Three genetic mechanisms activate oncogenes in human neoplasms: 1) mutations, 2) gene amplification, and 3) chromosome rearrangements. These mechanisms result in either an alteration of protooncogene structure or an i...Three genetic mechanisms activate oncogenes in human neoplasms: 1) mutations, 2) gene amplification, and 3) chromosome rearrangements. These mechanisms result in either an alteration of protooncogene structure or an increase in protooncogene expression. The role of epigenetic aberrancies in carcinogenesis has been described earlier however to clinicians, the biological implications of epigenetic therapies to prevent cancer and the mechanisms involved have been a mystery. Furthermore, there is no biomarker suggested to track the carcinogenesis steps long before cancer develops, and this has caused a significant lack of proactive and preventive measures to be taken as all recommendations in preventive oncology are either deficiently and blindly made or through screening methods which are too late in the game. Here we explored a very different approach by applying our deepest understanding of epigenetics and carcinogenesis and even further we developed a framework where our clinical findings could translate to the research and vice versa by generating advanced and novel hypotheses on “how we get cancer”, by exploring the relation between the host and the tumor cells in a way no one had perceived before. The role of specific cancer stem cell pathways is dissected and how to inhibit each of these initiators using multitargeted epigenetic therapies and off-label medications are explained. We should admit that without considering this sophisticated amazing biological network, cancer will remain an unsolved challenge. Further, we were able to solve this unsolved puzzle by bridging the gap from a hypothetical point of view/hypothesis to possibilities that explain the clinical findings we had observed, and conclude that such an approach can completely change the way practitioners are treating cancer.展开更多
In this paper we discuss the rationale of applying a “sequential” targeted therapy with a specific application in clinical practice, given our understanding of cancer heterogenous and dynamic biology. We explore the...In this paper we discuss the rationale of applying a “sequential” targeted therapy with a specific application in clinical practice, given our understanding of cancer heterogenous and dynamic biology. We explore the advantages of “single inhibition” to combinational therapies and dual inhibition on key pathways, as well as a multi-step approach to use “oncological addiction” and “oncogenic shock” as a suicide plan for cancer. We specifically explain how the downstream targets can be used to “create” feedback loops in an advantage for creating actionable targets in upstream signaling molecules. We apply this hypothesis in the clinical setting, with superior outcomes shown in a series of case studies. We conclude that “sequential and dual inhibition” can be considered a meaningful approach to checkmate the tumor, with minimum chance of tumor resistance. We recommend further clinical studies to generate further hypotheses based on each actionable target.展开更多
The disagreements in clinical data and therapy recommendations extracted from different sources/studies are a common finding in oncology research. Knowingly “biology is less reproducible than physics and mechanic eng...The disagreements in clinical data and therapy recommendations extracted from different sources/studies are a common finding in oncology research. Knowingly “biology is less reproducible than physics and mechanic engineering”, in order to overcome the disagreements and to find common grounds, we still rely on meta-analysis and systemic reviews for the highest level of evidence. To gather systemic review data base, a bibliographic search usually is conducted in the PubMed and in Cochrane Central Register of Controlled Trials databases to address a common clinical challenge. That said, frequently due to common conflicts between articles outcomes, an opinion of a third investigator is sought. Here in this article, we propose a rationale that could explain the differences in outcomes as a result of imperfect understanding of the current research database secondary to the unique biology of the tumor, rather than statistical interpretation on findings. We believe that the differences in findings merely are based on blinded inclusion criteria, and lack of accurate companion diagnostics to correlate the magnitude of response to each therapy. The objective of this article is to discuss a strategy to overcome such discordance by providing quantitative biological measures for genomic classification and correlation of tumor response to the selected targeted therapy. We further review such analysis in a case series of Her 2 positive breast cancer and conclude that translational research would be clinically relevant when customized to the biological findings.展开更多
文摘Three genetic mechanisms activate oncogenes in human neoplasms: 1) mutations, 2) gene amplification, and 3) chromosome rearrangements. These mechanisms result in either an alteration of protooncogene structure or an increase in protooncogene expression. The role of epigenetic aberrancies in carcinogenesis has been described earlier however to clinicians, the biological implications of epigenetic therapies to prevent cancer and the mechanisms involved have been a mystery. Furthermore, there is no biomarker suggested to track the carcinogenesis steps long before cancer develops, and this has caused a significant lack of proactive and preventive measures to be taken as all recommendations in preventive oncology are either deficiently and blindly made or through screening methods which are too late in the game. Here we explored a very different approach by applying our deepest understanding of epigenetics and carcinogenesis and even further we developed a framework where our clinical findings could translate to the research and vice versa by generating advanced and novel hypotheses on “how we get cancer”, by exploring the relation between the host and the tumor cells in a way no one had perceived before. The role of specific cancer stem cell pathways is dissected and how to inhibit each of these initiators using multitargeted epigenetic therapies and off-label medications are explained. We should admit that without considering this sophisticated amazing biological network, cancer will remain an unsolved challenge. Further, we were able to solve this unsolved puzzle by bridging the gap from a hypothetical point of view/hypothesis to possibilities that explain the clinical findings we had observed, and conclude that such an approach can completely change the way practitioners are treating cancer.
文摘In this paper we discuss the rationale of applying a “sequential” targeted therapy with a specific application in clinical practice, given our understanding of cancer heterogenous and dynamic biology. We explore the advantages of “single inhibition” to combinational therapies and dual inhibition on key pathways, as well as a multi-step approach to use “oncological addiction” and “oncogenic shock” as a suicide plan for cancer. We specifically explain how the downstream targets can be used to “create” feedback loops in an advantage for creating actionable targets in upstream signaling molecules. We apply this hypothesis in the clinical setting, with superior outcomes shown in a series of case studies. We conclude that “sequential and dual inhibition” can be considered a meaningful approach to checkmate the tumor, with minimum chance of tumor resistance. We recommend further clinical studies to generate further hypotheses based on each actionable target.
文摘The disagreements in clinical data and therapy recommendations extracted from different sources/studies are a common finding in oncology research. Knowingly “biology is less reproducible than physics and mechanic engineering”, in order to overcome the disagreements and to find common grounds, we still rely on meta-analysis and systemic reviews for the highest level of evidence. To gather systemic review data base, a bibliographic search usually is conducted in the PubMed and in Cochrane Central Register of Controlled Trials databases to address a common clinical challenge. That said, frequently due to common conflicts between articles outcomes, an opinion of a third investigator is sought. Here in this article, we propose a rationale that could explain the differences in outcomes as a result of imperfect understanding of the current research database secondary to the unique biology of the tumor, rather than statistical interpretation on findings. We believe that the differences in findings merely are based on blinded inclusion criteria, and lack of accurate companion diagnostics to correlate the magnitude of response to each therapy. The objective of this article is to discuss a strategy to overcome such discordance by providing quantitative biological measures for genomic classification and correlation of tumor response to the selected targeted therapy. We further review such analysis in a case series of Her 2 positive breast cancer and conclude that translational research would be clinically relevant when customized to the biological findings.
