This article discusses the role of epithelial mesenchymal transition (EMT) and addresses the scientific merits on epigenetic regulation of EMT. The importance of EMT as a prognostic biomarker is explored and the ratio...This article discusses the role of epithelial mesenchymal transition (EMT) and addresses the scientific merits on epigenetic regulation of EMT. The importance of EMT as a prognostic biomarker is explored and the rationale on application of multitargeted epigenetic therapy is discussed. We describe a literature review of the epigenetic influence of such process and we present a potentially effective method to reverse the epigenetic switch in favor for MET, in a clinical setting. A case series of advanced solid tumors are summarized aiming at generating hypothesis for the future recommendations for clinical trials targeting the tumor’s biological behavior through inhibition of EMT. Hypothesis: We propose an integral and integrative approach that can modify tumor’s biological behavior through inhibition of EMT, and further reduce the chances of metastasis, that can translate to improved outcome and patient’s survival in advanced disease.展开更多
In most cases, cancer develops as a result of non-inheritable somatic mutations (epimutations), acquired by the individual adult cell, during the evolution of the cell, and propagated into an expanding clone of progen...In most cases, cancer develops as a result of non-inheritable somatic mutations (epimutations), acquired by the individual adult cell, during the evolution of the cell, and propagated into an expanding clone of progeny of the cells by natural selection [1]. The role of microenvironment in selection for such acquired mutations, or epimutations, is a focus of scientific research in carcinogenesis [2]. Here we describe a defective DNA response to hypoxia due to epigenetic aberrancies, in cancer cellular biology [3]. We also summarize a literature review on hypoxia mediated epigenetic responses, and its role in carcinogenesis and metastasis. Further, we review a novel method of treating hypoxic solid tumors with a combination of epigenetic modifiers with both in vitro and in vivo results in human, translating to an improved prognosis and clinical outcome. We propose that this approach both independently and synergistically (with the current standard of care) can provide an improved outcome.展开更多
Mutations in the KRAS gene have long been implicated in the pathogenesis of colorectal cancer(CRC).KRAS G12C inhibitors overcome the“undruggable”challenge,enabling precision therapy.Garsorasib(D-1553),a highly poten...Mutations in the KRAS gene have long been implicated in the pathogenesis of colorectal cancer(CRC).KRAS G12C inhibitors overcome the“undruggable”challenge,enabling precision therapy.Garsorasib(D-1553),a highly potent and selective KRAS G12C inhibitor,has demonstrated promising anti-tumor activity and favorable safety profile in early clinical trials.We conducted an openlabel,nonrandomized phase II trial(ClinicalTrials.gov,NCT04585035)to assess the safety and efficacy of garsorasib with or without cetuximab in KRAS G12C-mutated CRC.In the monotherapy cohort(n=26),objective response rate(ORR)was 19.2%(95%CI,6.6-39.4),disease control rate(DCR)was 92.3%(95%CI,74.9-99.1),median progression-free survival(PFS)was 5.5 months(95%CI,2.9-11.6)and median overall survival(OS)was 13.1 months(95%CI,9.5-NE).In the combination cohort(n=42),ORR was 45.2%(95%CI,29.8-61.3),DCR was 92.9%(95%CI,80.5-98.5),median PFS was 7.5 months(95%CI,5.5-8.1),and median OS was not reached.Grade≥3 treatment-related adverse events occurred in 5(19.2%)and 6(14.3%)patients in monotherapy and combination cohort,respectively.Garsorasib with or without cetuximab showed a promising efficacy and manageable safety profiles in heavily pretreated patients with KRAS G12C-mutated CRC,providing a potential new treatment approach for such population.展开更多
文摘This article discusses the role of epithelial mesenchymal transition (EMT) and addresses the scientific merits on epigenetic regulation of EMT. The importance of EMT as a prognostic biomarker is explored and the rationale on application of multitargeted epigenetic therapy is discussed. We describe a literature review of the epigenetic influence of such process and we present a potentially effective method to reverse the epigenetic switch in favor for MET, in a clinical setting. A case series of advanced solid tumors are summarized aiming at generating hypothesis for the future recommendations for clinical trials targeting the tumor’s biological behavior through inhibition of EMT. Hypothesis: We propose an integral and integrative approach that can modify tumor’s biological behavior through inhibition of EMT, and further reduce the chances of metastasis, that can translate to improved outcome and patient’s survival in advanced disease.
文摘In most cases, cancer develops as a result of non-inheritable somatic mutations (epimutations), acquired by the individual adult cell, during the evolution of the cell, and propagated into an expanding clone of progeny of the cells by natural selection [1]. The role of microenvironment in selection for such acquired mutations, or epimutations, is a focus of scientific research in carcinogenesis [2]. Here we describe a defective DNA response to hypoxia due to epigenetic aberrancies, in cancer cellular biology [3]. We also summarize a literature review on hypoxia mediated epigenetic responses, and its role in carcinogenesis and metastasis. Further, we review a novel method of treating hypoxic solid tumors with a combination of epigenetic modifiers with both in vitro and in vivo results in human, translating to an improved prognosis and clinical outcome. We propose that this approach both independently and synergistically (with the current standard of care) can provide an improved outcome.
基金sponsored by InventisBio.Medical writing assistance for this manuscript was provided by Xinying Liu from InventisBio.
文摘Mutations in the KRAS gene have long been implicated in the pathogenesis of colorectal cancer(CRC).KRAS G12C inhibitors overcome the“undruggable”challenge,enabling precision therapy.Garsorasib(D-1553),a highly potent and selective KRAS G12C inhibitor,has demonstrated promising anti-tumor activity and favorable safety profile in early clinical trials.We conducted an openlabel,nonrandomized phase II trial(ClinicalTrials.gov,NCT04585035)to assess the safety and efficacy of garsorasib with or without cetuximab in KRAS G12C-mutated CRC.In the monotherapy cohort(n=26),objective response rate(ORR)was 19.2%(95%CI,6.6-39.4),disease control rate(DCR)was 92.3%(95%CI,74.9-99.1),median progression-free survival(PFS)was 5.5 months(95%CI,2.9-11.6)and median overall survival(OS)was 13.1 months(95%CI,9.5-NE).In the combination cohort(n=42),ORR was 45.2%(95%CI,29.8-61.3),DCR was 92.9%(95%CI,80.5-98.5),median PFS was 7.5 months(95%CI,5.5-8.1),and median OS was not reached.Grade≥3 treatment-related adverse events occurred in 5(19.2%)and 6(14.3%)patients in monotherapy and combination cohort,respectively.Garsorasib with or without cetuximab showed a promising efficacy and manageable safety profiles in heavily pretreated patients with KRAS G12C-mutated CRC,providing a potential new treatment approach for such population.
