AIM To investigate the relationship between the onsets of multikinase inhibitor(MKI)-associated hand-foot skin reaction(HFSR) and prognosis under intervention by pharmacists after the introduction of sorafenib.METHODS...AIM To investigate the relationship between the onsets of multikinase inhibitor(MKI)-associated hand-foot skin reaction(HFSR) and prognosis under intervention by pharmacists after the introduction of sorafenib.METHODS We conducted a retrospective study involving 40 patients treated with sorafenib. Intervention by pharmacists began at the time of treatment introduction and continued until the appearance of symptomatic exacerbation or non-permissible adverse reactions. We examined the relationship between MKI-associated HFSR and overall survival(OS) after the initiation of treatment.RESULTS The median OS was 10.9 mo in the MKI-associated HFSR group and 3.4 mo in the no HFSR group, showing a significant difference in multivariate analysis. A multivariate analysis of the time to treatment failure indicated that the intervention by pharmacists and MKI-associated HFSR were significant factors. The median cumulative dose and the mean medication possession ratio were significantly higher in the intervention group than in the non-intervention group. A borderline significant difference was observed in terms of OS in this group.CONCLUSION Intervention by pharmacists increased drug adherence. Under increased adherence, MKI-associated HFSR was an advantageous surrogate marker. Intervention by healthcare providers needs to be performed for adequate sorafenib treatment.展开更多
The current landscape for advanced hepatocellular carcinoma(HCC)has evolved drastically in recent years,with the ever-increasing development of novel standard first-line therapeutic strategies(e.g.,the combination of ...The current landscape for advanced hepatocellular carcinoma(HCC)has evolved drastically in recent years,with the ever-increasing development of novel standard first-line therapeutic strategies(e.g.,the combination of atezolizumab and bevacizumab)and the approval of several new agents for second line strategies,such as regorafenib and cabozantinib(1,2).Although a large number of treatment options are available for advanced HCC patients,multikinase inhibitor(MKI)-based immunotherapy doublet has become notably complex,especially after the publication of the COSMIC-312 trial(3).This study evaluated the efficacy and safety of cabozantinib combined with atezolizumab versus sorafenib as the first-line treatment of patients with advanced HCC.Although the primary endpoint of progression-free survival(PFS)was significantly improved with treatment using cabozantinib combined with atezolizumab compared with sorafenib in the COSMIC-312 trial,the overall survival(OS)did not improve,and the response rate was lower than expected(3).Nevertheless,this was a crucial randomized controlled trial(RCT)evaluating the efficacy of MKI-based immunotherapy doublet as the first-line systemic therapy for advanced HCC,paving the way for future investigations to determine the underlying mechanism of these connections.We have several concerns with the interpretation of this study.展开更多
Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different mult...Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different multikinase inhibitor,was shown to be non-inferior to sorafenib,in terms of survival,while all other agents previously tested failed to prove non-inferiority(or superiority)when compared to sorafenib.Similarly,in the second-line setting,most investigational drugs failed to provide better survival outcomes than placebo.However,in the last 2 years three positive phase III trials have been published in this setting.The RESORCE trial,a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib,showed better outcomes with regorafenib compared to placebo.More recently,the phase III CELESTIAL trial demonstrated the superiority of cabozantinib,a multikinase inhibitor targeting vascular endothelial growth factor receptor,MET,and AXL,vs placebo in the second-and third-line setting in patients progressing on or intolerant to sorafenib.The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels.Overall,the adverse events reported in these trials were in line with the known safety profiles of the tested agents.After nearly a decade of a certain degree of stagnation,we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.展开更多
Hepatocellular carcinoma(HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality.Although there is a broad spectrum of treatment options to choose from,only a few patien...Hepatocellular carcinoma(HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality.Although there is a broad spectrum of treatment options to choose from,only a few patients are eligible candidates to receive a curative therapy according to their stage of disease,and thus palliative treatment is implemented in the majority of the patients suffering from liver cancer.Sorafenib,a multikinase inhibitor,is the only currently approved agent for systemic therapy in patients with advanced stage HCC and early stage liver disease.It has been shown to improve the overall survival,but with various side effects,while its cost is not negligible.Sorafenib has been in the market for a decade and has set the stage for personalized targeted therapy.Its role during this time has ranged from monotherapy to neoadjuvant and adjuvant treatment with surgical resection,liver transplantation and chemoembolization or even in combination with other chemotherapeutic agents.In this review our aim is to highlight in depth the current position of Sorafenib in the armamentarium against HCC and how that has evolved over time in its use either as a single agent or in combination with other therapies.展开更多
Objective:To examine the efficacy and safety of anlotinib as first-line therapy to treat locally advanced or metastatic soft-tissue sarcoma.Methods:This is a single-arm trial.Treatment-naïve patients(≥14 years)w...Objective:To examine the efficacy and safety of anlotinib as first-line therapy to treat locally advanced or metastatic soft-tissue sarcoma.Methods:This is a single-arm trial.Treatment-naïve patients(≥14 years)with locally advanced or metastatic soft tissue sarcoma were eligible.Each treatment cycle lasted for 3 weeks,and included liposomal doxorubicin(40-50 mg/m^(2))on day 1 and anlotinib(12 mg)on days 8-21.Starting from the 9th cycle,treatment consisted of only anlotinib.Treatment continued until disease progression or intolerable toxicities.The primary efficacy end point was progression-free survival(PFS).Results:Eight patients were enrolled between July 25,2019 and January 8,2020.The median number of treatment cycles was 5.5.Within 5.9 months median follow-up,PFS events occurred in 4(4/8,50%)patients.The median PFS was 11.3 months and the 6-month PFS rate was 56%.No patients attained complete response and 2 patients(fibrosarcoma,1 patient and undifferentiated pleomorphic sarcoma,1 patient)achieved partial response.Three patients(fibrosarcoma,2 patients and synovial sarcoma,1 patient)had stable disease.The objective response rate was 25%(2/8)for the study population,and the disease control rate was 75%(6/8).No new safety concerns emerged.Conclusions:Anlotinib plus liposomal doxorubicin demonstrated antitumor activities in previously untreated locally advanced or metastatic soft tissue sarcomas.Due to the small sample size,further investigations with a larger population should be undertaken to confirm the study findings.展开更多
The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially increased.Approximately 10%of patients with DTC exhibit recurrent or metastatic dise...The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially increased.Approximately 10%of patients with DTC exhibit recurrent or metastatic disease,and about two-thirds of the latter will be defined as refractory to radioactive iodine(RAIR)treatment.Since this condition implies 10-year survival rates less than 10% after detection,using available treatments,such as systemic and targeted therapies,have become increasingly relevant.The initiation of these treatments aims to reach stabilization,tumor volume reduction,and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient’s features.Considering that despite enlarged progression-free survival was proven,multikinase inhibitors remain non-curative,their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction.In this context,molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy,progression free survival,overall survival and adverse events profile.This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC,including approved target therapies as well as those for off-label use,RAI resensitization agents,and immunotherapy.展开更多
Inositol 1,4,5-trisphosphate 3-kinase(IP33-kinase/IP3K)plays an important role in signal transduction in animal cellsby phosphorylating inositol 1,4,5-trisphosphate(IP3)to inositol 1,3,4,5-tetrakisphosphate(IP4).Both ...Inositol 1,4,5-trisphosphate 3-kinase(IP33-kinase/IP3K)plays an important role in signal transduction in animal cellsby phosphorylating inositol 1,4,5-trisphosphate(IP3)to inositol 1,3,4,5-tetrakisphosphate(IP4).Both IP3 and IP4 arecritical second messengers which regulate calcium(Ca2+)homeostasis.Mammalian IP3Ks are involved in many biologicalprocesses,including brain development,memory,learning and so on.It is widely reported that Ca2+is a canonicalsecond messenger in higher plants.Therefore,plant IP3K should also play a crucial role in plant development.Recently,we reported the identification of plant IP3K gene(AtIpk2β/AtIP3K)from Arabidopsis thaliana and its characterization.Here,we summarize the molecular cloning,biochemical properties and biological functions of IP3Ks from animal,yeastand plant.This review also discusses potential functions of IP3Ks in signaling crosstalk,inositol phosphate metabolism,gene transcriptional control and so on.展开更多
Renal cell carcinoma (RCC) is known as a highly aggressive malignancy with frequent metastasis that the major sites being lungs, lymphatic ganglions, bones, liver and brain. Cutaneous metastasis is uncommon with only ...Renal cell carcinoma (RCC) is known as a highly aggressive malignancy with frequent metastasis that the major sites being lungs, lymphatic ganglions, bones, liver and brain. Cutaneous metastasis is uncommon with only a few reported cases in the literature. We report a case of a women patient aged 49 years old with RCC who underwent nephrectomy and 8 months previously, she consulted the dermatological service due to the development of recent skin lesions that had been diagnosed as cutaneous metastasis of her RCC. The treatment has associated surgical excision and systemic therapy based on sunitinib.展开更多
BACKGROUND Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer(mCRC).Regorafenib has shown significant benefits in ov...BACKGROUND Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer(mCRC).Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy.AIM To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib.METHODS Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers.The proteins evaluated(TNF-α,TGF-β,VEGF,CCL-2,CCL-4,and CCL-5)were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis.RESULTS We found that TNF-αbasal level was significantly higher in mCRC patients compared to healthy individuals.Non Responder(NR)patients showing progression of disease(n=12)had higher basal level of TGF-β,TNF-α,VEGF,CCL-2 and CCL-5 compared to Responder(R)patients(complete response CR,n=1;partial response PR,n=1;Stable Disease SD,n=3).On the contrary,plasma basal level of CCL-4 was higher in R compared to NR patients.High values of TGF-βand TNF-αnegatively correlated with progression free survival.CONCLUSION These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.展开更多
Hepatocellular carcinoma (HCC) is a dreadful cancer and a major cause of death among patients with chronic liver disease and cirrhosis. The apparent alterations in a diversity of intracellular pathways found in HCC ha...Hepatocellular carcinoma (HCC) is a dreadful cancer and a major cause of death among patients with chronic liver disease and cirrhosis. The apparent alterations in a diversity of intracellular pathways found in HCC has set the rational for developing molecular-directed drugs that simultaneously inhibit multiple pathways, such as the multi-kinase inhibitor Sorafenib. However, recently this concept has been challenged by showing that HCC is heavily dependent on a single oncogene designated late SV-40 factor (LSF), a transcription factor that is over-expressed in liver cancer cells and that its expression is strongly correlated with tumor grade and aggressiveness. Furthermore, using an intensive screening for drugs that inhibit LSF activity, Grant et al have found a molecule designated factor quinolinone inhibitor 1 that can specifically block the ability of LSF to bind its target promoters, resulting in a massive death of HCC cells both in vitro and in vivo. The innovative findings of HCC representing "oncogene addiction" to LSF and the ability of a single molecule to block the activity of this oncogene resulting in tumor abolishment are encouraging and provide us with the hope that the "Achilles heel" of HCC has been found.展开更多
HA121-28,a promising multikinase inhibitor,mainly targets rearranged during transfection(RET)fusions and selectively targets vascular endothelial growth factor receptor-2,endothelial growth factor receptor,and fibrobl...HA121-28,a promising multikinase inhibitor,mainly targets rearranged during transfection(RET)fusions and selectively targets vascular endothelial growth factor receptor-2,endothelial growth factor receptor,and fibroblast growth factor receptor 1-3.The safety,pharmacokinetics,and efficacy of HA121-28 were assessed in advanced solid tumors(phase 1,ClinicalTrials.gov NCT03994484)and advanced RET fusion-positive non-small-cell lung cancer(RET-TKI naive NSCLC,phase 2,ClinicalTrials.gov NCT05117658).HA121-28 was administered orally in doses range from 25 to 800 mg under the 21-day on/7-day off scheme for a 28-day cycle in phase 1 trial.The recommended dose identified in phase 1(450 mg)was administered for patients during phase 2.The primary endpoints were the maximum tolerated dose(MTD)in phase 1 and the objective response rate(ORR)in phase 2.162 patients were enrolled in phase 1 and 48 in phase 2.A total of 600 mg once daily was set as MTD.Across 100-800 mg,the exposure of HA121-28 increased in a dose-dependent manner.Consistent between both trials,diarrhea,rash,and prolonged QTc interval,were the most reported treatment-emergent adverse events.40.0%(phase 1)and 62.5%(phase 2)patients experienced grade≥3 treatment-related adverse events,respectively.The overall ORR was 26.8%and the median progression-free survival(PFS)was 5.5 months among 97 NSCLC patients with advanced RET fusion receiving a dose at≥450 mg once daily.HA121-28 showed encouraging efficacy in advanced RET fusion NSCLC and its toxicity was tolerable in most patients.Nevertheless,cardiotoxicity is a notable concern that warrants careful attention.展开更多
文摘AIM To investigate the relationship between the onsets of multikinase inhibitor(MKI)-associated hand-foot skin reaction(HFSR) and prognosis under intervention by pharmacists after the introduction of sorafenib.METHODS We conducted a retrospective study involving 40 patients treated with sorafenib. Intervention by pharmacists began at the time of treatment introduction and continued until the appearance of symptomatic exacerbation or non-permissible adverse reactions. We examined the relationship between MKI-associated HFSR and overall survival(OS) after the initiation of treatment.RESULTS The median OS was 10.9 mo in the MKI-associated HFSR group and 3.4 mo in the no HFSR group, showing a significant difference in multivariate analysis. A multivariate analysis of the time to treatment failure indicated that the intervention by pharmacists and MKI-associated HFSR were significant factors. The median cumulative dose and the mean medication possession ratio were significantly higher in the intervention group than in the non-intervention group. A borderline significant difference was observed in terms of OS in this group.CONCLUSION Intervention by pharmacists increased drug adherence. Under increased adherence, MKI-associated HFSR was an advantageous surrogate marker. Intervention by healthcare providers needs to be performed for adequate sorafenib treatment.
文摘The current landscape for advanced hepatocellular carcinoma(HCC)has evolved drastically in recent years,with the ever-increasing development of novel standard first-line therapeutic strategies(e.g.,the combination of atezolizumab and bevacizumab)and the approval of several new agents for second line strategies,such as regorafenib and cabozantinib(1,2).Although a large number of treatment options are available for advanced HCC patients,multikinase inhibitor(MKI)-based immunotherapy doublet has become notably complex,especially after the publication of the COSMIC-312 trial(3).This study evaluated the efficacy and safety of cabozantinib combined with atezolizumab versus sorafenib as the first-line treatment of patients with advanced HCC.Although the primary endpoint of progression-free survival(PFS)was significantly improved with treatment using cabozantinib combined with atezolizumab compared with sorafenib in the COSMIC-312 trial,the overall survival(OS)did not improve,and the response rate was lower than expected(3).Nevertheless,this was a crucial randomized controlled trial(RCT)evaluating the efficacy of MKI-based immunotherapy doublet as the first-line systemic therapy for advanced HCC,paving the way for future investigations to determine the underlying mechanism of these connections.We have several concerns with the interpretation of this study.
文摘Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different multikinase inhibitor,was shown to be non-inferior to sorafenib,in terms of survival,while all other agents previously tested failed to prove non-inferiority(or superiority)when compared to sorafenib.Similarly,in the second-line setting,most investigational drugs failed to provide better survival outcomes than placebo.However,in the last 2 years three positive phase III trials have been published in this setting.The RESORCE trial,a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib,showed better outcomes with regorafenib compared to placebo.More recently,the phase III CELESTIAL trial demonstrated the superiority of cabozantinib,a multikinase inhibitor targeting vascular endothelial growth factor receptor,MET,and AXL,vs placebo in the second-and third-line setting in patients progressing on or intolerant to sorafenib.The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels.Overall,the adverse events reported in these trials were in line with the known safety profiles of the tested agents.After nearly a decade of a certain degree of stagnation,we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.
文摘Hepatocellular carcinoma(HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality.Although there is a broad spectrum of treatment options to choose from,only a few patients are eligible candidates to receive a curative therapy according to their stage of disease,and thus palliative treatment is implemented in the majority of the patients suffering from liver cancer.Sorafenib,a multikinase inhibitor,is the only currently approved agent for systemic therapy in patients with advanced stage HCC and early stage liver disease.It has been shown to improve the overall survival,but with various side effects,while its cost is not negligible.Sorafenib has been in the market for a decade and has set the stage for personalized targeted therapy.Its role during this time has ranged from monotherapy to neoadjuvant and adjuvant treatment with surgical resection,liver transplantation and chemoembolization or even in combination with other chemotherapeutic agents.In this review our aim is to highlight in depth the current position of Sorafenib in the armamentarium against HCC and how that has evolved over time in its use either as a single agent or in combination with other therapies.
文摘Objective:To examine the efficacy and safety of anlotinib as first-line therapy to treat locally advanced or metastatic soft-tissue sarcoma.Methods:This is a single-arm trial.Treatment-naïve patients(≥14 years)with locally advanced or metastatic soft tissue sarcoma were eligible.Each treatment cycle lasted for 3 weeks,and included liposomal doxorubicin(40-50 mg/m^(2))on day 1 and anlotinib(12 mg)on days 8-21.Starting from the 9th cycle,treatment consisted of only anlotinib.Treatment continued until disease progression or intolerable toxicities.The primary efficacy end point was progression-free survival(PFS).Results:Eight patients were enrolled between July 25,2019 and January 8,2020.The median number of treatment cycles was 5.5.Within 5.9 months median follow-up,PFS events occurred in 4(4/8,50%)patients.The median PFS was 11.3 months and the 6-month PFS rate was 56%.No patients attained complete response and 2 patients(fibrosarcoma,1 patient and undifferentiated pleomorphic sarcoma,1 patient)achieved partial response.Three patients(fibrosarcoma,2 patients and synovial sarcoma,1 patient)had stable disease.The objective response rate was 25%(2/8)for the study population,and the disease control rate was 75%(6/8).No new safety concerns emerged.Conclusions:Anlotinib plus liposomal doxorubicin demonstrated antitumor activities in previously untreated locally advanced or metastatic soft tissue sarcomas.Due to the small sample size,further investigations with a larger population should be undertaken to confirm the study findings.
文摘The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially increased.Approximately 10%of patients with DTC exhibit recurrent or metastatic disease,and about two-thirds of the latter will be defined as refractory to radioactive iodine(RAIR)treatment.Since this condition implies 10-year survival rates less than 10% after detection,using available treatments,such as systemic and targeted therapies,have become increasingly relevant.The initiation of these treatments aims to reach stabilization,tumor volume reduction,and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient’s features.Considering that despite enlarged progression-free survival was proven,multikinase inhibitors remain non-curative,their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction.In this context,molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy,progression free survival,overall survival and adverse events profile.This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC,including approved target therapies as well as those for off-label use,RAI resensitization agents,and immunotherapy.
基金supported by grants from the National Natural Science Foundation of China(No.30370142)the National Special Key Project on Functional Genomics and Biochip of China(No.2002AA2Z1002)the Project sponsored by the Scientific Research Foundation for the Returned Oversea Chinese Scholars,State Education Ministry.
文摘Inositol 1,4,5-trisphosphate 3-kinase(IP33-kinase/IP3K)plays an important role in signal transduction in animal cellsby phosphorylating inositol 1,4,5-trisphosphate(IP3)to inositol 1,3,4,5-tetrakisphosphate(IP4).Both IP3 and IP4 arecritical second messengers which regulate calcium(Ca2+)homeostasis.Mammalian IP3Ks are involved in many biologicalprocesses,including brain development,memory,learning and so on.It is widely reported that Ca2+is a canonicalsecond messenger in higher plants.Therefore,plant IP3K should also play a crucial role in plant development.Recently,we reported the identification of plant IP3K gene(AtIpk2β/AtIP3K)from Arabidopsis thaliana and its characterization.Here,we summarize the molecular cloning,biochemical properties and biological functions of IP3Ks from animal,yeastand plant.This review also discusses potential functions of IP3Ks in signaling crosstalk,inositol phosphate metabolism,gene transcriptional control and so on.
文摘Renal cell carcinoma (RCC) is known as a highly aggressive malignancy with frequent metastasis that the major sites being lungs, lymphatic ganglions, bones, liver and brain. Cutaneous metastasis is uncommon with only a few reported cases in the literature. We report a case of a women patient aged 49 years old with RCC who underwent nephrectomy and 8 months previously, she consulted the dermatological service due to the development of recent skin lesions that had been diagnosed as cutaneous metastasis of her RCC. The treatment has associated surgical excision and systemic therapy based on sunitinib.
文摘BACKGROUND Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer(mCRC).Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy.AIM To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib.METHODS Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers.The proteins evaluated(TNF-α,TGF-β,VEGF,CCL-2,CCL-4,and CCL-5)were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis.RESULTS We found that TNF-αbasal level was significantly higher in mCRC patients compared to healthy individuals.Non Responder(NR)patients showing progression of disease(n=12)had higher basal level of TGF-β,TNF-α,VEGF,CCL-2 and CCL-5 compared to Responder(R)patients(complete response CR,n=1;partial response PR,n=1;Stable Disease SD,n=3).On the contrary,plasma basal level of CCL-4 was higher in R compared to NR patients.High values of TGF-βand TNF-αnegatively correlated with progression free survival.CONCLUSION These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.
文摘Hepatocellular carcinoma (HCC) is a dreadful cancer and a major cause of death among patients with chronic liver disease and cirrhosis. The apparent alterations in a diversity of intracellular pathways found in HCC has set the rational for developing molecular-directed drugs that simultaneously inhibit multiple pathways, such as the multi-kinase inhibitor Sorafenib. However, recently this concept has been challenged by showing that HCC is heavily dependent on a single oncogene designated late SV-40 factor (LSF), a transcription factor that is over-expressed in liver cancer cells and that its expression is strongly correlated with tumor grade and aggressiveness. Furthermore, using an intensive screening for drugs that inhibit LSF activity, Grant et al have found a molecule designated factor quinolinone inhibitor 1 that can specifically block the ability of LSF to bind its target promoters, resulting in a massive death of HCC cells both in vitro and in vivo. The innovative findings of HCC representing "oncogene addiction" to LSF and the ability of a single molecule to block the activity of this oncogene resulting in tumor abolishment are encouraging and provide us with the hope that the "Achilles heel" of HCC has been found.
基金funded by Sun Yat-sen University clinical research 5010 program(84000-31630002)Cancer Innovative Research Program of Sun Yat-sen University Cancer Center(CIRP-SYSUCC-0004)+4 种基金the National Natural Science Foundation of China(82073396)CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-036)the Guangdong Basic and Applied Basic Research Foundation(2021A1515110697)the Guangzhou Key Research and Development Plan(202206010141)CSPC ZhongQi Pharmaceutical Technology(Shijiazhuang)Co.
文摘HA121-28,a promising multikinase inhibitor,mainly targets rearranged during transfection(RET)fusions and selectively targets vascular endothelial growth factor receptor-2,endothelial growth factor receptor,and fibroblast growth factor receptor 1-3.The safety,pharmacokinetics,and efficacy of HA121-28 were assessed in advanced solid tumors(phase 1,ClinicalTrials.gov NCT03994484)and advanced RET fusion-positive non-small-cell lung cancer(RET-TKI naive NSCLC,phase 2,ClinicalTrials.gov NCT05117658).HA121-28 was administered orally in doses range from 25 to 800 mg under the 21-day on/7-day off scheme for a 28-day cycle in phase 1 trial.The recommended dose identified in phase 1(450 mg)was administered for patients during phase 2.The primary endpoints were the maximum tolerated dose(MTD)in phase 1 and the objective response rate(ORR)in phase 2.162 patients were enrolled in phase 1 and 48 in phase 2.A total of 600 mg once daily was set as MTD.Across 100-800 mg,the exposure of HA121-28 increased in a dose-dependent manner.Consistent between both trials,diarrhea,rash,and prolonged QTc interval,were the most reported treatment-emergent adverse events.40.0%(phase 1)and 62.5%(phase 2)patients experienced grade≥3 treatment-related adverse events,respectively.The overall ORR was 26.8%and the median progression-free survival(PFS)was 5.5 months among 97 NSCLC patients with advanced RET fusion receiving a dose at≥450 mg once daily.HA121-28 showed encouraging efficacy in advanced RET fusion NSCLC and its toxicity was tolerable in most patients.Nevertheless,cardiotoxicity is a notable concern that warrants careful attention.
