each of the studied compounds,and these conformers were docked into each possible binding site in both wild-type and mutant K-ras proteins.The free energy of binding of the compounds with the wild-type and mutant K-ras proteins was performed using prime molecular mechanics with generalized Born and solvent accessibility(MM-GBSA)approach.RESULTS The conformers of AGP,SRJ09 and SRJ23that were found to form the most stable complex inside each possible binding siteas indicated by the highest binding free energy,both in wild-type and mutant proteins,were selected.A common binding site between switchⅠ and Ⅱregions,where a pocket surrounded by amino acid residues Lys5,Leu6,Val7,Ser39,Asp54,Leu56,Tyr71,Thr74,and Gly75,was found in all K-rasG12 mutants.This site corresponds to the hydrophobic binding pockets having aliphatic side-chain portionsas found previously for other Ras binders,which are located betweenα-helix 2 and the core β-sheets(between switchⅠ and Ⅱregions).This common binding pocket was not observed in the wild-type K-ras.A binding pocket adjacent to switchⅡregion(amino acid 60-72),where all ligands bind well,was found instead.All compoundsanchor well inside the common binding pocket in each of the K-fasG12 mutants and these compounds showed the strongest binding interactions to K-fasG12 C.SRJ09 and SRJ23 showed stronger binding interactions to both wild-type and mutant K-ras proteins as compared with the parent compound.Overall,the compounds displayed higher binding energies toall three mutant proteins as compared to their wild-type counterpart.CONCLUSION AGP,SRJ09,and SRJ23 are potential K-ras-targeting anti-cancer agents.The compounds target both wild-type and mutant K-ras but they bind to a different binding pocket in the wild-type protein.Both binding pockets found in wild-type and mutant K-ras involve switchⅡ region that binds the guanine nucleotide exchange factor(GEF)such as Son of Sevenless.These suggest a possible inhibition of exchange factor binding to both wild-type and mutant K-ras proteins.Lower binding energies of the compounds to wild-type K-ras protein suggest a transient binding and inhibition.Stronger binding of all compounds to mutant K-ras proteins could lead to more targeted and prolonged inhibition.
