Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the im...Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 （PD-1） and its ligand （PD-L1）, on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab~ another anti PD-1 antibod）5 has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer （NSCLC）, supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.展开更多
Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonf...Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonfunctional because of epigenetic control or deactivating mutations. However, a correlation between HERVs and human cancer has been described and many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K(HML6) and HERV-K(HML2). Although the causative role of HERVs in cancer is controversial, data from animal models demonstrated that endogenous retroviruses are potentially oncogenic. HERV protein expression in human cells generates an immune response by activating innate and adaptive immunities. Some HERV-derived peptides have antigenic properties. For example, HERV-K(HML-6) encodes the HER-K MEL peptide recognized by CD8+ lymphocytes. In addition, HERVs are twoedged immunomodulators. HERVs show immunosuppressive activity. The presence of genomic retroviral elements in host-cell cytosol may activate an interferon type I response. Therefore, targeting HERVs through cellular vaccines or immunomodulatory drugs combined with checkpoint inhibitors is attracting interest because they could be active in human tumors.展开更多
Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific mol...Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific molecular processes. However, the shortcoming of interpreting gene lists by using predefined sets of genes has resulted in the development of novel methods that heavily rely on network-based concepts. These algorithms have the advantage that they allow a more holistic view of the signaling properties of the condition under study as well as that they are suitable for integrating different data types like gene expression, gene mutation, and even histological parameters.展开更多
Genetic alterations to serine-threonine kinase 11(STK11)have been implicated in Peutz-Jeghers syndrome and tumorigenesis.Further exploration of the context-specific roles of liver kinase B1(LKB1;encoded by STK11)obser...Genetic alterations to serine-threonine kinase 11(STK11)have been implicated in Peutz-Jeghers syndrome and tumorigenesis.Further exploration of the context-specific roles of liver kinase B1(LKB1;encoded by STK11)observed that it regulates AMP-activated protein ki-nase(AMPK)and AMPK-related kinases.Given that both migration and proliferation are enhanced with the loss of LKB1 activity combined with the prevalence of STK11 genetic alter-ations in cancer biopsies,LKB1 was markedas a tumor suppressor.However,the roleof LKB1 in tumorigenesis is paradoxical as LKB1 activates autophagy and reactive oxygen species scav-enging while dampening anoikis,which contribute to cancer cell survival.Due to the pro-tumor-igenic properties of LKB1,targeting LKB1 pathways is now relevant for cancer treatment.With the recent successes of targeting LKB1 signaling in research and clinical settings,and enhanced cytotoxicity of chemical compounds in LKB1-deficient tumors,there is now a need for LKB1 in-hibitors.However,validating LKB1 inhibitors is challenging as LKB1 adaptor proteins,nucleocy-toplasmic shuttling,and splice variants all manipulate LKB1 activity.Furthermore,STE-20-related kinase adaptor protein(STRAD)and mouse protein 25 dictate LKB1 cellular localization and kinase activity.For these reasons,prior to assessing the efficacy and potency of pharmaco-logical candidates,the functional status of LKB1 needs to be defined.Therefore,to improve the understanding of LKB1 in physiology and oncology,this review highlights the role of LKB1 in tumorigenesis and addresses the therapeutic relevancy of LKB1 inhibitors..展开更多
文摘Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 （PD-1） and its ligand （PD-L1）, on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab~ another anti PD-1 antibod）5 has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer （NSCLC）, supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.
文摘Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonfunctional because of epigenetic control or deactivating mutations. However, a correlation between HERVs and human cancer has been described and many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K(HML6) and HERV-K(HML2). Although the causative role of HERVs in cancer is controversial, data from animal models demonstrated that endogenous retroviruses are potentially oncogenic. HERV protein expression in human cells generates an immune response by activating innate and adaptive immunities. Some HERV-derived peptides have antigenic properties. For example, HERV-K(HML-6) encodes the HER-K MEL peptide recognized by CD8+ lymphocytes. In addition, HERVs are twoedged immunomodulators. HERVs show immunosuppressive activity. The presence of genomic retroviral elements in host-cell cytosol may activate an interferon type I response. Therefore, targeting HERVs through cellular vaccines or immunomodulatory drugs combined with checkpoint inhibitors is attracting interest because they could be active in human tumors.
文摘Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific molecular processes. However, the shortcoming of interpreting gene lists by using predefined sets of genes has resulted in the development of novel methods that heavily rely on network-based concepts. These algorithms have the advantage that they allow a more holistic view of the signaling properties of the condition under study as well as that they are suitable for integrating different data types like gene expression, gene mutation, and even histological parameters.
文摘Genetic alterations to serine-threonine kinase 11(STK11)have been implicated in Peutz-Jeghers syndrome and tumorigenesis.Further exploration of the context-specific roles of liver kinase B1(LKB1;encoded by STK11)observed that it regulates AMP-activated protein ki-nase(AMPK)and AMPK-related kinases.Given that both migration and proliferation are enhanced with the loss of LKB1 activity combined with the prevalence of STK11 genetic alter-ations in cancer biopsies,LKB1 was markedas a tumor suppressor.However,the roleof LKB1 in tumorigenesis is paradoxical as LKB1 activates autophagy and reactive oxygen species scav-enging while dampening anoikis,which contribute to cancer cell survival.Due to the pro-tumor-igenic properties of LKB1,targeting LKB1 pathways is now relevant for cancer treatment.With the recent successes of targeting LKB1 signaling in research and clinical settings,and enhanced cytotoxicity of chemical compounds in LKB1-deficient tumors,there is now a need for LKB1 in-hibitors.However,validating LKB1 inhibitors is challenging as LKB1 adaptor proteins,nucleocy-toplasmic shuttling,and splice variants all manipulate LKB1 activity.Furthermore,STE-20-related kinase adaptor protein(STRAD)and mouse protein 25 dictate LKB1 cellular localization and kinase activity.For these reasons,prior to assessing the efficacy and potency of pharmaco-logical candidates,the functional status of LKB1 needs to be defined.Therefore,to improve the understanding of LKB1 in physiology and oncology,this review highlights the role of LKB1 in tumorigenesis and addresses the therapeutic relevancy of LKB1 inhibitors..
