The document analyzes the tumor transcriptomics profile of a patient with stage IV gallbladder cancer. It identifies the top 200 most significantly activated expression regulators in the patient's tumor using sub-network enrichment analysis software. Key regulators identified include histone deacetylases and DNA methyltransferases. The analysis suggests treatment with the HDAC inhibitor vorinostat and discusses how activated regulators like HDACs, PDCD1, and CTLA4 may be contributing to tumor proliferation and immune evasion. Graphical summaries show pathways enriched with active regulators in the tumor related to cancer hallmarks like histone modification and immune response evasion.
MED12 controls the response to multiple cancer drugs through regulation of TG...Anirudh Prahallad
This study used an RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex, as a determinant of response to ALK and EGFR inhibitors in lung cancer cell lines. The study found that suppressing MED12 expression resulted in resistance to these targeted therapies. MED12 was found to negatively regulate TGF-β receptor signaling through physical interaction, and its suppression activated TGF-β signaling. Activation of TGF-β signaling led to MEK/ERK pathway activation, which conferred resistance to MEK, BRAF, and other cancer drugs. Loss of MED12 also induced an EMT-like phenotype associated with chemotherapy resistance in other cancer types. Inhibiting TGF-β receptor signaling
Pharmacogenomics uses a patient's genetic profile to select optimal drug therapies and dosages. Gene polymorphisms like substitutions, deletions and insertions can affect drug efficacy and toxicity. Biomarkers can help predict cancer prognosis and treatment response. For example, EGFR mutations predict response to EGFR inhibitors in NSCLC, while BRAF mutations indicate response to BRAF inhibitors in melanoma. Resistance often develops from additional mutations that prevent drug binding. Combination therapies can overcome resistance by targeting alternate pathways.
Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kd...Mark Lipstein
This document summarizes a study examining the combination of a novel PI3Kδ inhibitor, TGR-1202, with the proteasome inhibitor carfilzomib for treating hematological malignancies. The study found that TGR-1202 synergizes strongly with carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary cells by silencing c-Myc translation. This synergistic effect is driven by TGR-1202's unexpected additional activity of inhibiting CK1ε, which contributes to repressing phosphorylation of 4E-BP1 and lowering c-Myc protein levels. The results suggest that TGR-1202, as a dual PI3Kδ/CK1ε inhibitor, may have
DRUG INFORMATIONOF GILTERITINIB AND ITS EFFICACY IN REFRACTORY FLT3- MUTATED AMLPARUL UNIVERSITY
Acute myeloid leukemia is a malignancy of proliferative, abnormally, or poorly differentiated cells of the hematopoietic system,
characterized by genetic heterogeneity. FMS-like tyrosine kinase 3- internal tandem duplication remains one of the most frequently mutated
genes in acute myeloid leukemia, especially in those with normal cytogenetics. The FMS-like tyrosine kinase 3- internal tandem duplication
and FLT3 tyrosine kinase domain mutations are biomarkers for high-risk acute myeloid leukemia and are associated with drug resistance
and high risk of relapse. Various FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin,
gilteritinib, and crenolanib. Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases that also act as FMS-like tyrosine
kinase 3. Gilteritinib, a next-generation tyrosine kinase inhibitor, is approved in several countries worldwide for the treatment of relapsed or
refractory acute myeloid leukemia in adults with FMS-like tyrosine kinase 3 mutations. Gilteritinib demonstrated the ability to inhibit FLT3
receptor signaling and production in cells exogenously expressing FLT3 including FLT3 internal tandem duplication and tyrosine kinase
domain mutations FLT3-D835Y and FLT3-ITD-D835Y, and it induced apoptosis in leukemic cells possessing FLT3 internal tandem
duplication. In conclusion, gilteritinib therapy led to higher percentages of patients with the response and longer survival than salvage
chemotherapy among patients with relapsed or refractory FLT3-mutated acute myeloid leukemia
This document discusses regulation of deoxynucleotide metabolism in cancer and its therapeutic implications. It describes how imbalanced levels of deoxynucleotide triphosphates (dNTPs) can lead to genomic instability and increased cancer risk. Several key points are made: 1) Enzymes like ribonucleotide reductase and SAMHD1 regulate dNTP levels and maintain genomic stability. 2) Mutations or dysregulation of these enzymes can cause elevated dNTP pools and increased mutagenesis, facilitating cancer development. 3) Many cancer therapies target dNTP synthesis pathways to inhibit tumor growth. 4) SAMHD1 specifically acts as a tumor suppressor by maintaining low dNTP levels
Maytansinoid immunoconjugate IMGN901 is cytotoxicEllen Gunn
IMGN901 is a maytansinoid immunoconjugate targeting CD56, which is expressed in 70% of multiple myeloma cases. The study evaluated IMGN901 alone and in combination with lenalidomide and dexamethasone to determine if it can overcome environmental-mediated drug resistance (EM-DR) in multiple myeloma. While adhesion to extracellular matrix reduced IMGN901 potency, it remained cytotoxic with an LC50 of 43 nM. However, only a combination of IMGN901, lenalidomide, and dexamethasone was able to overcome drug resistance arising from direct contact between multiple myeloma and stromal cells. Drug resistance in this condition was associated with upregulation of multi-drug
This study examined the expression of Kdm6a and Kdm6b genes in malignant pleural mesothelioma (MPM) cell lines and patient tumor samples. The study found that both Kdm6a and Kdm6b were significantly overexpressed at the mRNA level in MPM compared to normal mesothelial cells. However, treating MPM cell lines with a small molecule inhibitor (GSK-J4) that targets Kdm6a/b was found to have a greater anti-proliferative effect on normal mesothelial cells compared to MPM cells. Inhibition of Kdm6a/b also induced apoptosis and increased pro-inflammatory cytokine expression in MPM cells. Therefore, while
MED12 controls the response to multiple cancer drugs through regulation of TG...Anirudh Prahallad
This study used an RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex, as a determinant of response to ALK and EGFR inhibitors in lung cancer cell lines. The study found that suppressing MED12 expression resulted in resistance to these targeted therapies. MED12 was found to negatively regulate TGF-β receptor signaling through physical interaction, and its suppression activated TGF-β signaling. Activation of TGF-β signaling led to MEK/ERK pathway activation, which conferred resistance to MEK, BRAF, and other cancer drugs. Loss of MED12 also induced an EMT-like phenotype associated with chemotherapy resistance in other cancer types. Inhibiting TGF-β receptor signaling
Pharmacogenomics uses a patient's genetic profile to select optimal drug therapies and dosages. Gene polymorphisms like substitutions, deletions and insertions can affect drug efficacy and toxicity. Biomarkers can help predict cancer prognosis and treatment response. For example, EGFR mutations predict response to EGFR inhibitors in NSCLC, while BRAF mutations indicate response to BRAF inhibitors in melanoma. Resistance often develops from additional mutations that prevent drug binding. Combination therapies can overcome resistance by targeting alternate pathways.
Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kd...Mark Lipstein
This document summarizes a study examining the combination of a novel PI3Kδ inhibitor, TGR-1202, with the proteasome inhibitor carfilzomib for treating hematological malignancies. The study found that TGR-1202 synergizes strongly with carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary cells by silencing c-Myc translation. This synergistic effect is driven by TGR-1202's unexpected additional activity of inhibiting CK1ε, which contributes to repressing phosphorylation of 4E-BP1 and lowering c-Myc protein levels. The results suggest that TGR-1202, as a dual PI3Kδ/CK1ε inhibitor, may have
DRUG INFORMATIONOF GILTERITINIB AND ITS EFFICACY IN REFRACTORY FLT3- MUTATED AMLPARUL UNIVERSITY
Acute myeloid leukemia is a malignancy of proliferative, abnormally, or poorly differentiated cells of the hematopoietic system,
characterized by genetic heterogeneity. FMS-like tyrosine kinase 3- internal tandem duplication remains one of the most frequently mutated
genes in acute myeloid leukemia, especially in those with normal cytogenetics. The FMS-like tyrosine kinase 3- internal tandem duplication
and FLT3 tyrosine kinase domain mutations are biomarkers for high-risk acute myeloid leukemia and are associated with drug resistance
and high risk of relapse. Various FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin,
gilteritinib, and crenolanib. Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases that also act as FMS-like tyrosine
kinase 3. Gilteritinib, a next-generation tyrosine kinase inhibitor, is approved in several countries worldwide for the treatment of relapsed or
refractory acute myeloid leukemia in adults with FMS-like tyrosine kinase 3 mutations. Gilteritinib demonstrated the ability to inhibit FLT3
receptor signaling and production in cells exogenously expressing FLT3 including FLT3 internal tandem duplication and tyrosine kinase
domain mutations FLT3-D835Y and FLT3-ITD-D835Y, and it induced apoptosis in leukemic cells possessing FLT3 internal tandem
duplication. In conclusion, gilteritinib therapy led to higher percentages of patients with the response and longer survival than salvage
chemotherapy among patients with relapsed or refractory FLT3-mutated acute myeloid leukemia
This document discusses regulation of deoxynucleotide metabolism in cancer and its therapeutic implications. It describes how imbalanced levels of deoxynucleotide triphosphates (dNTPs) can lead to genomic instability and increased cancer risk. Several key points are made: 1) Enzymes like ribonucleotide reductase and SAMHD1 regulate dNTP levels and maintain genomic stability. 2) Mutations or dysregulation of these enzymes can cause elevated dNTP pools and increased mutagenesis, facilitating cancer development. 3) Many cancer therapies target dNTP synthesis pathways to inhibit tumor growth. 4) SAMHD1 specifically acts as a tumor suppressor by maintaining low dNTP levels
Maytansinoid immunoconjugate IMGN901 is cytotoxicEllen Gunn
IMGN901 is a maytansinoid immunoconjugate targeting CD56, which is expressed in 70% of multiple myeloma cases. The study evaluated IMGN901 alone and in combination with lenalidomide and dexamethasone to determine if it can overcome environmental-mediated drug resistance (EM-DR) in multiple myeloma. While adhesion to extracellular matrix reduced IMGN901 potency, it remained cytotoxic with an LC50 of 43 nM. However, only a combination of IMGN901, lenalidomide, and dexamethasone was able to overcome drug resistance arising from direct contact between multiple myeloma and stromal cells. Drug resistance in this condition was associated with upregulation of multi-drug
This study examined the expression of Kdm6a and Kdm6b genes in malignant pleural mesothelioma (MPM) cell lines and patient tumor samples. The study found that both Kdm6a and Kdm6b were significantly overexpressed at the mRNA level in MPM compared to normal mesothelial cells. However, treating MPM cell lines with a small molecule inhibitor (GSK-J4) that targets Kdm6a/b was found to have a greater anti-proliferative effect on normal mesothelial cells compared to MPM cells. Inhibition of Kdm6a/b also induced apoptosis and increased pro-inflammatory cytokine expression in MPM cells. Therefore, while
1) Prodigiosin, a bacterial metabolite, induces apoptosis in human breast cancer cells. Gene expression profiling found that prodigiosin strongly increased expression of the NAG-1 gene.
2) Experiments showed that prodigiosin triggers accumulation of the tumor suppressor protein p53, but induction of NAG-1 was independent of p53.
3) Prodigiosin causes inhibition of AKT and activation of glycogen synthase kinase-3B (GSK-3B). Induction of NAG-1 and apoptosis correlated with GSK-3B activation. Inhibiting GSK-3B reduced apoptosis, suggesting GSK-3B plays a key role in the proap
The next generation of glioma biomarkers: MGMT methylation, BRAF fusions and ...Loki Stormbringer
For some, glioma biomarkers have been expected to solve common diagnostic problems in routine neuropathology service caused by insufficient material, technical shortcomings or lack of experience. Further, biomarkers should predict patient outcome and direct optimal therapy for the individual patient. Unfortunately, current biomarkers still fall somewhat short of these grand expectations. While there has been some progress, it has generally been slow and in small steps. In this review, the newest set of glioma biomarkers: O(6) -methylguanine-DNA methyltransferase (MGMT) methylation, BRAF fusion and IDH1 mutation are discussed. MGMT methylation is well established as a prognostic/predictive marker for glioblastoma; however, technical questions regarding testing remain, it is not currently utilized widely in guiding patient management, and it has proven to be of no assistance in diagnostics. In contrast, BRAF fusion and IDH1 mutation analyses promise to be very helpful for classifying and grading gliomas, while their potential predictive value has yet to be established.
Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. The term pharmacogenetics is often used interchangeably with the term pharmacogenomics which also investigates the role of acquired and inherited genetic differences in relation to drug response and drug behavior through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.
This document compares the efficacy of 5 different FGFR inhibitors - AZD4547, BGJ398, JNJ42756493, PD173074 and TKI258 - at inhibiting FGFR1 signaling and cell proliferation in solid tumor cell lines and leukemia cell lines that overexpress FGFR1. It finds that the pan-FGFR inhibitors AZD4547, BGJ398 and JNJ42756493 more potently suppress FGFR1 phosphorylation and downstream signaling, cause more cell cycle arrest, and have lower GI50 values, indicating they more efficiently inhibit cell growth. It also shows that BGJ398 treatment significantly suppresses leukemia progression in a xenograft model of primary human AML overexpressing FGFR1, supporting
Chemotherapy is the main treatment for disseminated cancers. It involves using multiple drugs in cycles to target rapidly dividing cancer cells. Common drugs include alkylating agents, antimetabolites, microtubule inhibitors, and monoclonal antibodies. Combination chemotherapy aims to maximize responses while avoiding overlapping toxicities. Doses are based on body surface area and adjusted for individual factors. Treatment intervals allow time for normal tissues to recover between cycles. Toxicities include myelosuppression, nausea/vomiting, and alopecia. Response is evaluated based on tumor shrinkage or progression.
Platinum drugs like cisplatin, carboplatin, and oxaliplatin have been used successfully to treat cancers for decades. They work by binding to and damaging DNA, which kills tumor cells. Cisplatin was the first such drug developed but caused severe side effects. This led researchers to develop analogs with improved tolerability profiles. Carboplatin and oxaliplatin were created and are now also approved for use, with carboplatin having less kidney toxicity and oxaliplatin showing activity against cisplatin-resistant cancers. Ongoing research focuses on developing newer platinum complexes and drug delivery methods to expand use and reduce side effects.
Pharmacogenomics is the study of how an individual's genetic inheritance affects their response to drugs. It aims to develop personalized medicine by determining the "right dose of the right drug to the right person". Genetic variations can influence drug pharmacokinetics, pharmacodynamics, and disease mechanisms. Examples include CYP2C19 polymorphisms affecting clopidogrel metabolism and VKORC1/CYP2C9 variants influencing warfarin dosing. While pharmacogenomics holds promise for optimizing drug therapy, barriers include complexity in identifying clinically-relevant genetic factors and challenges in educating healthcare providers and patients.
Vorinostat combined with DNMTi epigenetically controls the proliferation of l...MustafaFathy6
This study evaluated the effects of combining the histone deacetylase inhibitor (HDACi) vorinostat with other chemotherapeutic drugs on lung cancer cells. Vorinostat alone and in combination with carboplatin was most effective at reducing cell viability of A549 lung cancer cells. Global DNA methylation patterns varied depending on the drug combinations, with vorinostat and carboplatin causing hypomethylation and vorinostat and cyclophosphamide resulting in hypermethylation. The results suggest that combining epigenetic and chemotherapeutic drugs may be more effective at controlling lung cancer proliferation than single agents alone. However, more experiments are needed to confirm these findings.
The document summarizes a study investigating the expression and role of apoptosis-related molecules like TRAIL, FasL, and their receptors in pancreatic adenocarcinoma cell lines. The key findings were:
1) The pancreatic cancer cell lines expressed high levels of apoptosis-inducing ligands and receptors but showed variable susceptibility to TRAIL-induced cell death.
2) Treatment with chemotherapy drugs did not increase their susceptibility to apoptosis, likely due to their differential expression of decoy receptors and inhibitor molecules.
3) This suggests pancreatic cancers develop resistance to immune-mediated apoptosis, allowing immune evasion and tumor progression.
This document provides an overview of principles of systemic therapy in cancer, including chemotherapy, endocrine therapy, immunotherapy, and targeted therapy. It discusses various classes of chemotherapeutic agents and their mechanisms of action, administration methods, principles of combination chemotherapy, and parameters for evaluating treatment responses and toxicities. It also summarizes several hormonal agents used in endocrine therapy for cancers like breast and prostate cancer. Immunotherapies and targeted therapies discussed include monoclonal antibodies, tyrosine kinase inhibitors, and other small molecule inhibitors used to treat various cancers.
This document summarizes the pharmacogenetics of warfarin, an anticoagulant drug with a narrow therapeutic index. Variants in the CYP2C9 and VKORC1 genes influence patients' warfarin dose requirements by affecting the drug's metabolism and mechanism of action. Studies show pharmacogenetic testing can identify patients who require lower or higher than average warfarin doses to achieve therapeutic anticoagulation more accurately than clinical algorithms alone. Further research is still needed, but pharmacogenetic testing may help improve warfarin dosing and reduce bleeding risks.
Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecu...Joshua Mangerel
This document summarizes the results of a study that integrated genomic data to identify molecular subgroups in diffuse intrinsic pontine glioma (DIPG), a deadly childhood brain cancer. The study found that DIPG comprises three distinct subgroups - MYCN, silent, and H3-K27M - with differences in mutations, gene expression, methylation, and clinical features. A novel recurrent mutation was discovered in the ACVR1 gene in 20% of DIPGs. The identification of distinct molecular subgroups highlights the heterogeneity of DIPG and could help guide more targeted treatment approaches for this incurable cancer.
pharmacogenomics helps to improve healthcare sector by providing information about variability among genes for a particular class of drug hence reduces adverse drug reactions.
Pharmacogenetics involves studying genetic variations that lead to differences in individual drug responses. The goals are to optimize drug therapy and limit toxicity based on a person's genetic profile by choosing the best drug, dose, and duration for that individual. Genetic variations can occur as single nucleotide polymorphisms, which are single base pair differences between individuals. Polymorphisms in genes encoding drug-metabolizing enzymes, such as CYP2D6 and CYP2C9, are clinically significant as they can result in poor, intermediate, extensive, or ultrarapid metabolism of certain drugs. This can impact treatment outcomes and risk of adverse effects.
This document discusses emerging treatment paradigms for acute myeloid leukemia (AML) using FLT3 inhibitors. It describes how mutations in the FLT3 gene are common in AML and drive proliferation. Several generations of FLT3 inhibitors have been developed, including lestaurtinib, sorafenib, midostaurin, quizartinib, crenolanib, and gilteritinib. Clinical trials show that midostaurin and chemotherapy improves survival for FLT3 mutated AML. Quizartinib improves outcomes for relapsed AML. Ongoing research continues to evaluate FLT3 inhibitors in combination with chemotherapy.
This document summarizes a study investigating the role of microRNA-122 (miR-122) in regulating intrahepatic metastasis of hepatocellular carcinoma (HCC). The study found that miR-122 expression is significantly downregulated in HCC tumors with intrahepatic metastasis. Restoring miR-122 expression in metastatic HCC cell lines reduced in vitro migration, invasion, and tumor growth in vivo. Computational analysis identified multiple target genes of miR-122, including ADAM17, which was shown to be involved in metastasis. Silencing ADAM17 had similar effects as restoring miR-122, reducing in vitro and in vivo measures of metastasis. The study suggests that miR-122 acts as a tumor suppressor
This study analyzed 264 gastric cancers for mutations in exons 9 and 20 of the PIK3CA gene. PIK3CA mutations were found in 42 cases (16%), all heterozygous missense mutations. The most common mutation was H1047R in exon 20 (62% of mutations) and the second most common was Q546K in exon 9 (9.5% of mutations). A meta-analysis of 27 publications found that the ratio of exon 20 to exon 9 mutations varied by cancer type, being highest in gastric cancer. The exon mutation selectivity is a signature of the cancer type.
This document discusses directions and issues in the treatment of acute myeloid leukemia (AML). It addresses challenging existing treatment dogmas regarding chemotherapy drug doses and post-remission therapies. Specifically, it summarizes several studies investigating optimal dose levels of cytarabine and anthracyclines during induction and consolidation for AML. It also reviews evidence comparing the effectiveness of autologous stem cell transplantation versus chemotherapy alone as post-remission consolidation approaches. The document advocates moving beyond conventional chemotherapy regimens to more personalized precision medicine approaches for AML patients.
This document discusses genetic polymorphisms in drug transport proteins and how they can impact drug pharmacokinetics and toxicity. It introduces two major superfamilies of transport proteins - ATP-binding cassette (ABC) transporters and solute carrier (SLC) proteins. Specific ABC transporters discussed include P-glycoprotein (ABCB1), the multidrug resistance proteins ABCC1 and ABCG2. The document also summarizes key SLC transporters and provides examples of important substrates for each. Genetic variations in these transport proteins can significantly influence individual responses to drugs like irinotecan used in cancer chemotherapy.
pharmacogenomics is a new drug discovry approach. It is the study of how genes affect a person's response to drugs, combining pharmacology and genomics
This document summarizes recent research on the role of epigenetic regulation in human cancers. It discusses how epigenetic mechanisms like DNA methylation and histone modifications can disrupt gene expression and lead to tumorigenesis. Specifically, it describes how hypermethylation of CpG islands can silence tumor suppressor genes, and how certain histone modifications are associated with transcriptional activation or repression. The document also reviews emerging epigenetic therapies and challenges in the field, such as a lack of predictive biomarkers and unclear mechanisms of response/resistance.
1) Prodigiosin, a bacterial metabolite, induces apoptosis in human breast cancer cells. Gene expression profiling found that prodigiosin strongly increased expression of the NAG-1 gene.
2) Experiments showed that prodigiosin triggers accumulation of the tumor suppressor protein p53, but induction of NAG-1 was independent of p53.
3) Prodigiosin causes inhibition of AKT and activation of glycogen synthase kinase-3B (GSK-3B). Induction of NAG-1 and apoptosis correlated with GSK-3B activation. Inhibiting GSK-3B reduced apoptosis, suggesting GSK-3B plays a key role in the proap
The next generation of glioma biomarkers: MGMT methylation, BRAF fusions and ...Loki Stormbringer
For some, glioma biomarkers have been expected to solve common diagnostic problems in routine neuropathology service caused by insufficient material, technical shortcomings or lack of experience. Further, biomarkers should predict patient outcome and direct optimal therapy for the individual patient. Unfortunately, current biomarkers still fall somewhat short of these grand expectations. While there has been some progress, it has generally been slow and in small steps. In this review, the newest set of glioma biomarkers: O(6) -methylguanine-DNA methyltransferase (MGMT) methylation, BRAF fusion and IDH1 mutation are discussed. MGMT methylation is well established as a prognostic/predictive marker for glioblastoma; however, technical questions regarding testing remain, it is not currently utilized widely in guiding patient management, and it has proven to be of no assistance in diagnostics. In contrast, BRAF fusion and IDH1 mutation analyses promise to be very helpful for classifying and grading gliomas, while their potential predictive value has yet to be established.
Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. The term pharmacogenetics is often used interchangeably with the term pharmacogenomics which also investigates the role of acquired and inherited genetic differences in relation to drug response and drug behavior through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.
This document compares the efficacy of 5 different FGFR inhibitors - AZD4547, BGJ398, JNJ42756493, PD173074 and TKI258 - at inhibiting FGFR1 signaling and cell proliferation in solid tumor cell lines and leukemia cell lines that overexpress FGFR1. It finds that the pan-FGFR inhibitors AZD4547, BGJ398 and JNJ42756493 more potently suppress FGFR1 phosphorylation and downstream signaling, cause more cell cycle arrest, and have lower GI50 values, indicating they more efficiently inhibit cell growth. It also shows that BGJ398 treatment significantly suppresses leukemia progression in a xenograft model of primary human AML overexpressing FGFR1, supporting
Chemotherapy is the main treatment for disseminated cancers. It involves using multiple drugs in cycles to target rapidly dividing cancer cells. Common drugs include alkylating agents, antimetabolites, microtubule inhibitors, and monoclonal antibodies. Combination chemotherapy aims to maximize responses while avoiding overlapping toxicities. Doses are based on body surface area and adjusted for individual factors. Treatment intervals allow time for normal tissues to recover between cycles. Toxicities include myelosuppression, nausea/vomiting, and alopecia. Response is evaluated based on tumor shrinkage or progression.
Platinum drugs like cisplatin, carboplatin, and oxaliplatin have been used successfully to treat cancers for decades. They work by binding to and damaging DNA, which kills tumor cells. Cisplatin was the first such drug developed but caused severe side effects. This led researchers to develop analogs with improved tolerability profiles. Carboplatin and oxaliplatin were created and are now also approved for use, with carboplatin having less kidney toxicity and oxaliplatin showing activity against cisplatin-resistant cancers. Ongoing research focuses on developing newer platinum complexes and drug delivery methods to expand use and reduce side effects.
Pharmacogenomics is the study of how an individual's genetic inheritance affects their response to drugs. It aims to develop personalized medicine by determining the "right dose of the right drug to the right person". Genetic variations can influence drug pharmacokinetics, pharmacodynamics, and disease mechanisms. Examples include CYP2C19 polymorphisms affecting clopidogrel metabolism and VKORC1/CYP2C9 variants influencing warfarin dosing. While pharmacogenomics holds promise for optimizing drug therapy, barriers include complexity in identifying clinically-relevant genetic factors and challenges in educating healthcare providers and patients.
Vorinostat combined with DNMTi epigenetically controls the proliferation of l...MustafaFathy6
This study evaluated the effects of combining the histone deacetylase inhibitor (HDACi) vorinostat with other chemotherapeutic drugs on lung cancer cells. Vorinostat alone and in combination with carboplatin was most effective at reducing cell viability of A549 lung cancer cells. Global DNA methylation patterns varied depending on the drug combinations, with vorinostat and carboplatin causing hypomethylation and vorinostat and cyclophosphamide resulting in hypermethylation. The results suggest that combining epigenetic and chemotherapeutic drugs may be more effective at controlling lung cancer proliferation than single agents alone. However, more experiments are needed to confirm these findings.
The document summarizes a study investigating the expression and role of apoptosis-related molecules like TRAIL, FasL, and their receptors in pancreatic adenocarcinoma cell lines. The key findings were:
1) The pancreatic cancer cell lines expressed high levels of apoptosis-inducing ligands and receptors but showed variable susceptibility to TRAIL-induced cell death.
2) Treatment with chemotherapy drugs did not increase their susceptibility to apoptosis, likely due to their differential expression of decoy receptors and inhibitor molecules.
3) This suggests pancreatic cancers develop resistance to immune-mediated apoptosis, allowing immune evasion and tumor progression.
This document provides an overview of principles of systemic therapy in cancer, including chemotherapy, endocrine therapy, immunotherapy, and targeted therapy. It discusses various classes of chemotherapeutic agents and their mechanisms of action, administration methods, principles of combination chemotherapy, and parameters for evaluating treatment responses and toxicities. It also summarizes several hormonal agents used in endocrine therapy for cancers like breast and prostate cancer. Immunotherapies and targeted therapies discussed include monoclonal antibodies, tyrosine kinase inhibitors, and other small molecule inhibitors used to treat various cancers.
This document summarizes the pharmacogenetics of warfarin, an anticoagulant drug with a narrow therapeutic index. Variants in the CYP2C9 and VKORC1 genes influence patients' warfarin dose requirements by affecting the drug's metabolism and mechanism of action. Studies show pharmacogenetic testing can identify patients who require lower or higher than average warfarin doses to achieve therapeutic anticoagulation more accurately than clinical algorithms alone. Further research is still needed, but pharmacogenetic testing may help improve warfarin dosing and reduce bleeding risks.
Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecu...Joshua Mangerel
This document summarizes the results of a study that integrated genomic data to identify molecular subgroups in diffuse intrinsic pontine glioma (DIPG), a deadly childhood brain cancer. The study found that DIPG comprises three distinct subgroups - MYCN, silent, and H3-K27M - with differences in mutations, gene expression, methylation, and clinical features. A novel recurrent mutation was discovered in the ACVR1 gene in 20% of DIPGs. The identification of distinct molecular subgroups highlights the heterogeneity of DIPG and could help guide more targeted treatment approaches for this incurable cancer.
pharmacogenomics helps to improve healthcare sector by providing information about variability among genes for a particular class of drug hence reduces adverse drug reactions.
Pharmacogenetics involves studying genetic variations that lead to differences in individual drug responses. The goals are to optimize drug therapy and limit toxicity based on a person's genetic profile by choosing the best drug, dose, and duration for that individual. Genetic variations can occur as single nucleotide polymorphisms, which are single base pair differences between individuals. Polymorphisms in genes encoding drug-metabolizing enzymes, such as CYP2D6 and CYP2C9, are clinically significant as they can result in poor, intermediate, extensive, or ultrarapid metabolism of certain drugs. This can impact treatment outcomes and risk of adverse effects.
This document discusses emerging treatment paradigms for acute myeloid leukemia (AML) using FLT3 inhibitors. It describes how mutations in the FLT3 gene are common in AML and drive proliferation. Several generations of FLT3 inhibitors have been developed, including lestaurtinib, sorafenib, midostaurin, quizartinib, crenolanib, and gilteritinib. Clinical trials show that midostaurin and chemotherapy improves survival for FLT3 mutated AML. Quizartinib improves outcomes for relapsed AML. Ongoing research continues to evaluate FLT3 inhibitors in combination with chemotherapy.
This document summarizes a study investigating the role of microRNA-122 (miR-122) in regulating intrahepatic metastasis of hepatocellular carcinoma (HCC). The study found that miR-122 expression is significantly downregulated in HCC tumors with intrahepatic metastasis. Restoring miR-122 expression in metastatic HCC cell lines reduced in vitro migration, invasion, and tumor growth in vivo. Computational analysis identified multiple target genes of miR-122, including ADAM17, which was shown to be involved in metastasis. Silencing ADAM17 had similar effects as restoring miR-122, reducing in vitro and in vivo measures of metastasis. The study suggests that miR-122 acts as a tumor suppressor
This study analyzed 264 gastric cancers for mutations in exons 9 and 20 of the PIK3CA gene. PIK3CA mutations were found in 42 cases (16%), all heterozygous missense mutations. The most common mutation was H1047R in exon 20 (62% of mutations) and the second most common was Q546K in exon 9 (9.5% of mutations). A meta-analysis of 27 publications found that the ratio of exon 20 to exon 9 mutations varied by cancer type, being highest in gastric cancer. The exon mutation selectivity is a signature of the cancer type.
This document discusses directions and issues in the treatment of acute myeloid leukemia (AML). It addresses challenging existing treatment dogmas regarding chemotherapy drug doses and post-remission therapies. Specifically, it summarizes several studies investigating optimal dose levels of cytarabine and anthracyclines during induction and consolidation for AML. It also reviews evidence comparing the effectiveness of autologous stem cell transplantation versus chemotherapy alone as post-remission consolidation approaches. The document advocates moving beyond conventional chemotherapy regimens to more personalized precision medicine approaches for AML patients.
This document discusses genetic polymorphisms in drug transport proteins and how they can impact drug pharmacokinetics and toxicity. It introduces two major superfamilies of transport proteins - ATP-binding cassette (ABC) transporters and solute carrier (SLC) proteins. Specific ABC transporters discussed include P-glycoprotein (ABCB1), the multidrug resistance proteins ABCC1 and ABCG2. The document also summarizes key SLC transporters and provides examples of important substrates for each. Genetic variations in these transport proteins can significantly influence individual responses to drugs like irinotecan used in cancer chemotherapy.
pharmacogenomics is a new drug discovry approach. It is the study of how genes affect a person's response to drugs, combining pharmacology and genomics
This document summarizes recent research on the role of epigenetic regulation in human cancers. It discusses how epigenetic mechanisms like DNA methylation and histone modifications can disrupt gene expression and lead to tumorigenesis. Specifically, it describes how hypermethylation of CpG islands can silence tumor suppressor genes, and how certain histone modifications are associated with transcriptional activation or repression. The document also reviews emerging epigenetic therapies and challenges in the field, such as a lack of predictive biomarkers and unclear mechanisms of response/resistance.
DNA methylation, an epigenetic mechanism, plays a major role in gene expression and silencing. Changes in DNA methylation patterns, including global hypomethylation and hypermethylation of tumor suppressor genes, are consistently observed in cancer cells and contribute to tumor formation. Both hypomethylation of oncogenes and hypermethylation of tumor suppressor genes can provide a selective growth advantage for cancer cells.
This document discusses DNA methylation and its role in cancer development. It begins by defining epigenetics and describing the three main stages of epigenetic regulation: nucleosome positioning, histone modification, and DNA methylation. It then focuses on DNA methylation, the enzymes involved like DNMTs and TETs, and the processes of methylation and demethylation. Numerous studies have found that cancer cells exhibit disruptions to DNA methylation patterns, including hypomethylation of repetitive DNA and hypermethylation of CpG islands in gene promoters. These changes are associated with genomic instability, aberrant gene transcription, and silencing of tumor suppressor genes, which can promote cancer progression. Understanding DNA methylation alterations
The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15
years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we
present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it
is time to embrace the central role of epigenetics in cancer.
Cancer Epigenetics: Concepts, Challenges and PromisesMrinmoy Pal
The presentation highlights how recent investigations have shown extensive reprogramming of almost every component of the epigenetic machinery in cancer leading to the emergence of the promising field of epigenetic therapy.
Undergraduate Research Symposium PosterTim Krueger
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Gallbladder cancer patient analysis
1. Analysis of tumor transcriptomics profile for the
Patient with stage IV gallbladder cancer
Contents
1. NGS data normalization..................................................................................................................................................1
2. Identification of regulators responsible for differential gene expression in patient tumor................1
3. Graphical summaries of findings from analysis tumor transcriptomics profile.......................................2
HDACs activation causes NFkB inhibition, activation of cell cycle and inhibition of apotosis................2
PDCD1 protein is activated in patient tumor .............................................................................................................2
CTLA4 protein is activated in patient tumor..............................................................................................................3
Cancer Hallmarks pathways enriched with active expression regulators in patient tumor ........................3
Deacetylases Activation in Histone Deacetylation in Cancer ...............................................................................4
Methylases in Histone Methylation Cancer.................................................................................................................5
Table 1. List of top 200 statistically significant activated expression regulators identified by sub-
network enrichment analysis (SNEA) in Pathway Studio..........................................................................................6
1. NGS data normalization
NGS RNAseq tumor transcriptomics profile was generated by Genoanalytica, Moscow Russia. RPKM
values for every gene measured in tumor sample were normalized on transcriptomics profile from
three samples of normal gallbladder from publicly available GSE132223 data from National Cancer
Institute (NCBI): M3-741_tpm, M3-760_tpm, M3-817_tpm
2. Identification of regulators responsible for differential gene
expression in patient tumor
Normalized NGS RNAseq tumor transcriptomics profile was imported into Pathway Studio software
from Elsevier to determine expression regulators upstream of the differentially expressed genes
using sub-network enrichment analysis option “What proteins regulate expression of entities
enriched in the input data?”. The list of identified top 200 significant most active regulators is shown
in Table 1. Among top most active regulators 5 were found to be histone deacetylases (HDACs).
Overexpression of histone deacetylase 2 predicts unfavorable prognosis in human gallbladder
2. carcinoma (Du, 2013), HDAC1 promoted migration and invasion binding with TCF12 by promoting
EMT progress in gallbladder cancer (He, 2016). Because it was shown that Zolinza inhibits
proliferation of galdbladder carcinoma cells (Yamaguchi, 2010) we suggest using HDAC inhibitors for
treatment. Zolinza from Merck USA is the most studied and safe HDAC inhibitor on the market.
HDAC activation enables tumor proliferation through suppression of cell cycle inhibitors CDKNs and
through evasion of immune response by down-regulation of NFkB. Other proteins found active in the
tumor is PDCD1 and CTLA4 (Table 1). Activation of these proteins provides additional mechanism
for suppression of immune response. PDCD1 is the target of immunotherapy drugs Opdivo, Keytruda.
CTLA4 is the target of immunotherapy drugs Tremelimumab and Yervoy.
3. Graphical summaries of findings from analysis tumor
transcriptomics profile.
Red proteins – activated expression regulators in tumor according to SNEA in Pathway Studio. Blue
proteins - inhibited expression regulators in tumor according to SNEA in Pathway Studio. Tumor
transcriptomics analysis has revealed profound down-regulation of inflammatory cytokines and their
receptors in the tumor, which is likely due to down-regulation of NFkB family of transcription factors.
HDACs activation causes NFkB inhibition, activation of cell cycle and inhibition of apoptosis.
Suberoylanilide hydroxamic acid is a chemical name of Zolinza.
3. PDCD1 protein is activated in patient tumor
CTLA4 protein is activated in patient tumor
Cancer Hallmarks pathways enriched with active expression
regulators in patient tumor
Collection of Cancer Hallmarks pathways is readily available in Pathway Studio. It provides
foundation for building personalized cancer mechanistic model from patient molecular profiling data.
4. Pathways below were found enriched with active expression regulators identified by sub-network
enrichment of patient tumor transcriptomics data. Red proteins – activated expression regulators in
tumor according to SNEA in Pathway Studio. Blue proteins - inhibited expression regulators in tumor
according to SNEA in Pathway Studio.
Deacetylases Activation in Histone Deacetylation in Cancer
Cancer Hallmark: Hallmarks of Cancer (9) Genome Instability
Notes: Headnote: The epigenetic changes including histone acetylation/deacetylation are thought to participate in
the onset of genomic instability and progression of cancer in numerous tumor types.
Signaling description: The acetylation status of histones H3 and H4 largely determines the status of chromatin
condensation, and, consequently, gene expression. Histone acetylation is regulated by the opposing activities
of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histone acetylation conducted by HATs
removes the positive charge of the histone molecule, thus diminishing the interaction of the histone N termini
with the negatively charged DNA phosphate groups. This relaxes chromatin condensation allowing for a
greater level of gene transcription (highly condensed heterochromatin becomes transcriptionally active
euchromatin). The reverse process of chromatin condensation is conducted by HDACs. There exist four classes
of HDACs: class I consists of HDAC 1, 2, 3, and 8; class II consists of HDAC 4, 5, 6, 7, 9, and 10; class III consists
of sirtuins (SIRT 1-7); and class IV consists of HDAC 11, which have features of both class I and II HDACs. HDAC
2, 4, SIRT 1, 6, 7 may be mutated in cancer. HDAC 1, 2, 3, 6, 7, 8, SIRT 1 and 7 may be overexpressed in cancer,
SIRT 4 and 6 may be down-regulated.
Outcome effects: Deregulation of HDACs creates an impairment of histone acetylation and chromatin
remodeling leading to oncogenic progression. An extensive number of HDAC inhibitors are developed and
explored in clinical trials showing anti-tumor activities. The most extensively studied HDAC inhibitors target
class I and or II, and a separate set of inhibitors target class III HDACs (sirtuins).
5. Methylases in Histone Methylation Cancer
Cancer Hallmark: Hallmarks of Cancer (9) Genome Instability
Notes: Headnote: Epigenetic changes including histone methylation are now thought to participate in the onset and
progression of cancer in numerous tumor types. Methylation of specific residues in the core histones H3 and
H4 have been identified as a marker of tumor cells.
Signaling description: Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the
transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment
of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. According
to modern data, histone methylation can either repress or activate transcription. In general, methylation at
H3K4, H3K36, and H3K79 is associated with transcriptional activation, whereas H3K9, H3K27, and H3K20
methylation is associated with transcriptional repression. Monomethylations at H3K27, H3K9, H4K20, H3K79,
and H2BK5 are all linked to gene activation, whereas trimethylations at H3K27, H3K9, and H3K79 are linked to
repression. A number of HMTs can be mutated in cancer, including KMT2A/C/D, NSD1, WHSC1, WHSC1L1,
EZH2, PRDM1/2/12/16, MECOM. DOT1L may be activated by fusion proteins MLL-AF10, MLL-AF4, MLL-ELL.
Outcome effects: Deregulation of HMT leads to the impairment of chromatin remodeling and makes impact to
oncogenic progression.