Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/...Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF- 2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development.展开更多
The hedgehog （Hh） signaling pathway plays an essential role in the embryonic development and homeostasis of diverse adult tissues, and its deregulation has been implicated in the tumorigenesis and metastasis of vari...The hedgehog （Hh） signaling pathway plays an essential role in the embryonic development and homeostasis of diverse adult tissues, and its deregulation has been implicated in the tumorigenesis and metastasis of various malignancies including breast cancer. Aberrant activation of the Hh pathway includes the following mechanisms： （I） Hh ligand-independent mechanism - Loss of function mutations in the Hh receptor Patched 1 （PTCH1） or gain of function mutations in the Smoothened （SMO） lead to constitutive activation of this pathway; （II） Autocrine signaling- Ith ligand produced by tumor cells stimulates the Hh signaling in tumor cells; （III） Paracrine signaling - tumor cell produced-Hh ligand activates stromal and endothelial cells that produce growth factors in microenvironment for supporting tumor growth and survival; and （IV） Reverse paracrine signaling - Hh ligand produced by stromal cells support tumor growth and survival. Upon the pathway activation, the Gli transcription factors, effectors of the Hh signaling, activate or inhibit transcription by binding to their responsive genes and interacting with the transcriptional complex. The Gli transcription factor family includes Glil, Gli2, and Gli3 （1）. Glil is a transcriptional activator whose expression has been recognized as an activation state of the Hh signaling pathway, Gli2 is either an activator or repressor, and Gli3 is a strong repressor of transcriptional activities. To date, a ligand-dependent autocrine model of activating the Hh signaling has been described in breast cancer, and both an autocrine and paracrine mechanisms in colorectal cancer, pancreatic cancer and prostate cancer （2,3）. Notably, a ligand-independent mechanism （mutationsin PTCHI and SMO） of the signaling has been well demonstrated in basal cell carcinoma and medulloblastoma （4,5）.展开更多
The US Chinese Anti-Cancer Association(USCACA)teamed up with Chinese Society of Clinical Oncology(CSCO)to host a joint session at the17th CSCO Annual Meeting on September 20th,2014in Xiamen,China.With a focus on break...The US Chinese Anti-Cancer Association(USCACA)teamed up with Chinese Society of Clinical Oncology(CSCO)to host a joint session at the17th CSCO Annual Meeting on September 20th,2014in Xiamen,China.With a focus on breakthrough cancer medicines,the session featured innovative approaches to evaluate breakthrough agents and established a platform to interactively share successful experiences from case studies of 6 novel agents from both the United States and China.The goal of the session is to inspire scientific and practical considerations for clinical trial design and strategy to expedite cancer drug development in China.A panel discussion further provided in-depth advice on advancing both early and full development of novel cancer medicines in China.展开更多
Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhi...Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints." These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibodybased therapies targeting cytotoxic T-lymphocyte antigen 4(CTLA4), programmed cell death 1(PD-1), and programmed cell death ligand 1(PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non-small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development.展开更多
Background:The combined use of anti-programmed cell death protein1(PD-1)/anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4)check-point inhibitors has been effective in various cancer types.The SouthwestOncology ...Background:The combined use of anti-programmed cell death protein1(PD-1)/anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4)check-point inhibitors has been effective in various cancer types.The SouthwestOncology Group(SWOG)Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors(DART)S1609 study investigated ipilimumab and nivolumab in ultra-rare cancers,including small cell carcinoma of the ovary,hypercalcemic type(SCCOHT).The purpose of the study wasto evaluate the potential clinical benefitof ipilimumab and nivolumab in patients with SCCOHT.Methods:DART was a prospective,open-labeled,multicenter(>1,000 US sites),multi-cohort phase II clinical trial of intravenous administration of ipilimumab(1 mg/kg,every 6 weeks)plus nivolumab(240 mg,every 2 weeks).The pri-mary endpoint was overall response rate[ORR,confirmed complete response(CR)and partial response(PR)]per RECIST.Secondary endpoints includedprogression-free survival(PFS),overall survival(OS),clinical benefit rate(CBR;overall response plus stable disease≥6 months),and toxicity.Immune responseswere also evaluated.Results:Six patients(median age,30.5 years;median,2 prior therapies;nopriorimmunotherapy exposure)with advanced/metastatic SCCOHT were evalu-able.ORR and CBR were both 16.7%(1/6)with one patient having a confirmedCR lasting 46.2+months.However,another patient had a confirmed immuneCR(iCR)with immune PFS(iPFS)of 53+months[ORR/iORR,33.3%(2/6)].Notably,the latter patient had a progressing lesion at 24 weeks after initialresponse,but with renewed regression with ongoing therapy,suggesting delayedpseudo-progression.At 12-months,3 patients remained alive.Median PFS was1.4 months(range,0.9 months-not reached);median OS was 14.2 months(2months-not reached).No adverse events caused treatment discontinuation.Conclusion:Two of 6 patients(33.3%)with SCCOHT achieved durable CR/iCRand long-term survival with ipilimumab plus nivolumab.Correlative studies todetermine response and resistance markers are ongoing.展开更多
文摘Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF- 2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development.
文摘The hedgehog （Hh） signaling pathway plays an essential role in the embryonic development and homeostasis of diverse adult tissues, and its deregulation has been implicated in the tumorigenesis and metastasis of various malignancies including breast cancer. Aberrant activation of the Hh pathway includes the following mechanisms： （I） Hh ligand-independent mechanism - Loss of function mutations in the Hh receptor Patched 1 （PTCH1） or gain of function mutations in the Smoothened （SMO） lead to constitutive activation of this pathway; （II） Autocrine signaling- Ith ligand produced by tumor cells stimulates the Hh signaling in tumor cells; （III） Paracrine signaling - tumor cell produced-Hh ligand activates stromal and endothelial cells that produce growth factors in microenvironment for supporting tumor growth and survival; and （IV） Reverse paracrine signaling - Hh ligand produced by stromal cells support tumor growth and survival. Upon the pathway activation, the Gli transcription factors, effectors of the Hh signaling, activate or inhibit transcription by binding to their responsive genes and interacting with the transcriptional complex. The Gli transcription factor family includes Glil, Gli2, and Gli3 （1）. Glil is a transcriptional activator whose expression has been recognized as an activation state of the Hh signaling pathway, Gli2 is either an activator or repressor, and Gli3 is a strong repressor of transcriptional activities. To date, a ligand-dependent autocrine model of activating the Hh signaling has been described in breast cancer, and both an autocrine and paracrine mechanisms in colorectal cancer, pancreatic cancer and prostate cancer （2,3）. Notably, a ligand-independent mechanism （mutationsin PTCHI and SMO） of the signaling has been well demonstrated in basal cell carcinoma and medulloblastoma （4,5）.
文摘The US Chinese Anti-Cancer Association(USCACA)teamed up with Chinese Society of Clinical Oncology(CSCO)to host a joint session at the17th CSCO Annual Meeting on September 20th,2014in Xiamen,China.With a focus on breakthrough cancer medicines,the session featured innovative approaches to evaluate breakthrough agents and established a platform to interactively share successful experiences from case studies of 6 novel agents from both the United States and China.The goal of the session is to inspire scientific and practical considerations for clinical trial design and strategy to expedite cancer drug development in China.A panel discussion further provided in-depth advice on advancing both early and full development of novel cancer medicines in China.
文摘Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints." These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibodybased therapies targeting cytotoxic T-lymphocyte antigen 4(CTLA4), programmed cell death 1(PD-1), and programmed cell death ligand 1(PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non-small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development.
基金National Institutes of HealthNational Cancer Institute,Grant/Award Numbers:U10CA180888,U10CA180819,UG1CA233320,UG1CA233193,UG1CA233198,UG1CA233340Bristol Myers Squibb Company。
文摘Background:The combined use of anti-programmed cell death protein1(PD-1)/anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4)check-point inhibitors has been effective in various cancer types.The SouthwestOncology Group(SWOG)Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors(DART)S1609 study investigated ipilimumab and nivolumab in ultra-rare cancers,including small cell carcinoma of the ovary,hypercalcemic type(SCCOHT).The purpose of the study wasto evaluate the potential clinical benefitof ipilimumab and nivolumab in patients with SCCOHT.Methods:DART was a prospective,open-labeled,multicenter(>1,000 US sites),multi-cohort phase II clinical trial of intravenous administration of ipilimumab(1 mg/kg,every 6 weeks)plus nivolumab(240 mg,every 2 weeks).The pri-mary endpoint was overall response rate[ORR,confirmed complete response(CR)and partial response(PR)]per RECIST.Secondary endpoints includedprogression-free survival(PFS),overall survival(OS),clinical benefit rate(CBR;overall response plus stable disease≥6 months),and toxicity.Immune responseswere also evaluated.Results:Six patients(median age,30.5 years;median,2 prior therapies;nopriorimmunotherapy exposure)with advanced/metastatic SCCOHT were evalu-able.ORR and CBR were both 16.7%(1/6)with one patient having a confirmedCR lasting 46.2+months.However,another patient had a confirmed immuneCR(iCR)with immune PFS(iPFS)of 53+months[ORR/iORR,33.3%(2/6)].Notably,the latter patient had a progressing lesion at 24 weeks after initialresponse,but with renewed regression with ongoing therapy,suggesting delayedpseudo-progression.At 12-months,3 patients remained alive.Median PFS was1.4 months(range,0.9 months-not reached);median OS was 14.2 months(2months-not reached).No adverse events caused treatment discontinuation.Conclusion:Two of 6 patients(33.3%)with SCCOHT achieved durable CR/iCRand long-term survival with ipilimumab plus nivolumab.Correlative studies todetermine response and resistance markers are ongoing.
