Recent publication showing an interesting approach to identify potential cancer cells and related cell signalling inhibitors in development of anticancer drugs.
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
CAR-T cells are T cells that are genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens on tumor cells. The first CAR-T cell therapy, Kymriah, was approved in 2017 for treating B-cell acute lymphoblastic leukemia. It showed high rates of complete remission. While effective, CAR-T cells can cause cytokine release syndrome and neurotoxicity as side effects. Ongoing research aims to expand CAR-T cell use in solid tumors and improve their safety profile.
Third-generation EGFR TKIs such as AZD9291 were developed to target the T790M mutation and sensitizing EGFR mutations more selectively than wild-type EGFR. However, resistance still develops. The study profiled tumors from patients treated with third-generation TKIs and identified potential resistance mechanisms, including ERBB2 and MET amplification as well as a secondary KRAS mutation. Dual inhibition of EGFR and downstream effectors like MEK may help overcome resistance caused by these bypass mechanisms.
Cancer is the second leading cause of death and costs billions annually. The paper examines the role of PA28γ in regulating cell fate decisions through the ERK and Akt pathways. Murine embryonic fibroblasts deficient or proficient in PA28γ were treated with staurosporine, an inhibitor of protein kinases. PA28γ deficient cells showed hypersensitivity to staurosporine, with decreased viability and ERK phosphorylation but no change in Akt expression. This suggests PA28γ enhances ERK signaling to modulate cell fate, demonstrating its role in survival pathways.
This document provides an overview of the history and development of immunology and immunotherapy. It begins with a definition of immunology and its applications. It then provides a detailed timeline from 1549 to 2018 outlining major discoveries and advances in the field, including early practices like variolation and vaccination, germ theory, development of vaccines and monoclonal antibodies, discovery of immune cells and mechanisms, and recent approvals of CAR T-cell and immune checkpoint therapies. The timeline traces the progression of knowledge from basic concepts of infectious disease to modern immunotherapies.
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-
1. Aberrations in sphingolipid metabolism are implicated in promoting glioblastoma multiforme (GBM) aggressiveness. GBM exhibits lower levels of ceramide and higher levels of sphingosine-1-phosphate (S1P) compared to normal brain tissue.
2. GBM manipulates sphingolipid pathways to shift the balance towards higher S1P and lower ceramide. Mechanisms include upregulating S1P-producing enzymes and downregulating ceramide-producing enzymes and phosphatases.
3. Receptors for the bioactive sphingolipid S1P are also upregulated in GBM, suggesting S1P signaling contributes to GBM
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
CAR-T cells are T cells that are genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens on tumor cells. The first CAR-T cell therapy, Kymriah, was approved in 2017 for treating B-cell acute lymphoblastic leukemia. It showed high rates of complete remission. While effective, CAR-T cells can cause cytokine release syndrome and neurotoxicity as side effects. Ongoing research aims to expand CAR-T cell use in solid tumors and improve their safety profile.
Third-generation EGFR TKIs such as AZD9291 were developed to target the T790M mutation and sensitizing EGFR mutations more selectively than wild-type EGFR. However, resistance still develops. The study profiled tumors from patients treated with third-generation TKIs and identified potential resistance mechanisms, including ERBB2 and MET amplification as well as a secondary KRAS mutation. Dual inhibition of EGFR and downstream effectors like MEK may help overcome resistance caused by these bypass mechanisms.
Cancer is the second leading cause of death and costs billions annually. The paper examines the role of PA28γ in regulating cell fate decisions through the ERK and Akt pathways. Murine embryonic fibroblasts deficient or proficient in PA28γ were treated with staurosporine, an inhibitor of protein kinases. PA28γ deficient cells showed hypersensitivity to staurosporine, with decreased viability and ERK phosphorylation but no change in Akt expression. This suggests PA28γ enhances ERK signaling to modulate cell fate, demonstrating its role in survival pathways.
This document provides an overview of the history and development of immunology and immunotherapy. It begins with a definition of immunology and its applications. It then provides a detailed timeline from 1549 to 2018 outlining major discoveries and advances in the field, including early practices like variolation and vaccination, germ theory, development of vaccines and monoclonal antibodies, discovery of immune cells and mechanisms, and recent approvals of CAR T-cell and immune checkpoint therapies. The timeline traces the progression of knowledge from basic concepts of infectious disease to modern immunotherapies.
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-
1. Aberrations in sphingolipid metabolism are implicated in promoting glioblastoma multiforme (GBM) aggressiveness. GBM exhibits lower levels of ceramide and higher levels of sphingosine-1-phosphate (S1P) compared to normal brain tissue.
2. GBM manipulates sphingolipid pathways to shift the balance towards higher S1P and lower ceramide. Mechanisms include upregulating S1P-producing enzymes and downregulating ceramide-producing enzymes and phosphatases.
3. Receptors for the bioactive sphingolipid S1P are also upregulated in GBM, suggesting S1P signaling contributes to GBM
This PPT is about immune system and immune therapy, some basic knowledge about Chimeric Antigen Receptor or CAR technology and its application on tumor therapy.
This presentation summarizes data related to the CAR-T cell technology and its potential application for cancer therapy. This oral presentation was presented at the 39th PAMM winter meeting in Roma the 8th f February 2018 by Eric Raymond
1. The document describes the synthesis and biological evaluation of SB-T-1216, a potent second-generation taxoid.
2. Enantiopure β-lactam is prepared via chiral ester-enolate imine cyclocondensation and Staudinger cycloaddition, then coupled to a modified baccatan.
3. SB-T-1216 shows greater efficacy than paclitaxel against drug-resistant cancer cell lines, with IC50 values over 100-fold lower for resistant cell lines. It induces microtubule bundling and cell death at lower concentrations than paclitaxel.
1) The document discusses tumor immunology and mechanisms of tumor immune evasion. It describes how tumors can downregulate MHC expression, secrete immunosuppressive factors, inhibit T cell function through checkpoint pathways like PD-1/PD-L1, and recruit immunosuppressive cells like Tregs.
2) Checkpoint pathways like CTLA-4 and PD-1 normally regulate T cell activation, but tumors can exploit these pathways to evade immune destruction by overexpressing ligands that bind these inhibitory receptors.
3) Several immunotherapies targeting CTLA-4 and PD-1/PD-L1 have been developed including ipilimumab, nivolumab, pembrol
This slides briefly introduced why car t cell validation assay is essential for car t therapy development and which assays should be done to validate the safety, identity, purity and potency of car t cell products.
Cardiotoxicity is unfortunately a common side effect of many modern chemotherapeutic agents. The mechanisms that underlie these detrimental effects on heart muscle, however, remain unclear. The Drug Toxicity Signature Generation Center at ISMMS aims to address this unresolved issue by providing a bridge between molecular changes in cells and the prediction of pathophysiological effects. I will discuss ongoing work in which we use next-generation sequencing to quantify changes in gene expression that occur in cardiac myocytes after they are treated with potentially toxic chemotherapeutic agents. I will focus in particular on the computational pipeline we are developing that integrates sophisticated sequence alignment, statistical and network analysis, and dynamical mathematical models to develop novel predictions about the mechanisms underlying drug-induced cardiotoxicity.
Jaehee Shim is a Ph.D candidate in the Biophysics and Systems Pharmacology Program at Icahn School of Medicine at Mount Sinai (ISMMS). As a part of her Ph.D. studies, she is building dynamical prediction models based on analysis of gene expression data generated by the Drug Toxicity Signature Generation Center at ISMMS. She received her B.S in Biochemistry from the University of Michigan-Dearborn. Prior to starting her Ph.D, Jaehee worked at the ISMMS Genomics Core with a team of senior scientists and gained experience in improving and troubleshooting RNA sequencing protocols using Next Generation Sequencing Platforms.
This document discusses targeted cancer therapy and provides several examples. It compares chemotherapy to targeted therapy, noting targeted therapy drugs inhibit more specific targets and include many oral agents. Examples discussed include Gleevec for CML targeting BCR-ABL fusion, EGFR mutations in lung cancer treated by drugs like Iressa, ALK rearrangements in lung cancer treated by crizotinib, BRAF mutations in melanoma treated by vemurafenib, and HER2-positive breast cancers treated by Herceptin. New immunotherapies and antibody-drug conjugates are also mentioned.
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.
This document summarizes Keiya Ozawa's research on CD19-targeted CAR T-cell therapy for B-cell lymphoma. It describes the design of CARs to target the CD19 antigen on B-cells, experimental data showing CD19-CAR T-cells effectively killed CD19-positive lymphoma cells in vitro and in mouse models, and outlines Ozawa's ongoing clinical trial testing CD19-CAR T-cell therapy in patients with relapsed/refractory B-cell lymphoma. The clinical trial uses lymphodepletion prior to infusing autologous T-cells engineered to express an anti-CD19 CAR to determine the maximum tolerated dose.
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.
CAR T-cell Therapy_A New Era in Cancer ImmunotherapyTuhin Samanta
Illusory Antigen Receptor (CAR) T-cell treatment includes hereditary alteration of patient's autologous T-cells to express a CAR explicit for a tumor antigen, following by ex vivo cell extension and re-imbuement back to the patient. Vehicles are combination proteins of a chose single-chain section variable from a particular monoclonal immune response and at least one T-cell receptor intracellular flagging spaces. This T-cell hereditary change may happen either by means of viral-based quality exchange strategies or nonviral techniques, for example, DNA-based transposons, CRISPR/Cas9 innovation or direct exchange of in vitro deciphered mRNA by electroporation.
genetic variations and its role in health/ pharmacologysrivani mandaloju
Here is the reference for the above topic. I have collected the maximum information that i got from the internet. If any one need the complete information comment here.
The document discusses hypoxia-inducible factor (HIF) activation by hypoxia. It describes how hypoxia leads to the activation of HIF, which upregulates genes like VEGF and EPO. It discusses the role of the von Hippel-Lindau tumor suppressor protein and prolyl hydroxylases in the HIF pathway. The document also summarizes VEGF structure and signaling, how it promotes angiogenesis, and the role of differential splicing in producing pro-angiogenic and anti-angiogenic isoforms. Finally, it discusses how anti-angiogenic therapies target tumor vasculature and their limitations.
This document provides an overview of genetic polymorphism and its relationship to periodontal disease. It begins with definitions of key genetic terms like allele, chromosome, DNA and discusses different types of genetic disorders. It then examines various human gene polymorphisms that have been associated with periodontal diseases, such as IL-1, IL-10, TNF-α, and FcγR gene polymorphisms. The document reviews studies that have investigated the relationship between these polymorphisms and chronic or aggressive periodontitis. It concludes by stating that identifying genetic risk factors could allow for more personalized prevention and treatment approaches for periodontal diseases in the future.
This document discusses the immunobiology of cancer. It begins with an outline and then covers cancer causes including genetic factors and carcinogens. It describes the innate and adaptive immune system, including mechanisms of immunosurveillance and immunoediting that allow tumors to evade detection. As an example, it examines hepatocellular carcinoma and the failure of immune responses against it. The document concludes by discussing immunotherapy approaches like passive monoclonal antibody therapy and active vaccination strategies that aim to harness the immune system against cancer.
- Richard Champlin is a professor and chair of the Department of Stem Cell Transplantation and Cellular Therapy at MD Anderson Cancer Center, with over 30 years of experience in hematopoietic stem cell transplantation research.
- He discusses using chimeric antigen receptor (CAR) T-cells and natural killer (NK) cells for cellular immunotherapy of acute myeloid leukemia (AML). Possible targets for CAR T-cells include CD123, CD33, WT1, and PR1, to direct T-cells against leukemia cells while sparing normal hematopoiesis.
- Clinical trials are investigating using ex vivo expanded NK cells and CAR T-cells to augment graft-versus-le
This is the Powerpoint presentation from my recent presentation at the TTP LabTech US Acumen Users Group Meeting (UGM) held at the British Consulate-General in Cambridge, MA on May 18, 2010
Novel Tyrosine Kinase Inhibitors for Ovarian CancerZuleika86
This document outlines an undergraduate research project studying novel tyrosine kinase inhibitors for ovarian cancer. Specifically, it investigates whether the JAK2 inhibitor JAK2-10 can also inhibit focal adhesion kinase (FAK) in ovarian cancer cells. The student hypothesizes that JAK2-10 will inhibit FAK phosphorylation. Their aims are to determine if JAK2-10 inhibits FAK activation in SKOV3 ovarian cancer cells over 72 hours. Preliminary results show JAK2-10 inhibits FAK phosphorylation but not cell growth. The student plans to further test the inhibitor's effects on cell migration and invasion.
Analyzing ASCO 2016: Developments, takeaways, and implications from the confe...Pharma Intelligence
In conjunction with a Key Opinion Leader, Dr. Peter Lee MD Chair, Department of Immuno-Oncology at City of Hope Comprehensive Cancer Center, CA, several Informa analysts discuss the major developments of the conference and key take-aways via a Webinar.
Watch our recording of Biomedtracker's Robert Jeng, Ph,D., Citeline's Allison Bruce, Scrip's Mary Jo Laffler, and Datamonitor Healthcare's Zachary McLellan as they download and debrief following the always-exciting ASCO weekend.
View and listen to the full webinar here https://www.youtube.com/watch?v=7yMsCb3R5X8
This PPT is about immune system and immune therapy, some basic knowledge about Chimeric Antigen Receptor or CAR technology and its application on tumor therapy.
This presentation summarizes data related to the CAR-T cell technology and its potential application for cancer therapy. This oral presentation was presented at the 39th PAMM winter meeting in Roma the 8th f February 2018 by Eric Raymond
1. The document describes the synthesis and biological evaluation of SB-T-1216, a potent second-generation taxoid.
2. Enantiopure β-lactam is prepared via chiral ester-enolate imine cyclocondensation and Staudinger cycloaddition, then coupled to a modified baccatan.
3. SB-T-1216 shows greater efficacy than paclitaxel against drug-resistant cancer cell lines, with IC50 values over 100-fold lower for resistant cell lines. It induces microtubule bundling and cell death at lower concentrations than paclitaxel.
1) The document discusses tumor immunology and mechanisms of tumor immune evasion. It describes how tumors can downregulate MHC expression, secrete immunosuppressive factors, inhibit T cell function through checkpoint pathways like PD-1/PD-L1, and recruit immunosuppressive cells like Tregs.
2) Checkpoint pathways like CTLA-4 and PD-1 normally regulate T cell activation, but tumors can exploit these pathways to evade immune destruction by overexpressing ligands that bind these inhibitory receptors.
3) Several immunotherapies targeting CTLA-4 and PD-1/PD-L1 have been developed including ipilimumab, nivolumab, pembrol
This slides briefly introduced why car t cell validation assay is essential for car t therapy development and which assays should be done to validate the safety, identity, purity and potency of car t cell products.
Cardiotoxicity is unfortunately a common side effect of many modern chemotherapeutic agents. The mechanisms that underlie these detrimental effects on heart muscle, however, remain unclear. The Drug Toxicity Signature Generation Center at ISMMS aims to address this unresolved issue by providing a bridge between molecular changes in cells and the prediction of pathophysiological effects. I will discuss ongoing work in which we use next-generation sequencing to quantify changes in gene expression that occur in cardiac myocytes after they are treated with potentially toxic chemotherapeutic agents. I will focus in particular on the computational pipeline we are developing that integrates sophisticated sequence alignment, statistical and network analysis, and dynamical mathematical models to develop novel predictions about the mechanisms underlying drug-induced cardiotoxicity.
Jaehee Shim is a Ph.D candidate in the Biophysics and Systems Pharmacology Program at Icahn School of Medicine at Mount Sinai (ISMMS). As a part of her Ph.D. studies, she is building dynamical prediction models based on analysis of gene expression data generated by the Drug Toxicity Signature Generation Center at ISMMS. She received her B.S in Biochemistry from the University of Michigan-Dearborn. Prior to starting her Ph.D, Jaehee worked at the ISMMS Genomics Core with a team of senior scientists and gained experience in improving and troubleshooting RNA sequencing protocols using Next Generation Sequencing Platforms.
This document discusses targeted cancer therapy and provides several examples. It compares chemotherapy to targeted therapy, noting targeted therapy drugs inhibit more specific targets and include many oral agents. Examples discussed include Gleevec for CML targeting BCR-ABL fusion, EGFR mutations in lung cancer treated by drugs like Iressa, ALK rearrangements in lung cancer treated by crizotinib, BRAF mutations in melanoma treated by vemurafenib, and HER2-positive breast cancers treated by Herceptin. New immunotherapies and antibody-drug conjugates are also mentioned.
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.
This document summarizes Keiya Ozawa's research on CD19-targeted CAR T-cell therapy for B-cell lymphoma. It describes the design of CARs to target the CD19 antigen on B-cells, experimental data showing CD19-CAR T-cells effectively killed CD19-positive lymphoma cells in vitro and in mouse models, and outlines Ozawa's ongoing clinical trial testing CD19-CAR T-cell therapy in patients with relapsed/refractory B-cell lymphoma. The clinical trial uses lymphodepletion prior to infusing autologous T-cells engineered to express an anti-CD19 CAR to determine the maximum tolerated dose.
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.
CAR T-cell Therapy_A New Era in Cancer ImmunotherapyTuhin Samanta
Illusory Antigen Receptor (CAR) T-cell treatment includes hereditary alteration of patient's autologous T-cells to express a CAR explicit for a tumor antigen, following by ex vivo cell extension and re-imbuement back to the patient. Vehicles are combination proteins of a chose single-chain section variable from a particular monoclonal immune response and at least one T-cell receptor intracellular flagging spaces. This T-cell hereditary change may happen either by means of viral-based quality exchange strategies or nonviral techniques, for example, DNA-based transposons, CRISPR/Cas9 innovation or direct exchange of in vitro deciphered mRNA by electroporation.
genetic variations and its role in health/ pharmacologysrivani mandaloju
Here is the reference for the above topic. I have collected the maximum information that i got from the internet. If any one need the complete information comment here.
The document discusses hypoxia-inducible factor (HIF) activation by hypoxia. It describes how hypoxia leads to the activation of HIF, which upregulates genes like VEGF and EPO. It discusses the role of the von Hippel-Lindau tumor suppressor protein and prolyl hydroxylases in the HIF pathway. The document also summarizes VEGF structure and signaling, how it promotes angiogenesis, and the role of differential splicing in producing pro-angiogenic and anti-angiogenic isoforms. Finally, it discusses how anti-angiogenic therapies target tumor vasculature and their limitations.
This document provides an overview of genetic polymorphism and its relationship to periodontal disease. It begins with definitions of key genetic terms like allele, chromosome, DNA and discusses different types of genetic disorders. It then examines various human gene polymorphisms that have been associated with periodontal diseases, such as IL-1, IL-10, TNF-α, and FcγR gene polymorphisms. The document reviews studies that have investigated the relationship between these polymorphisms and chronic or aggressive periodontitis. It concludes by stating that identifying genetic risk factors could allow for more personalized prevention and treatment approaches for periodontal diseases in the future.
This document discusses the immunobiology of cancer. It begins with an outline and then covers cancer causes including genetic factors and carcinogens. It describes the innate and adaptive immune system, including mechanisms of immunosurveillance and immunoediting that allow tumors to evade detection. As an example, it examines hepatocellular carcinoma and the failure of immune responses against it. The document concludes by discussing immunotherapy approaches like passive monoclonal antibody therapy and active vaccination strategies that aim to harness the immune system against cancer.
- Richard Champlin is a professor and chair of the Department of Stem Cell Transplantation and Cellular Therapy at MD Anderson Cancer Center, with over 30 years of experience in hematopoietic stem cell transplantation research.
- He discusses using chimeric antigen receptor (CAR) T-cells and natural killer (NK) cells for cellular immunotherapy of acute myeloid leukemia (AML). Possible targets for CAR T-cells include CD123, CD33, WT1, and PR1, to direct T-cells against leukemia cells while sparing normal hematopoiesis.
- Clinical trials are investigating using ex vivo expanded NK cells and CAR T-cells to augment graft-versus-le
This is the Powerpoint presentation from my recent presentation at the TTP LabTech US Acumen Users Group Meeting (UGM) held at the British Consulate-General in Cambridge, MA on May 18, 2010
Novel Tyrosine Kinase Inhibitors for Ovarian CancerZuleika86
This document outlines an undergraduate research project studying novel tyrosine kinase inhibitors for ovarian cancer. Specifically, it investigates whether the JAK2 inhibitor JAK2-10 can also inhibit focal adhesion kinase (FAK) in ovarian cancer cells. The student hypothesizes that JAK2-10 will inhibit FAK phosphorylation. Their aims are to determine if JAK2-10 inhibits FAK activation in SKOV3 ovarian cancer cells over 72 hours. Preliminary results show JAK2-10 inhibits FAK phosphorylation but not cell growth. The student plans to further test the inhibitor's effects on cell migration and invasion.
Analyzing ASCO 2016: Developments, takeaways, and implications from the confe...Pharma Intelligence
In conjunction with a Key Opinion Leader, Dr. Peter Lee MD Chair, Department of Immuno-Oncology at City of Hope Comprehensive Cancer Center, CA, several Informa analysts discuss the major developments of the conference and key take-aways via a Webinar.
Watch our recording of Biomedtracker's Robert Jeng, Ph,D., Citeline's Allison Bruce, Scrip's Mary Jo Laffler, and Datamonitor Healthcare's Zachary McLellan as they download and debrief following the always-exciting ASCO weekend.
View and listen to the full webinar here https://www.youtube.com/watch?v=7yMsCb3R5X8
Powerpoint presentation of CDK inhibitors as cancer treatment. Cell proliferation is a hallmark of cancer and cell cycle plays vital role in cell proliferation. Therefore by controlling the activity of cell cycle we can bring cancer in control.
Cancer is abnormal and uncontrolled cell growth that can invade tissues and spread to other parts of the body. It is caused by changes in gene expression leading to imbalanced cell proliferation and death. The document defines several key cancer-related terms and describes how cancers are classified based on their origin, morphology, grade, and stage. It also lists several hallmarks of cancer cells, including unlimited growth, self-sufficiency, evasion of cell death, angiogenesis, and metastasis.
Cancer biology senescence & imortalisationGaurav Kumar
This document discusses tumor suppressor mechanisms and senescence. It notes that 1% of neonatal cord blood contains malignant clones and 1/3 of adults possess an IgH-BCL2 translocation responsible for follicular leukemia. Senescence is a process of permanent growth arrest in response to telomere erosion, DNA damage, or oncogene activation. Chromosome 9p21 contains the INK4a/ARF/INK4b locus that encodes the p16, p15, and ARF proteins involved in senescence. Telomeres form protective T-loops at chromosomal ends to prevent DNA damage. NUTLINS and DNA methyltransferase inhibitors can reactivate p53 and p15/
Cancer is the general name for a group of more than 100 diseases. Although there are many kinds of cancer, all cancers start because of abnormal cells grow out of control.
CURE's mission is to conquer childhood cancer through research, education, and family support. It provides crisis support for Georgia children with cancer, including financial assistance, hospital support, and bereavement care. It seeks $115,000 for its Family Emergency Fund to provide financial assistance to families of children with cancer to help stabilize them during treatment. CURE operates on a $1.9 million budget from special events, donations, and grants. It dedicates 85% of expenses to program services and the remaining 15% to management, fundraising, and administration.
Autophagy is a catabolic process in which cells degrade unnecessary or dysfunctional components through lysosomes. It plays an important but complex role in cancer by modulating cell death, quality control, the immune response, and acting as a tumor suppressor. The PI3K/AKT/mTOR pathway is a key regulator of autophagy and is often deregulated in cancer, leading to abnormal autophagy. Recent studies suggest autophagy may be important in cancer development, progression, and response to treatment, though its specific effects depend on the context.
Cancer causes a significant number of deaths in the United States each year, including nearly 1,600 people per day. The document discusses several cases of childhood cancer, including Ronan Thompson who passed away from neuroblastoma at age 3. It also mentions that the Children's Cancer Foundation aims to help families dealing with childhood cancer through financial assistance and cancer research efforts.
A tyrosine kinase is an enzyme that transfers a phosphate group from ATP to tyrosine residues on proteins. This phosphorylation regulates protein activity and signal transduction within cells. Tyrosine kinase inhibitors, like nilotinib, are drugs that bind to and inhibit tyrosine kinases. Nilotinib was approved to treat chronic myeloid leukemia and research found it was effective against drug-resistant forms of the disease. It works by binding the inactive form of the Abl kinase to prevent phosphorylation and cancer cell growth.
Imatinib is the first FDA approved targeted protein kinase inhibitor for chronic myelogenous leukemia and gastrointestinal stromal tumors. It binds to and inactivates the BCR-ABL tyrosine kinase. Dasatinib and nilotinib are also BCR-ABL tyrosine kinase inhibitors approved for CML. Gefitinib, erlotinib and lapatinib inhibit the epidermal growth factor receptor tyrosine kinase and are approved for various cancers. Sunitinib, sorafenib, pazopanib, and vatalanib inhibit vascular endothelial growth factor receptors and are approved for renal cell carcinoma and other cancers. These oral tyrosine kinase inhibitors are important targeted cancer therapies.
The document discusses principles of cancer chemotherapy and summarizes various classes of chemotherapeutic agents. It describes how chemotherapy can be used at different stages of treatment and highlights common toxicities. It also reviews mechanisms of action and examples of classical anticancer agents like alkylating agents, antimetabolites, natural products and hormone therapies. Novel targeted agents are discussed such as tyrosine kinase inhibitors, PARP inhibitors, angiogenesis inhibitors, HSP90 inhibitors and others.
This document discusses tyrosine kinase inhibitors (TKIs), a class of targeted cancer drugs. It begins by introducing protein kinases and their role in cell signaling. There are two main categories of protein kinases - those that phosphorylate tyrosine residues and those that phosphorylate serine and threonine residues. Tyrosine kinases function as on/off switches in many cellular functions by adding phosphate groups to tyrosine residues on proteins. The document then discusses the different types of tyrosine kinases and how they can become mutated and cause unregulated cell growth leading to cancer. It describes targeted therapy and TKIs as targeted drugs that block specific molecules needed for tumor growth. The final sections provide examples of approved TKIs
The document discusses several key concepts in cancer biology including:
1) Tumorigenesis is a multi-step process that begins with initial genetic changes in cells and progresses to increased proliferation, decreased cell death, and further genetic alterations that promote characteristics like invasiveness and metastasis.
2) Cancers evolve and progress through anatomical transformation, interactions with the microenvironment, and development of heterogeneity and metastases.
3) Angiogenesis, the formation of new blood vessels, is important for tumor growth and is mediated by various growth factors and molecules released by tumor and host cells.
A comprehensive presentation on cancer biochemistry including biochemical changes,carcinogens,mechanism of chemical carcinogenesis ,oncogenes & activation,monoclonal antibodies for cancer therapy,diet ,prevention &tumor markers
1. Several molecular pathways are involved in breast cancer pathogenesis, including steroid hormone receptors, HER2/neu, cell cycle proteins, and growth factors.
2. Risk factors for breast cancer include increasing age, female gender, family history, genetic mutations, personal history of breast cancer or other breast diseases, reproductive factors, and hormone use.
3. High risk patients are identified using tools like the Gail model and managed through increased screening including breast self-exams, clinical exams, mammograms, and MRI. Preventive options include tamoxifen, raloxifen, and prophylactic surgeries.
This document summarizes key concepts about cell biology and cancer. It states that cancer results from genetic changes related to cell division, growth control, genetic instability, and other cellular processes. These genetic changes disable normal controls that prevent uncontrolled cell growth and invasion. The abnormalities usually result from mutations in genes regulating cell division. Cancer development involves mutations in tumor suppressor genes and oncogenes. If cancer cells spread to other parts of the body, it can form new tumors in a process called metastasis.
This document discusses tyrosine kinase inhibitors, which are drugs that target tyrosine kinases. It begins by introducing tyrosine kinases and their role in cell signaling pathways. It then describes several important tyrosine kinase inhibitors, including BCR-ABL inhibitors like imatinib, dasatinib, and nilotinib; EGFR inhibitors like gefitinib and erlotinib; and VEGF inhibitors like sunitinib and sorafenib. For each drug, it provides information on mechanisms of action, pharmacokinetics, dosing, toxicity profiles, and FDA-approved indications. The document concludes by discussing mechanisms of resistance to BCR-ABL kinase inhibitors.
This document discusses a proposed study to target cancer stem cells in leukemia using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based immunotoxins. The objectives are to identify and characterize cancer stem cells from leukemia cell lines and patients, construct recombinant TRAIL-based chimeric proteins to selectively target these cancer stem cells, and test the efficacy and selectivity of the proteins. Cancer stem cells are resistant to chemotherapy and responsible for leukemia recurrence. TRAIL selectively induces apoptosis in cancer cells and has advantages over chemotherapy. The study aims to develop dual receptor targeted immunotoxins linking TRAIL to the interleukin-2 receptor to more effectively treat leukemia by eliminating drug-resistant cancer stem cells.
BioMAP<sup>®</sup> Primary Human Cell-Based Systems for Drug DiscoveryBioMAP® Systems
The document discusses BioMAP, a platform using primary human cell-based disease models to characterize compounds and discover their mechanisms of action and toxicity. It can assess over 2000 compounds across diverse pathways and targets. BioMAP generates biological profiles for compounds and uses these to classify compounds by similarity of mechanism. It has been used in collaborations to efficiently profile EPA ToxCast compounds and identify unexpected targets. The platform bridges molecular and cellular data to help validate targets and indications and connect to in vivo studies.
The document summarizes key information from a conference on gene profiling in clinical oncology, including:
1) New markers such as EGFR, KRAS, ALK, HER2, and PI3K mutations are defining subsets of non-small cell lung cancer and informing targeted therapy approaches.
2) Drugs like erlotinib, gefitinib, and crizotinib, which target EGFR, ALK, and c-MET mutations respectively, have shown efficacy in molecularly selected patient populations.
3) Comprehensive genomic profiling of lung tumors is needed to discover new targets, as around a third of cases still have unknown driver mutations.
The document summarizes a presentation on using gene profiling and biomarkers to better classify and treat non-small cell lung cancer (NSCLC). It discusses current and emerging markers like EGFR mutations, ALK translocations, and FGFR1 amplifications that define NSCLC subtypes and can guide targeted therapies. Integrating multiple genomic analyses may help characterize unknown abnormalities in a third of NSCLC tumors and identify new treatment opportunities.
1. Receptor tyrosine kinases (RTKs) drive key cancer pathways and can be exploited as therapeutic targets, as shown by drugs like imatinib that inhibit mutated kinases in cancers.
2. RTK inhibitors have shown efficacy against cancers dependent on single kinases, but resistance often emerges through secondary mutations or bypass pathways.
3. Effective combination therapies are needed to overcome resistance, such as combining RTK inhibitors with other drugs that block downstream or bypass pathways.
This document summarizes research finding that elevated activity of the Akt protein protects prostate cancer LNCaP cells from apoptosis induced by TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). The researchers found that LNCaP cells have high constitutive Akt activity due to lack of the PTEN lipid phosphatase. Inhibiting PI3-kinase, which activates Akt, sensitized LNCaP cells to TRAIL-induced apoptosis. TRAIL alone activated caspases 8 and XIAP in LNCaP cells but failed to induce full apoptosis. Combining TRAIL with Akt inhibitors allowed cleavage of BID and subsequent mitochondrial apoptosis steps. Akt inhibition of BID cleavage appears to mediate the protective effect
Proteasome inhibitors in treatment of multiple myelomaAlok Gupta
This document summarizes the development of the proteasome inhibitor bortezomib, including its mechanism of action, clinical trials, safety profile, and peripheral neuropathy issues. Key findings include:
- Bortezomib is a reversible inhibitor of the proteasome's chymotrypsin-like activity and was found to induce apoptosis in cancer cells.
- Phase I and II clinical trials demonstrated efficacy in hematological malignancies like multiple myeloma with a tolerable safety profile.
- Peripheral neuropathy is a common side effect that can often improve after stopping treatment.
- Further research aimed to improve response rates, overcome resistance, expand use to solid tumors, and address neuropathy issues.
Rolf Stahel presented a document on various oncogenic pathways and targeted therapies. The document discussed:
1) The ALK pathway and its role in cancers like NSCLC and neuroblastoma. Drugs like Crizotinib have shown responses in ALK-positive NSCLC.
2) The RET pathway's role in medullary thyroid cancer. Drugs like Vandetanib have shown responses in RET-mutated MTC.
3) The Hedgehog pathway's role in basal cell carcinoma and medulloblastoma. Inhibitors like GDC-0449 have induced responses in Hedgehog pathway-driven tumors.
Targeting PIM kinase to overcome drug resistance in NSCLC - Dr Kathy GatelyHannahMcCarthy31
Dr Kathy Gately is a Clinical Scientist at St James's Hospital and Clinical Senior Lecturer at Trinity College Dublin. Dr Gately's research interests are Drug Resistance Mechanisms in Non-Small Cell Lung Cancer, Liquid Biopsy and Organoid models.
Use of signaling targets in cancer therapySree Parvathy
This document discusses signaling pathways that can be targeted for cancer therapy. It outlines that cancer development is a complex, multi-step genetic process involving acquired capabilities like uncontrolled growth. Key signaling targets include protein tyrosine kinases, receptor tyrosine kinases, and cytoplasmic intermediates like the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Mutations in genes that regulate these pathways are common in many cancer types. The document also notes there is signaling cross-talk between pathways, and combination drug therapies targeting multiple pathways may be more effective than single pathway inhibitors for treating aggressive cancers.
Undergraduate Research Symposium PosterTim Krueger
Treatment with epigenetic drugs that inhibit DNA methyltransferases or histone deacetylases increased expression of the cancer-testis antigen SSX2 in prostate cancer cell lines. BET bromodomain inhibition with JQ1 decreased expression of most antigens and antigen processing machinery, making it a poor choice for increasing immune recognition of prostate cancer cells. However, JQ1 increased expression of the androgen receptor and prostate-specific antigen in androgen receptor-positive cell lines, demonstrating that epigenetic inhibitors can modulate genes involved in immune recognition. Further study of other bromodomain inhibitors may identify alternatives that reverse aberrant gene silencing in prostate cancer.
The document summarizes research on targeting cancer stem cells in acute myeloid leukemia (AML). It discusses how AML stem cells, or leukemia stem cells (LSCs), drive leukemia but are overlooked by standard treatment. The research aims to understand LSC function at a molecular level to enable LSC-directed therapies for AML cure. Experiments show the transcription factor PU.1 regulates LSCs, and the drug eltrombopag may help treat thrombocytopenia in AML without activating LSCs.
The document summarizes research on targeting cancer stem cells in acute myeloid leukemia (AML). It discusses how AML stem cells, or leukemia stem cells (LSCs), differ from normal stem cells and bulk leukemia cells in their ability to self-renew and initiate leukemia. The research aims to identify molecular mechanisms driving LSC function and transforming events leading to LSC formation. Experiments show that reducing the transcription factor PU.1 induces AML by downregulating JunB expression. Additional work profiles gene expression differences between normal and AML stem/progenitor cells. The document also evaluates using the thrombopoietin receptor agonist eltrombopag to treat thrombocytopenia in AML/MDS patients,
The document summarizes research on targeting cancer stem cells in acute myeloid leukemia (AML). It discusses how AML stem cells, or leukemia stem cells (LSCs), differ from normal stem cells and bulk leukemia cells in their ability to self-renew and initiate leukemia. The research aims to identify molecular mechanisms driving LSC function and transforming events leading to LSC formation. Experiments show that reducing the transcription factor PU.1 induces AML by downregulating JunB expression. Additional work profiles gene expression differences between normal and AML stem/progenitor cells. The document also evaluates using the thrombopoietin receptor agonist eltrombopag to treat thrombocytopenia in AML/MDS patients,
The document summarizes research on targeting cancer stem cells in acute myeloid leukemia (AML). It discusses how AML stem cells (leukemia stem cells or LSCs) differ from normal stem cells in their ability to self-renew and initiate leukemia. The research aims to understand the molecular mechanisms that drive LSC function and identify transforming events involved in LSC formation and maintenance. Preclinical studies show that the transcription factor PU.1 regulates genes like JunB that are important for LSC function. The document also discusses using a small molecule drug called Eltrombopag to stimulate megakaryopoiesis in MDS/AML patients without activating LSCs, as a potential treatment for thrombocytopenia.
An allelic variant of mTOR leads to decreased DNA damage response in mouse embryonic fibroblasts. The variant allele, R628C, is found in BALB/c mice and results in a single amino acid substitution in the mTOR protein. Mice with the variant allele (KI mice) have decreased survival after radiation exposure and their embryonic fibroblasts show greater DNA damage, increased proliferation, and lower levels of the cell cycle inhibitor p27 compared to wild type mice. The results suggest the mTOR variant renders cells more susceptible to DNA damage and less able to repair it or arrest the cell cycle after radiation.
This document discusses molecular testing for lung adenocarcinoma, including common driver mutations, their prevalence, and associated targeted therapies. It describes the WHO classification of lung adenocarcinoma and lists frequently mutated genes found in this cancer. Key points covered include the role of EGFR, ALK, BRAF V600E, ROS1, MET, RET, NTRK, and KRAS mutations and the targeted therapies available to treat cancers driven by these alterations. Testing methods like NGS, PCR, and FISH are used to identify these genomic variants to guide treatment decisions.
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
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.