1) An RNA aptamer called A9g selectively inhibits the enzymatic activity of prostate-specific membrane antigen (PSMA) in prostate cancer cells.
2) Treatment of prostate cancer cells with A9g reduced cell migration and invasion in culture as well as metastatic disease in mouse models.
3) Pharmacokinetic and biodistribution studies in mice showed that A9g has target specificity for prostate cancer cells expressing PSMA and no significant off-target toxicity, supporting its potential as a novel targeted therapy for advanced prostate cancer.
Opportunities and challenges provided by crosstalk between signalling pathway...Anirudh Prahallad
This document summarizes opportunities and challenges in exploiting crosstalk between signaling pathways for cancer treatment. It discusses how inhibition of one pathway can activate a secondary survival pathway, conferring resistance. The review evaluates using genetic approaches to identify pathway crosstalk and develop combination therapies. It provides examples where targeting two interacting pathways showed stronger effects than single agents, including combinations of BRAF/EGFR inhibitors for BRAF mutant colon cancer and MEK/ERBB3 inhibitors for KRAS mutant cancers.
The document summarizes research on using a small molecule mimetic of the Sin3A interaction domain (SID) decoy (C16) alone or in combination with retinoic acid receptor alpha (RARα) agonists to treat triple negative breast cancer (TNBC). The key findings are:
1) C16 increases expression of RARβ2 and endogenous retinoic acid levels, activating RAR target gene expression.
2) C16 combined with the RARα agonist AM80 strongly activates RARE-driven reporter gene expression more than either treatment alone.
3) In 3D culture, C16 combined with RARα agonists induces acinar morphogenesis and inhibits tumors
Пятницкий М.А. Подбор персонализированной противоопухолевой терапии путем сис...bigdatabm
The document discusses developing a personalized cancer treatment approach through integrating multi-omics data from next-generation sequencing to identify molecular mechanisms and potential drug sensitivities of individual tumors. It presents a workflow that sequences tumor and non-tumor tissue, analyzes the exome, transcriptome and other omics data using bioinformatics, and integrates the data to generate hypotheses about a patient's cancer development and possible targeted pharmaceutical interventions. The goal is to rationally select therapies based on an individual tumor's oncogenesis model and avoid ineffective treatments.
The document discusses transient receptor potential (TRP) channels as therapeutic drug targets. It begins by explaining that TRP channels are appealing drug targets because they do not share homology with voltage-gated sodium and calcium channels, allowing for subtype-selective compounds. It also notes that TRP channels integrate several signaling systems and mutations can cause human diseases. The document then focuses on TRP channels in pain pathways, respiratory systems, and other pathophysiological processes. It highlights clinical trials of TRPV1 and TRPV3 antagonists for pain and discusses how TRPV1 antagonists affect heat perception in humans.
Angiogenesis in the compound literature Cell Cycle andcross-screening studies.dish33pest
The document discusses MAGE-A4, a protein involved in angiogenesis. It finds that lower doses of Adriamycin increase proteasome activity and promote the proteasome-mediated processing of MAGE-A4. Specifically, it shows that Adriamycin, but not other anticancer drugs, increases the processed form of MAGE-A4 under the conditions tested. The study analyzed the mechanism of MAGE-A4 processing and found that Adriamycin selectively increases proteasome-mediated cleavage of MAGE-A4 compared to other anticancer agents.
This study investigated the association between matrix metalloproteinase 9 (MMP-9) plasma levels, genetic variations of the MMP-9 gene, and cardiovascular outcomes in patients with coronary artery disease. The results showed that higher MMP-9 plasma levels were independently associated with increased risk of death from cardiovascular causes. Specific genetic variations in the MMP-9 gene were also associated with higher MMP-9 plasma levels and an increased risk of future cardiovascular events.
This document discusses targeted cancer therapies and their mechanisms of action. It outlines 10 hallmarks of cancer and describes targeted drugs that inhibit specific proteins and pathways involved in cancer growth. These targeted drugs include small molecule tyrosine kinase inhibitors, monoclonal antibodies, angiogenesis inhibitors, and proteosome inhibitors. Examples are provided of targeted therapies used to treat cancers like chronic myeloid leukemia, lung cancer, breast cancer, and multiple myeloma. Potential side effects of targeted therapies are also mentioned.
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
Opportunities and challenges provided by crosstalk between signalling pathway...Anirudh Prahallad
This document summarizes opportunities and challenges in exploiting crosstalk between signaling pathways for cancer treatment. It discusses how inhibition of one pathway can activate a secondary survival pathway, conferring resistance. The review evaluates using genetic approaches to identify pathway crosstalk and develop combination therapies. It provides examples where targeting two interacting pathways showed stronger effects than single agents, including combinations of BRAF/EGFR inhibitors for BRAF mutant colon cancer and MEK/ERBB3 inhibitors for KRAS mutant cancers.
The document summarizes research on using a small molecule mimetic of the Sin3A interaction domain (SID) decoy (C16) alone or in combination with retinoic acid receptor alpha (RARα) agonists to treat triple negative breast cancer (TNBC). The key findings are:
1) C16 increases expression of RARβ2 and endogenous retinoic acid levels, activating RAR target gene expression.
2) C16 combined with the RARα agonist AM80 strongly activates RARE-driven reporter gene expression more than either treatment alone.
3) In 3D culture, C16 combined with RARα agonists induces acinar morphogenesis and inhibits tumors
Пятницкий М.А. Подбор персонализированной противоопухолевой терапии путем сис...bigdatabm
The document discusses developing a personalized cancer treatment approach through integrating multi-omics data from next-generation sequencing to identify molecular mechanisms and potential drug sensitivities of individual tumors. It presents a workflow that sequences tumor and non-tumor tissue, analyzes the exome, transcriptome and other omics data using bioinformatics, and integrates the data to generate hypotheses about a patient's cancer development and possible targeted pharmaceutical interventions. The goal is to rationally select therapies based on an individual tumor's oncogenesis model and avoid ineffective treatments.
The document discusses transient receptor potential (TRP) channels as therapeutic drug targets. It begins by explaining that TRP channels are appealing drug targets because they do not share homology with voltage-gated sodium and calcium channels, allowing for subtype-selective compounds. It also notes that TRP channels integrate several signaling systems and mutations can cause human diseases. The document then focuses on TRP channels in pain pathways, respiratory systems, and other pathophysiological processes. It highlights clinical trials of TRPV1 and TRPV3 antagonists for pain and discusses how TRPV1 antagonists affect heat perception in humans.
Angiogenesis in the compound literature Cell Cycle andcross-screening studies.dish33pest
The document discusses MAGE-A4, a protein involved in angiogenesis. It finds that lower doses of Adriamycin increase proteasome activity and promote the proteasome-mediated processing of MAGE-A4. Specifically, it shows that Adriamycin, but not other anticancer drugs, increases the processed form of MAGE-A4 under the conditions tested. The study analyzed the mechanism of MAGE-A4 processing and found that Adriamycin selectively increases proteasome-mediated cleavage of MAGE-A4 compared to other anticancer agents.
This study investigated the association between matrix metalloproteinase 9 (MMP-9) plasma levels, genetic variations of the MMP-9 gene, and cardiovascular outcomes in patients with coronary artery disease. The results showed that higher MMP-9 plasma levels were independently associated with increased risk of death from cardiovascular causes. Specific genetic variations in the MMP-9 gene were also associated with higher MMP-9 plasma levels and an increased risk of future cardiovascular events.
This document discusses targeted cancer therapies and their mechanisms of action. It outlines 10 hallmarks of cancer and describes targeted drugs that inhibit specific proteins and pathways involved in cancer growth. These targeted drugs include small molecule tyrosine kinase inhibitors, monoclonal antibodies, angiogenesis inhibitors, and proteosome inhibitors. Examples are provided of targeted therapies used to treat cancers like chronic myeloid leukemia, lung cancer, breast cancer, and multiple myeloma. Potential side effects of targeted therapies are also mentioned.
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
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 slide contain information about antibody mediated anti-cancer therapy like antibody drug conjugates (ADC), Bispecific monoclonal antibody, Immuno-checkpoint therapy, biomarkers, mechanism of action of all 3 therapies, approved drugs of each category
Three key points:
1. A kinome-centered synthetic lethality screen identified that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors.
2. MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance.
3. Drugs targeting both EGFR and ERBB2, each capable of forming hetero-dimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM.
Erbitux (cetuximab) is a monoclonal antibody used to treat colon, rectal, and head and neck cancers. It works by interfering with cancer cell growth and slowing the spread of cancer in the body. Erbitux is often used in combination with chemotherapy and may cause infusion reactions or allergic reactions in some patients. A large clinical trial found that chemotherapy combined with either Erbitux or Avastin resulted in similar overall survival and progression-free survival for metastatic colorectal cancer patients without the KRAS gene mutation. This means that treatment can be selected based on individual factors like side effects.
Robert Anders, MD, PhD, Julie R. Brahmer, MD, MSc, and Christopher D. Gocke, MD, prepared useful Practice Aids pertaining to immunotherapy and biomarker testing for this CME/MOC/CC activity titled "Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications for Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era." For the full presentation, monograph, complete CME/MOC/CC information, and to apply for credit, please visit us at http://bit.ly/2L7zlSy. CME/MOC/CC credit will be available until May 2, 2020.
1. Several Pancratistatin (PST) analogs, including SVTH-7, SVTH-6, and SVTH-5, were found to have potent anti-cancer activity greater than PST and standard chemotherapeutics in a medium-throughput screen of various cancer cell lines.
2. The PST analogs disrupted mitochondrial function, activated the intrinsic apoptotic pathway, and reduced tumor growth in vivo. Inhibition of mitochondrial complexes II and III abrogated the pro-apoptotic effects of SVTH-7, suggesting it exploits a mitochondrial vulnerability.
3. This work identifies several PST analogs with high therapeutic potential and provides insight into distinct mitochondrial features of cancer
The role of peptid and DNA vaccines in myeloid leukemia immunotherapyAhmad Qudah
This document proposes a research thesis on using peptide and DNA vaccines for immunotherapy in myeloid leukemia. It discusses myeloid leukemia types (acute and chronic myeloid leukemia) and current chemotherapy treatments. Immunotherapy using vaccines derived from leukemia-specific or associated antigens is presented as a promising approach to prolong remission and eliminate minimal residual disease. Several potential antigen targets are described, including BCR-ABL, PML-RARα, WT1, PRAME, RHAMM, and cytokines like GM-CSF and interleukins. Preclinical and early clinical trials of peptide and DNA vaccines for these antigens are mentioned. The document concludes that leukemia vaccines may help eradicate residual disease after chemotherapy and warrants further investigation.
This document summarizes various targeted anticancer therapies. It discusses targeted therapies that interfere with molecular structures implicated in tumor growth like nuclear factors, cell survival factors, and angiogenesis factors. Primary targeted therapy tools are monoclonal antibodies and small synthetic molecules. Protein kinases and their role in signaling pathways are described. Examples of targeted therapies discussed include BCR-ABL tyrosine kinase inhibitors, EGFR inhibitors, HER2/NEU inhibitors, angiogenesis inhibitors targeting VEGF, mTOR inhibitors, proteasome inhibitors, MAPK pathway inhibitors, and monoclonal antibodies. Resistance mechanisms and newer agents to overcome resistance are also summarized.
Integrating Pathway Information with Gene Expression Data to Identify Novel ...Charlie Pei
This document describes a study that integrated pathway information with gene expression data from the Connectivity Map database to identify novel pathway-specific cancer drugs. The study focused on four major cancer pathways: p53 signaling, PI3K/AKT signaling, PTEN signaling, and Wnt/β-catenin signaling. A novel method was developed to calculate pathway enrichment scores and identify drugs that significantly affect the pathways. Several known cancer drugs were validated, and some potential new cancer drug indications were predicted, though none were found for the Wnt pathway. Future work could improve the method and integrate additional databases to further analyze drug effects on pathways.
Researchers generated isogenically matched Braf-inhibitor resistant primary and metastatic melanoma cell lines. A drug screen of 160 kinase inhibitors identified PKR and TPL2 as potential targets for overcoming resistance. Further experiments showed the primary resistant cells were sensitive to TPL2 inhibition but only modestly to PKR inhibition, while the metastatic resistant cells were highly sensitive to PKR inhibition but poorly responsive to TPL2 inhibition. Western blot analysis showed constitutive ERK phosphorylation in both resistant lines, while EGFR was only expressed in the primary resistant line. The results suggest different resistance mechanisms in the primary versus metastatic cells despite being isogenically matched, and that TPL2 and PKR inhibitors may overcome Braf-
This document discusses gene therapy approaches for prostate cancer that have been investigated. It outlines several strategies, including delivering genes to induce cell death or inhibit cell growth, activate the immune system against tumor cells, and target specific gene expression. Clinical trials are evaluating therapies using the herpes simplex virus gene with ganciclovir to activate a prodrug, as well as other approaches to manipulate cell proliferation, apoptosis, angiogenesis, and the immune response. Tissue-specific delivery and regulation of gene expression offer promise for gene therapy in prostate cancer.
Over-expression of APOBEC3B (A3B) has little to no effect on the efficacy of 5-Fluorouracil (5-FU) in killing mammary epithelial MCF10A cells. The study found that transfecting, transducing, or treating MCF10A cells with PMA to induce A3B expression did not significantly impact cell viability when treated with varying concentrations of 5-FU. Repeating the experiments in A3B-high cancer cell lines and investigating the mechanisms of how A3B and 5-FU may complement each other could provide insights for personalized cancer treatment.
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.
This study evaluated the effects of Amgen 386, a novel angiopoietin inhibitor, alone and in combination with a c-MET inhibitor (Compound A) on metastasis and survival in a patient-derived xenograft model of clear cell renal cell carcinoma. Treatment with Amgen 386 alone and in combination with Compound A significantly reduced the number and size of lung metastases and prolonged survival compared to the control. The combination treatment was more effective at reducing metastases than either drug alone, suggesting potential clinical benefit from combination therapy for treating metastatic kidney cancer.
1) The document reports that 6 out of 16 melanoma tumor samples analyzed acquired expression of EGFR after developing resistance to BRAF or MEK inhibitor drugs.
2) Using a shRNA library targeting chromatin regulators, the researchers found that suppression of SOX10 in melanoma cells leads to activation of TGF-β signaling and upregulation of EGFR and PDGFRB, conferring resistance to BRAF and MEK inhibitors.
3) Expression of EGFR in melanoma cells or treatment with TGF-β results in a slow-growth phenotype with cellular hallmarks of senescence. However, EGFR expression or TGF-β exposure becomes advantageous for proliferation in the presence of BRAF or
PARP-1 inhibitors have shown promise in oncology by potentiating the effects of DNA damaging chemotherapy agents. Cephalon identified a pyrrolocarbazole hit that inhibited PARP-1 but had poor properties. Through structure-based design and SAR studies, they developed CEP-8983, a potent PARP inhibitor. A prodrug, CEP-9722, was synthesized to improve solubility and pharmacokinetics. In preclinical studies, CEP-8983 and its active metabolite CEP-9397 potentiated the effects of temozolomide in tumor cell lines. CEP-9722 advanced to Phase 1 and 2 clinical trials for evaluation as monotherapy and
This document discusses principles of targeted cancer therapy and summarizes several studies. It describes how targeted therapies inhibit specific biological targets expressed by tumor cells, such as the epidermal growth factor receptor (EGFR). The document reviews EGFR inhibitors gefitinib and erlotinib, noting their efficacy in certain patient subgroups. It also discusses acquired resistance to these drugs via secondary mutations and the use of EGFR monoclonal antibodies like cetuximab. Further, it summarizes studies of anti-angiogenic therapy with bevacizumab and describes models used to study angiogenesis.
This document discusses various aspects of cancer treatment, including:
1. Local and systemic cancer treatments such as surgery, radiotherapy, chemotherapy, hormone therapy, and biological response modifiers. It also discusses different types, mechanisms of action, and targets of chemotherapy drugs.
2. The cell cycle and how different chemotherapy drugs target specific phases of the cell cycle. It provides details on chemotherapy administration, indications, contraindications, and monitoring.
3. Side effects of chemotherapy drugs on different organ systems. It also discusses concepts like drug resistance, dose modification, and the relationship between dose intensity and treatment response.
Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeu...Enrique Moreno Gonzalez
Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by
lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently
underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete.
Targeted therapy aims to inhibit specific molecular targets involved in cancer cell growth and survival. Chemotherapy treats the whole body but is less specific, while targeted therapy inhibits more specific cancer cell targets like tyrosine kinases, genes, angiogenesis factors, and survival signals. Examples include imatinib for CML and trastuzumab for HER2-positive breast cancer. Resistance can develop but may be overcome through combinations of targeted agents that inhibit multiple cancer cell pathways and processes. New targeted agents continue to be developed that exploit vulnerabilities in cancer signaling networks or stimulate anti-tumor immune responses.
Epigenetic regulation and role of metastasis suppressor genes in pancreatic d...Enrique Moreno Gonzalez
Pancreatic ductal adenocarcinoma (PDAC) is distinguished by rapid dissemination. Thus, genetic and/or epigenetic deregulation of metastasis suppressor genes (MSG) is a likely event during early pancreatic carcinogenesis and a potential diagnostic marker for the disease. We investigated 9 known MSGs for their role in the dissemination of PDAC and examined their promoters for methylation and its use in PDAC detection.
- The document examines the role of plasminogen activator inhibitor 1 (PAI-1) in the recruitment of mast cells (MCs) to glioma tumors.
- It finds that neutralizing PAI-1 attenuates the infiltration of MCs into glioma tumors. It also finds that MCs express the PAI-1 receptor LRP1, and blocking LRP1 also attenuates MC migration.
- Activation of the potential PAI-1/LRP1 axis in MCs by purified PAI-1 promotes increased phosphorylation of STAT3 and subsequent MC exocytosis. This indicates the PAI-1/LRP1 axis influences MC recruitment in glioma tumors.
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 slide contain information about antibody mediated anti-cancer therapy like antibody drug conjugates (ADC), Bispecific monoclonal antibody, Immuno-checkpoint therapy, biomarkers, mechanism of action of all 3 therapies, approved drugs of each category
Three key points:
1. A kinome-centered synthetic lethality screen identified that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors.
2. MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance.
3. Drugs targeting both EGFR and ERBB2, each capable of forming hetero-dimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM.
Erbitux (cetuximab) is a monoclonal antibody used to treat colon, rectal, and head and neck cancers. It works by interfering with cancer cell growth and slowing the spread of cancer in the body. Erbitux is often used in combination with chemotherapy and may cause infusion reactions or allergic reactions in some patients. A large clinical trial found that chemotherapy combined with either Erbitux or Avastin resulted in similar overall survival and progression-free survival for metastatic colorectal cancer patients without the KRAS gene mutation. This means that treatment can be selected based on individual factors like side effects.
Robert Anders, MD, PhD, Julie R. Brahmer, MD, MSc, and Christopher D. Gocke, MD, prepared useful Practice Aids pertaining to immunotherapy and biomarker testing for this CME/MOC/CC activity titled "Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications for Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era." For the full presentation, monograph, complete CME/MOC/CC information, and to apply for credit, please visit us at http://bit.ly/2L7zlSy. CME/MOC/CC credit will be available until May 2, 2020.
1. Several Pancratistatin (PST) analogs, including SVTH-7, SVTH-6, and SVTH-5, were found to have potent anti-cancer activity greater than PST and standard chemotherapeutics in a medium-throughput screen of various cancer cell lines.
2. The PST analogs disrupted mitochondrial function, activated the intrinsic apoptotic pathway, and reduced tumor growth in vivo. Inhibition of mitochondrial complexes II and III abrogated the pro-apoptotic effects of SVTH-7, suggesting it exploits a mitochondrial vulnerability.
3. This work identifies several PST analogs with high therapeutic potential and provides insight into distinct mitochondrial features of cancer
The role of peptid and DNA vaccines in myeloid leukemia immunotherapyAhmad Qudah
This document proposes a research thesis on using peptide and DNA vaccines for immunotherapy in myeloid leukemia. It discusses myeloid leukemia types (acute and chronic myeloid leukemia) and current chemotherapy treatments. Immunotherapy using vaccines derived from leukemia-specific or associated antigens is presented as a promising approach to prolong remission and eliminate minimal residual disease. Several potential antigen targets are described, including BCR-ABL, PML-RARα, WT1, PRAME, RHAMM, and cytokines like GM-CSF and interleukins. Preclinical and early clinical trials of peptide and DNA vaccines for these antigens are mentioned. The document concludes that leukemia vaccines may help eradicate residual disease after chemotherapy and warrants further investigation.
This document summarizes various targeted anticancer therapies. It discusses targeted therapies that interfere with molecular structures implicated in tumor growth like nuclear factors, cell survival factors, and angiogenesis factors. Primary targeted therapy tools are monoclonal antibodies and small synthetic molecules. Protein kinases and their role in signaling pathways are described. Examples of targeted therapies discussed include BCR-ABL tyrosine kinase inhibitors, EGFR inhibitors, HER2/NEU inhibitors, angiogenesis inhibitors targeting VEGF, mTOR inhibitors, proteasome inhibitors, MAPK pathway inhibitors, and monoclonal antibodies. Resistance mechanisms and newer agents to overcome resistance are also summarized.
Integrating Pathway Information with Gene Expression Data to Identify Novel ...Charlie Pei
This document describes a study that integrated pathway information with gene expression data from the Connectivity Map database to identify novel pathway-specific cancer drugs. The study focused on four major cancer pathways: p53 signaling, PI3K/AKT signaling, PTEN signaling, and Wnt/β-catenin signaling. A novel method was developed to calculate pathway enrichment scores and identify drugs that significantly affect the pathways. Several known cancer drugs were validated, and some potential new cancer drug indications were predicted, though none were found for the Wnt pathway. Future work could improve the method and integrate additional databases to further analyze drug effects on pathways.
Researchers generated isogenically matched Braf-inhibitor resistant primary and metastatic melanoma cell lines. A drug screen of 160 kinase inhibitors identified PKR and TPL2 as potential targets for overcoming resistance. Further experiments showed the primary resistant cells were sensitive to TPL2 inhibition but only modestly to PKR inhibition, while the metastatic resistant cells were highly sensitive to PKR inhibition but poorly responsive to TPL2 inhibition. Western blot analysis showed constitutive ERK phosphorylation in both resistant lines, while EGFR was only expressed in the primary resistant line. The results suggest different resistance mechanisms in the primary versus metastatic cells despite being isogenically matched, and that TPL2 and PKR inhibitors may overcome Braf-
This document discusses gene therapy approaches for prostate cancer that have been investigated. It outlines several strategies, including delivering genes to induce cell death or inhibit cell growth, activate the immune system against tumor cells, and target specific gene expression. Clinical trials are evaluating therapies using the herpes simplex virus gene with ganciclovir to activate a prodrug, as well as other approaches to manipulate cell proliferation, apoptosis, angiogenesis, and the immune response. Tissue-specific delivery and regulation of gene expression offer promise for gene therapy in prostate cancer.
Over-expression of APOBEC3B (A3B) has little to no effect on the efficacy of 5-Fluorouracil (5-FU) in killing mammary epithelial MCF10A cells. The study found that transfecting, transducing, or treating MCF10A cells with PMA to induce A3B expression did not significantly impact cell viability when treated with varying concentrations of 5-FU. Repeating the experiments in A3B-high cancer cell lines and investigating the mechanisms of how A3B and 5-FU may complement each other could provide insights for personalized cancer treatment.
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.
This study evaluated the effects of Amgen 386, a novel angiopoietin inhibitor, alone and in combination with a c-MET inhibitor (Compound A) on metastasis and survival in a patient-derived xenograft model of clear cell renal cell carcinoma. Treatment with Amgen 386 alone and in combination with Compound A significantly reduced the number and size of lung metastases and prolonged survival compared to the control. The combination treatment was more effective at reducing metastases than either drug alone, suggesting potential clinical benefit from combination therapy for treating metastatic kidney cancer.
1) The document reports that 6 out of 16 melanoma tumor samples analyzed acquired expression of EGFR after developing resistance to BRAF or MEK inhibitor drugs.
2) Using a shRNA library targeting chromatin regulators, the researchers found that suppression of SOX10 in melanoma cells leads to activation of TGF-β signaling and upregulation of EGFR and PDGFRB, conferring resistance to BRAF and MEK inhibitors.
3) Expression of EGFR in melanoma cells or treatment with TGF-β results in a slow-growth phenotype with cellular hallmarks of senescence. However, EGFR expression or TGF-β exposure becomes advantageous for proliferation in the presence of BRAF or
PARP-1 inhibitors have shown promise in oncology by potentiating the effects of DNA damaging chemotherapy agents. Cephalon identified a pyrrolocarbazole hit that inhibited PARP-1 but had poor properties. Through structure-based design and SAR studies, they developed CEP-8983, a potent PARP inhibitor. A prodrug, CEP-9722, was synthesized to improve solubility and pharmacokinetics. In preclinical studies, CEP-8983 and its active metabolite CEP-9397 potentiated the effects of temozolomide in tumor cell lines. CEP-9722 advanced to Phase 1 and 2 clinical trials for evaluation as monotherapy and
This document discusses principles of targeted cancer therapy and summarizes several studies. It describes how targeted therapies inhibit specific biological targets expressed by tumor cells, such as the epidermal growth factor receptor (EGFR). The document reviews EGFR inhibitors gefitinib and erlotinib, noting their efficacy in certain patient subgroups. It also discusses acquired resistance to these drugs via secondary mutations and the use of EGFR monoclonal antibodies like cetuximab. Further, it summarizes studies of anti-angiogenic therapy with bevacizumab and describes models used to study angiogenesis.
This document discusses various aspects of cancer treatment, including:
1. Local and systemic cancer treatments such as surgery, radiotherapy, chemotherapy, hormone therapy, and biological response modifiers. It also discusses different types, mechanisms of action, and targets of chemotherapy drugs.
2. The cell cycle and how different chemotherapy drugs target specific phases of the cell cycle. It provides details on chemotherapy administration, indications, contraindications, and monitoring.
3. Side effects of chemotherapy drugs on different organ systems. It also discusses concepts like drug resistance, dose modification, and the relationship between dose intensity and treatment response.
Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeu...Enrique Moreno Gonzalez
Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by
lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently
underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete.
Targeted therapy aims to inhibit specific molecular targets involved in cancer cell growth and survival. Chemotherapy treats the whole body but is less specific, while targeted therapy inhibits more specific cancer cell targets like tyrosine kinases, genes, angiogenesis factors, and survival signals. Examples include imatinib for CML and trastuzumab for HER2-positive breast cancer. Resistance can develop but may be overcome through combinations of targeted agents that inhibit multiple cancer cell pathways and processes. New targeted agents continue to be developed that exploit vulnerabilities in cancer signaling networks or stimulate anti-tumor immune responses.
Epigenetic regulation and role of metastasis suppressor genes in pancreatic d...Enrique Moreno Gonzalez
Pancreatic ductal adenocarcinoma (PDAC) is distinguished by rapid dissemination. Thus, genetic and/or epigenetic deregulation of metastasis suppressor genes (MSG) is a likely event during early pancreatic carcinogenesis and a potential diagnostic marker for the disease. We investigated 9 known MSGs for their role in the dissemination of PDAC and examined their promoters for methylation and its use in PDAC detection.
- The document examines the role of plasminogen activator inhibitor 1 (PAI-1) in the recruitment of mast cells (MCs) to glioma tumors.
- It finds that neutralizing PAI-1 attenuates the infiltration of MCs into glioma tumors. It also finds that MCs express the PAI-1 receptor LRP1, and blocking LRP1 also attenuates MC migration.
- Activation of the potential PAI-1/LRP1 axis in MCs by purified PAI-1 promotes increased phosphorylation of STAT3 and subsequent MC exocytosis. This indicates the PAI-1/LRP1 axis influences MC recruitment in glioma tumors.
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...Gul Muneer
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
This document discusses several predictive models and nomograms for prostate cancer outcomes:
- The CAPRA nomogram predicts outcomes after radical prostatectomy using clinical factors.
- The J-CAPRA nomogram was designed for patients receiving primary androgen deprivation therapy and predicts cancer progression and mortality.
- Nomograms have been developed to predict survival for patients with metastatic castration-resistant prostate cancer using PSA kinetics and other clinical variables.
- Additional nomograms aim to predict outcomes after specific therapies like docetaxel or abiraterone. Prospective validation of these tools is still needed to help guide treatment decisions.
1. The document discusses new targeted cancer therapies that inhibit specific deregulated proteins, which could enable individualized treatment approaches.
2. It describes RPPA (Reverse Phase Protein Microarray) technology, which can quantitatively measure proteins from tumor tissues and may help reliably screen for new therapeutic targets and biomarkers.
3. Several examples of currently used targeted cancer drugs are provided along with their tumor types and protein targets, which are detected using methods like IHC, FISH, and mutational analysis. The integration of DNA, RNA, and protein profiling is said to provide a comprehensive tumor description to select patients for individualized targeted therapies.
This document summarizes recent research on the role of noncoding RNAs, such as microRNAs and long noncoding RNAs, in prostate cancer progression and castration-resistant prostate cancer. It discusses how some noncoding RNAs are regulated by the androgen receptor and promote tumor growth by influencing processes like apoptosis, cell cycle, and cell invasion. The expression levels of certain microRNAs have been associated with prostate cancer diagnosis, aggressiveness, and treatment resistance. Integrative analyses of androgen receptor binding sites and regulated transcripts have provided new insights into the complex molecular mechanisms driven by noncoding RNAs in prostate cancer.
This document summarizes recent research on the role of noncoding RNAs, such as microRNAs and long noncoding RNAs, in prostate cancer progression and castration-resistant prostate cancer. It discusses how some noncoding RNAs are regulated by the androgen receptor and promote tumor growth by influencing processes like apoptosis, cell cycle, and epigenetic regulation. The expression levels of certain microRNAs have been associated with prostate cancer diagnosis, aggressiveness, and treatment resistance. Integrative analyses of androgen receptor binding sites and regulated transcripts have provided new insights into prostate cancer's molecular mechanisms.
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...JohnJulie1
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability...
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...AnonIshanvi
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...daranisaha
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability...
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...EditorSara
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability..
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...semualkaira
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability..
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...semualkaira
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability...
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...NainaAnon
This study examined the expression levels of deadenylases in small cell lung cancer (SCLC) clinical samples and their correlation to patient clinical characteristics and survival. Real-time PCR analysis found that the deadenylases PARN, CNOT6, CNOT7, and NOC were differentially expressed between malignant and normal lung tissue samples. Higher expression levels of PARN, CNOT6, and CNOT7 correlated with older patient age and decreased overall survival of 180 days or less. The results suggest these deadenylases may serve as prognostic biomarkers for SCLC patient outcomes.
Ultrasound treatment was found to reverse drug resistance in non-small cell lung cancer cells by positively regulating the expression of the long non-coding RNA BANCR. Experiments showed ultrasound increased BANCR expression in drug-resistant cancer cells and tumor tissue in mice, reducing expression of drug efflux proteins P-gp and MRP involved in multidrug resistance. Overexpression of BANCR similarly decreased P-gp and MRP levels, while inhibiting BANCR increased their expression. Thus, ultrasound may reverse drug resistance by regulating BANCR and subsequent expression of resistance proteins.
This document summarizes the development of optimized aptamer-siRNA chimeras for targeting prostate cancer cells expressing prostate-specific membrane antigen (PSMA). The researchers:
1) Truncated the aptamer portion of an earlier chimera to facilitate chemical synthesis while retaining binding to PSMA-expressing cells.
2) Introduced modifications to the siRNA portion like overhangs and strand swapping to enhance processing by Dicer and loading of the guide strand into RISC, increasing gene silencing effects.
3) Showed that the optimized second-generation chimeras achieved over 50 times greater silencing than the original chimera in vitro and induced tumor regression in mice after systemic administration, representing
This document summarizes information about PSMA PET-CT scans for imaging prostate cancer. It explains that PSMA is overexpressed in prostate cancer cells and is a good target for imaging. A new development is using radiolabeled PSMA ligands like Ga-68 for PET imaging, which can detect prostate cancer with high sensitivity and specificity, including small lymph nodes and bone metastases. The benefits of Ga-68 include its generator production and labeling chemistry allowing automated preparation with a short half-life for reduced radiation dose. PSMA PET is useful for staging, recurrence detection, and assessing treatment response in prostate cancer.
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 document describes cardiotoxicity observed in rodents and in rat and human-derived cardiomyocyte cell lines treated with nicotinamide phosphoribosyltransferase inhibitors (NAMPTi). Short-term administration of several NAMPTis to rodents resulted in sudden death and signs of congestive heart failure. Further studies demonstrated that NAMPTi-induced toxicity in rat and human cardiomyocyte cell lines was on-target and likely human-relevant. Co-administration of nicotinic acid partially mitigated toxicity in vitro but not consistently in vivo. Human-derived cardiomyocyte assays were useful for assessing cardiotoxicity of compounds prior to in vivo studies.