The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of the...The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of these MTAs extended the overall survival ofpatients with mCRC to a level that current chemotherapeutics alone could not achieve.In addition,improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC andMTAs have been found to have a significant role heretoo,as they aid resectability.However,for the majority of patients,mCRC remains an invariably incurabledisease necessitating continued courses of combinedtreatment modalities.During the course of these treatments,either cytotoxic or biological,cancer cells maintain their ability to acquire mitogenic mutations whichrender them resistant to treatment.Key challengesremain to identify appropriate subsets of patients whowill most likely benefit from these new MTAs and effectively select these based on validated biomarkers.Moreover,better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments,so that we can maximise the survivorship of mCRC patients.This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.展开更多
The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted...The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumour types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.展开更多
Gastric cancer and cancer of the gastro-oesophageal junction(GOJ) are the 4th most common cancer diagnoses worldwide with regional differences in incidence rates.The treatment of gastric and GOJ cancers is complex and...Gastric cancer and cancer of the gastro-oesophageal junction(GOJ) are the 4th most common cancer diagnoses worldwide with regional differences in incidence rates.The treatment of gastric and GOJ cancers is complex and requires multimodality treatment including chemotherapy treatment,surgery,and radiotherapy.During the past decade considerable improvements were achieved by advanced surgical techniques,tailored chemotherapies/radiotherapy and technical innovations in clinical diagnostics.In patients with advanced or metastatic gastric/GOJ cancer systemic chemotherapy with fluoropyrimidine/platinum-based regimens(+/-human epidermal growth factor receptor-2 antibody) is the mainstay of treatment.Despite these improvements,the clinical outcome for patients with advanced or metastatic disease is generally poor with 5-year survival rates ranging between 5%-15%.These poor survival rates may to some extent be related that standard therapies beyond first-line therapies have never been defined.Considering that this patient population is often not fit enough to receive further treatments there is an increasing body of evidence from phase-2 studies that in fact second-line therapies may have a positive impact in terms of overall survival.Moreover two recently published phase-3 studies support the use of second-line chemotherapy.A South Korean study compared either,irinotecan or docetaxel with best supportive care and a German study compared irinotecan with best supportive care-both studies met their primary endpoint overall survival.In this "Field of Vision" article,we review these recently published phase-3 studies and put them into the context of clinical prognostic factors helping to guide treatment decisions in patients who most likely benefit.展开更多
There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-sma...There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.展开更多
Small-cell lung cancer(SCLC)encounters up 15%of all lung cancers,and is characterized by a high rate of proliferation,a tendency for early metastasis and generally poor prognosis.Most of the patients present with dist...Small-cell lung cancer(SCLC)encounters up 15%of all lung cancers,and is characterized by a high rate of proliferation,a tendency for early metastasis and generally poor prognosis.Most of the patients present with distant metastatic disease at the time of clinical diagnosis,and only one-third are eligible for potentially curative treatment.Recently,investigations into the genomic make-up of SCLC show extensive chromosomal rearrangements,high mutational burden and loss-of-function mutations of several tumor suppressor genes.Although the clinical development of new treatments for SCLC has been limited in recent years,a better understanding of oncogenic driver alterations has found potential novel targets that might be suitable for therapeutic approaches.Currently,there are six types of potential treatable signaling pathways in SCLC,including signaling pathways targeting the cell cycle and DNA repair,tumor development,cell metabolism,epigenetic regulation,tumor immunity and angiogenesis.At this point,however,there is still a lack of understanding of their role in SCLC tumor biology and the promotion of cancer growth.Importantly optimizing drug targets,improving drug pharmacology,and identifying potential biomarkers are the main focus and further efforts are required to recognize patients who benefit most from novel therapies in development.This review will focus on the current learning on the signaling pathways,the status of immunotherapy,and targeted therapy in SCLC.展开更多
文摘The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of these MTAs extended the overall survival ofpatients with mCRC to a level that current chemotherapeutics alone could not achieve.In addition,improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC andMTAs have been found to have a significant role heretoo,as they aid resectability.However,for the majority of patients,mCRC remains an invariably incurabledisease necessitating continued courses of combinedtreatment modalities.During the course of these treatments,either cytotoxic or biological,cancer cells maintain their ability to acquire mitogenic mutations whichrender them resistant to treatment.Key challengesremain to identify appropriate subsets of patients whowill most likely benefit from these new MTAs and effectively select these based on validated biomarkers.Moreover,better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments,so that we can maximise the survivorship of mCRC patients.This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.
基金The Drug Development Unit of the Royal Marsden NHS Foundation TrustThe Institute of Cancer Research is supported in part by a program grant from Cancer Research U.K.+1 种基金Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research)the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research)
文摘The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumour types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.
文摘Gastric cancer and cancer of the gastro-oesophageal junction(GOJ) are the 4th most common cancer diagnoses worldwide with regional differences in incidence rates.The treatment of gastric and GOJ cancers is complex and requires multimodality treatment including chemotherapy treatment,surgery,and radiotherapy.During the past decade considerable improvements were achieved by advanced surgical techniques,tailored chemotherapies/radiotherapy and technical innovations in clinical diagnostics.In patients with advanced or metastatic gastric/GOJ cancer systemic chemotherapy with fluoropyrimidine/platinum-based regimens(+/-human epidermal growth factor receptor-2 antibody) is the mainstay of treatment.Despite these improvements,the clinical outcome for patients with advanced or metastatic disease is generally poor with 5-year survival rates ranging between 5%-15%.These poor survival rates may to some extent be related that standard therapies beyond first-line therapies have never been defined.Considering that this patient population is often not fit enough to receive further treatments there is an increasing body of evidence from phase-2 studies that in fact second-line therapies may have a positive impact in terms of overall survival.Moreover two recently published phase-3 studies support the use of second-line chemotherapy.A South Korean study compared either,irinotecan or docetaxel with best supportive care and a German study compared irinotecan with best supportive care-both studies met their primary endpoint overall survival.In this "Field of Vision" article,we review these recently published phase-3 studies and put them into the context of clinical prognostic factors helping to guide treatment decisions in patients who most likely benefit.
文摘There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.
文摘Small-cell lung cancer(SCLC)encounters up 15%of all lung cancers,and is characterized by a high rate of proliferation,a tendency for early metastasis and generally poor prognosis.Most of the patients present with distant metastatic disease at the time of clinical diagnosis,and only one-third are eligible for potentially curative treatment.Recently,investigations into the genomic make-up of SCLC show extensive chromosomal rearrangements,high mutational burden and loss-of-function mutations of several tumor suppressor genes.Although the clinical development of new treatments for SCLC has been limited in recent years,a better understanding of oncogenic driver alterations has found potential novel targets that might be suitable for therapeutic approaches.Currently,there are six types of potential treatable signaling pathways in SCLC,including signaling pathways targeting the cell cycle and DNA repair,tumor development,cell metabolism,epigenetic regulation,tumor immunity and angiogenesis.At this point,however,there is still a lack of understanding of their role in SCLC tumor biology and the promotion of cancer growth.Importantly optimizing drug targets,improving drug pharmacology,and identifying potential biomarkers are the main focus and further efforts are required to recognize patients who benefit most from novel therapies in development.This review will focus on the current learning on the signaling pathways,the status of immunotherapy,and targeted therapy in SCLC.
