Synthetic lethality is becoming more and more important in the precise treatment of oncology.Malignant tumors caused by gene mutations involve a complex DNA signaling process,and inhibition of DNA signaling in differe...Synthetic lethality is becoming more and more important in the precise treatment of oncology.Malignant tumors caused by gene mutations involve a complex DNA signaling process,and inhibition of DNA signaling in different ways may more effectively control the occurrence and development of tumors.Inhibition of tumor paired lethal genes effectively kills tumor cells,and more and more novel drugs that inhibit tumors are developing in this direction.This article reviews the synthetic lethal theory and discusses selection of drugs to target mutated genes in common solid tumors.The synthetic lethal gene pairs,representative targeted drugs,and related characteristics of four tumor types:lung cancer,breast cancer,colon cancer and prostate cancer,are systematically reviewed.展开更多
Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene and has a role in inhibiting the oncogenic AKT signaling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3 ) into phosphatidyli...Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene and has a role in inhibiting the oncogenic AKT signaling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3 ) into phosphatidylinositol 4,5-bisphosphate (PIP2 ). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumor phenotype and tumorigenesis. Identifying targeted therapies for inactive tumor suppressor genes such as PTEN has been challenging as it is difficult to restore the tumor suppressor functions. Therefore, focusing on the downstream signaling pathways to discover a targeted therapy for inactive tumor suppressor genes has highlighted the importance of synthetic lethality studies. This review focused on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.展开更多
Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancerrelated genes.Several therapeutic strategies targeting oncogenic KRAS(KRASonc) signaling pathways h...Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancerrelated genes.Several therapeutic strategies targeting oncogenic KRAS(KRASonc) signaling pathways have been suggested,including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways,targeted RNA replacement, and oncogene-induced senescence.Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy.To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date.An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.展开更多
Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrat...Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.展开更多
Synthetic nanoparticles can be used to carry drugs, genes, small interfering RNA （siRNA） and growth fac-tors into the inner ear, to repair, restore and induce cellular regeneration. Nanoparticles （NPs） have been d...Synthetic nanoparticles can be used to carry drugs, genes, small interfering RNA （siRNA） and growth fac-tors into the inner ear, to repair, restore and induce cellular regeneration. Nanoparticles （NPs） have been developed which are targetable to selected tissue, traceable in vivo, and equipped with controlled drug/gene release. The NPs are coated with a “stealth” layer, and decorated with targeting ligands, markers, transfection agents and endosomal escape peptides. As payloads, genes such as the BDNF -gene, Math1 -gene and Prestin -gene have been constructed and delivered in vitro. Short-hairpin RNA has been used in vitro to silence the negative regulator of Math1, the in-hibitors of differentiation and DNA binding. In order to facilitate the passage of cargo from the middle ear to the inner ear, the oval window transports gadolinium chelate more effciently than the round window and is the key element in introducing therapeutic agents into the vestibule and cochlea. Depending upon the type of NPs, different migration and cellular internalization pathways are employed, and optimal carriers should be designed depending on the cargo. The use of NPs as drug/gene/siRNA carriers is fascinating and can also be used as an intraoperative adjunct to cochlear implantation to attract the peripheral processes of the cochlear nerve.展开更多
文摘Synthetic lethality is becoming more and more important in the precise treatment of oncology.Malignant tumors caused by gene mutations involve a complex DNA signaling process,and inhibition of DNA signaling in different ways may more effectively control the occurrence and development of tumors.Inhibition of tumor paired lethal genes effectively kills tumor cells,and more and more novel drugs that inhibit tumors are developing in this direction.This article reviews the synthetic lethal theory and discusses selection of drugs to target mutated genes in common solid tumors.The synthetic lethal gene pairs,representative targeted drugs,and related characteristics of four tumor types:lung cancer,breast cancer,colon cancer and prostate cancer,are systematically reviewed.
基金supported by an Academy of Medical Sciences,United Kingdom/the Wellcome Trust Springboard Award(No.SBF002\1038)the Medical Research Council,United Kingdom(No.MR/S025480/1)+1 种基金supported by the Wessex Medical Trust,United KingdomFor the purpose of open access,the authors have applied a CC-BY public copyright license to any Author Accepted Manuscript version arising from this submission.
文摘Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene and has a role in inhibiting the oncogenic AKT signaling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3 ) into phosphatidylinositol 4,5-bisphosphate (PIP2 ). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumor phenotype and tumorigenesis. Identifying targeted therapies for inactive tumor suppressor genes such as PTEN has been challenging as it is difficult to restore the tumor suppressor functions. Therefore, focusing on the downstream signaling pathways to discover a targeted therapy for inactive tumor suppressor genes has highlighted the importance of synthetic lethality studies. This review focused on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.
基金supported by the European Network on Noonan Syndrome and Related Disorders (NSEuroNet, Grant No.01GM1602B)the German Federal Ministry of Education and Research(BMBF): German Network of RASopathy Research (GeNeRARe, Grant No.01GM1519D & 01GM1902C)
文摘Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancerrelated genes.Several therapeutic strategies targeting oncogenic KRAS(KRASonc) signaling pathways have been suggested,including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways,targeted RNA replacement, and oncogene-induced senescence.Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy.To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date.An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.
基金The study was supported by DOD Prostate Cancer Research Program PC150221,R.Stephenson Family Fund.
文摘Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.
文摘Synthetic nanoparticles can be used to carry drugs, genes, small interfering RNA （siRNA） and growth fac-tors into the inner ear, to repair, restore and induce cellular regeneration. Nanoparticles （NPs） have been developed which are targetable to selected tissue, traceable in vivo, and equipped with controlled drug/gene release. The NPs are coated with a “stealth” layer, and decorated with targeting ligands, markers, transfection agents and endosomal escape peptides. As payloads, genes such as the BDNF -gene, Math1 -gene and Prestin -gene have been constructed and delivered in vitro. Short-hairpin RNA has been used in vitro to silence the negative regulator of Math1, the in-hibitors of differentiation and DNA binding. In order to facilitate the passage of cargo from the middle ear to the inner ear, the oval window transports gadolinium chelate more effciently than the round window and is the key element in introducing therapeutic agents into the vestibule and cochlea. Depending upon the type of NPs, different migration and cellular internalization pathways are employed, and optimal carriers should be designed depending on the cargo. The use of NPs as drug/gene/siRNA carriers is fascinating and can also be used as an intraoperative adjunct to cochlear implantation to attract the peripheral processes of the cochlear nerve.
