The document discusses targeted therapies for breast cancer. It begins with an overview of breast anatomy and the different types of breast carcinoma. It then discusses various receptors that are overexpressed in breast cancer, including hormone receptors, HER2, and triple negative breast cancer. The remainder of the document details various targeted therapies that have been developed to inhibit specific molecular pathways involved in breast cancer growth and progression, such as tyrosine kinase inhibitors for receptors like EGFR, HER2, IGFR, FGFR, VEGFR, and PDGFR. It also discusses mTOR/PI3K inhibitors, PARP inhibitors, and SRC inhibitors as targeted therapies. In conclusion, targeted therapies hold promise for more selective treatment of breast cancer with fewer side effects.
Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR) with high affinity. It is approved as monotherapy or in combination with chemotherapy for wild-type KRAS metastatic colorectal cancer. Clinical trials have shown that panitumumab improves progression-free survival and overall survival when added to chemotherapy for first-line treatment of metastatic colorectal cancer patients with wild-type RAS tumors. Extended RAS testing beyond just KRAS exon 2 is important to identify patients most likely to benefit from panitumumab therapy. Common side effects include dermatological toxicities.
This document discusses fibroblast growth factor receptors (FGFRs) and FGFR inhibitors. It provides details on FGFR signaling pathways and the role of FGFRs in various cancers like urothelial carcinoma, osteosarcoma, and chondrosarcoma. It summarizes a phase 2 clinical trial investigating the FGFR inhibitor erdafitinib in patients with FGFR-altered metastatic or unresectable urothelial carcinoma, finding an objective response rate of 40% and median progression-free and overall survival of 5.5 and 13.8 months respectively. It concludes that FGFR inhibitors show promise for treating cancers driven by FGFR alterations.
A Look into Antibody–drug conjugates (ADCs) Targets.pdfDoriaFang
Approved ADC drugs list and the ongoing trails with hot ADC targets such as HER2, EGFR, TROP2, FRα, CLDN18.2,, c-Met, Nectin-4 and TF, with three targeting HER2 and two targeting CD22.
Molecular signaling involved in breast cancerainnie babarrr
Molecular signaling is very important to predict patient's clinical outcome. HER signaling is most important one, by its regulation cascade of pathways started. So, by understanding proteins over-expression we can target with inhibitors to suppress particular protein, which will results in treatment of breast cancer or Drug discovery.
PI3Kinase/AKT/mTOR Pathway in Breast Cancer; Pathogenesis and Prevention with...Dr Varruchi Sharma
The most recurrent and considered second most frequent cause of cancerrelated death in women is the breast cancer worldwide. In breast cancer cases patients are usually diagnosed in the beginning at the curable stage. However, its treatment remains a great clinical challenge. A number of studies have been carried out for the treatment of breast cancer which includes the targeted therapies and increased survival rates in women. Essential PI3K/mTOR signaling pathway activation is observed in most breast cancers. The cell growth and tumor development in this case involves phosphoinositide 3 kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) pathway. It has been observed, through preclinical and clinical trials, that there are a number of other inhibitors of PI3K/Akt/mTOR pathway, which either alone or in combination with other agents can be used for treatment of cancer. Pre-clinical studies have confirmed that P13K, Akt and mTOR inhibitors achieve anticancer effects by targeting different levels of the PI3K/Akt/mTOR pathway. This chapter evaluates the role of mTOR along with some of its inhibitors and the PI3K/Akt/mTOR pathway in the pathogenesis and prevention of breast cancer.
1) Prodigiosin, a bacterial metabolite, induces apoptosis in human breast cancer cells. Gene expression profiling found that prodigiosin strongly increased expression of the NAG-1 gene.
2) Experiments showed that prodigiosin triggers accumulation of the tumor suppressor protein p53, but induction of NAG-1 was independent of p53.
3) Prodigiosin causes inhibition of AKT and activation of glycogen synthase kinase-3B (GSK-3B). Induction of NAG-1 and apoptosis correlated with GSK-3B activation. Inhibiting GSK-3B reduced apoptosis, suggesting GSK-3B plays a key role in the proap
Epidermal growth factor (EGF) is a protein that binds to EGF receptors on epithelial and epidermal cells and initiates the EGF signaling pathway. When EGF binds to EGF receptors, it causes them to dimerize and activate their tyrosine kinase activity, leading to phosphorylation and activation of downstream proteins in the MAPK pathway. Mutations that cause constitutive activation of this pathway can lead to uncontrolled cell growth and cancer. Potential cancer treatments discussed include RGD-based peptides that target the αvβ3 integrin receptor involved in angiogenesis, and a conjugate of low molecular weight heparin and suramin that may inhibit tumor growth by blocking vascular endothelial growth factor (VEGF).
The document discusses targeted therapies for breast cancer. It begins with an overview of breast anatomy and the different types of breast carcinoma. It then discusses various receptors that are overexpressed in breast cancer, including hormone receptors, HER2, and triple negative breast cancer. The remainder of the document details various targeted therapies that have been developed to inhibit specific molecular pathways involved in breast cancer growth and progression, such as tyrosine kinase inhibitors for receptors like EGFR, HER2, IGFR, FGFR, VEGFR, and PDGFR. It also discusses mTOR/PI3K inhibitors, PARP inhibitors, and SRC inhibitors as targeted therapies. In conclusion, targeted therapies hold promise for more selective treatment of breast cancer with fewer side effects.
Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR) with high affinity. It is approved as monotherapy or in combination with chemotherapy for wild-type KRAS metastatic colorectal cancer. Clinical trials have shown that panitumumab improves progression-free survival and overall survival when added to chemotherapy for first-line treatment of metastatic colorectal cancer patients with wild-type RAS tumors. Extended RAS testing beyond just KRAS exon 2 is important to identify patients most likely to benefit from panitumumab therapy. Common side effects include dermatological toxicities.
This document discusses fibroblast growth factor receptors (FGFRs) and FGFR inhibitors. It provides details on FGFR signaling pathways and the role of FGFRs in various cancers like urothelial carcinoma, osteosarcoma, and chondrosarcoma. It summarizes a phase 2 clinical trial investigating the FGFR inhibitor erdafitinib in patients with FGFR-altered metastatic or unresectable urothelial carcinoma, finding an objective response rate of 40% and median progression-free and overall survival of 5.5 and 13.8 months respectively. It concludes that FGFR inhibitors show promise for treating cancers driven by FGFR alterations.
A Look into Antibody–drug conjugates (ADCs) Targets.pdfDoriaFang
Approved ADC drugs list and the ongoing trails with hot ADC targets such as HER2, EGFR, TROP2, FRα, CLDN18.2,, c-Met, Nectin-4 and TF, with three targeting HER2 and two targeting CD22.
Molecular signaling involved in breast cancerainnie babarrr
Molecular signaling is very important to predict patient's clinical outcome. HER signaling is most important one, by its regulation cascade of pathways started. So, by understanding proteins over-expression we can target with inhibitors to suppress particular protein, which will results in treatment of breast cancer or Drug discovery.
PI3Kinase/AKT/mTOR Pathway in Breast Cancer; Pathogenesis and Prevention with...Dr Varruchi Sharma
The most recurrent and considered second most frequent cause of cancerrelated death in women is the breast cancer worldwide. In breast cancer cases patients are usually diagnosed in the beginning at the curable stage. However, its treatment remains a great clinical challenge. A number of studies have been carried out for the treatment of breast cancer which includes the targeted therapies and increased survival rates in women. Essential PI3K/mTOR signaling pathway activation is observed in most breast cancers. The cell growth and tumor development in this case involves phosphoinositide 3 kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) pathway. It has been observed, through preclinical and clinical trials, that there are a number of other inhibitors of PI3K/Akt/mTOR pathway, which either alone or in combination with other agents can be used for treatment of cancer. Pre-clinical studies have confirmed that P13K, Akt and mTOR inhibitors achieve anticancer effects by targeting different levels of the PI3K/Akt/mTOR pathway. This chapter evaluates the role of mTOR along with some of its inhibitors and the PI3K/Akt/mTOR pathway in the pathogenesis and prevention of breast cancer.
1) Prodigiosin, a bacterial metabolite, induces apoptosis in human breast cancer cells. Gene expression profiling found that prodigiosin strongly increased expression of the NAG-1 gene.
2) Experiments showed that prodigiosin triggers accumulation of the tumor suppressor protein p53, but induction of NAG-1 was independent of p53.
3) Prodigiosin causes inhibition of AKT and activation of glycogen synthase kinase-3B (GSK-3B). Induction of NAG-1 and apoptosis correlated with GSK-3B activation. Inhibiting GSK-3B reduced apoptosis, suggesting GSK-3B plays a key role in the proap
Epidermal growth factor (EGF) is a protein that binds to EGF receptors on epithelial and epidermal cells and initiates the EGF signaling pathway. When EGF binds to EGF receptors, it causes them to dimerize and activate their tyrosine kinase activity, leading to phosphorylation and activation of downstream proteins in the MAPK pathway. Mutations that cause constitutive activation of this pathway can lead to uncontrolled cell growth and cancer. Potential cancer treatments discussed include RGD-based peptides that target the αvβ3 integrin receptor involved in angiogenesis, and a conjugate of low molecular weight heparin and suramin that may inhibit tumor growth by blocking vascular endothelial growth factor (VEGF).
Gene expression profiling in breast carcinomaghoshparthanrs
This document discusses gene expression profiling in breast cancer and its use in classifying tumor subtypes. It describes how gene expression profiling analyzes thousands of genes simultaneously to more accurately classify tumors. Breast cancer is classified into clinical subtypes based on receptor expression, including luminal, HER2-enriched, and basal subtypes. Gene signatures can provide prognostic information to help guide treatment decisions for early-stage breast cancer patients. Tests like Oncotype DX and Mammaprint analyze gene expression from tumor samples to predict the risk of recurrence.
Summary of Approved HER2 ADCs on The Market & in Clinical Trials.pdfDoriaFang
This document summarizes approved and investigational HER2-targeted antibody-drug conjugates (ADCs). Currently, three HER2 ADCs are approved: T-DM1, T-DXd, and RC48. T-DM1 and T-DXd are both comprised of the antibody trastuzumab linked to cytotoxic payloads (DM1 for T-DM1 and DXd for T-DXd). RC48 uses a different HER2-targeting antibody linked to MMAE. Many other HER2 ADCs are in clinical trials, including SYD985 which recently had its BLA accepted by the FDA. While some HER2 ADCs have been approved or shown promise, others like TAA013
This study investigated combining two anti-cancer agents, T40214 and JG244, to target both the Stat3 and HIF-1α pathways in prostate cancer. T40214 inhibits phosphorylated Stat3 and JG244 inhibits HIF-1α. In vitro and in vivo experiments in human and murine prostate cancer models found that combination treatment with T40214 and JG244 significantly suppressed tumor growth more than either agent alone. Combination treatment also greatly increased apoptosis in the tumors compared to single agent treatments. The results suggest targeting both Stat3 and HIF-1α pathways together provides a more potent strategy for prostate cancer therapy.
Metastatic breast cancer remains a major unmet medical need, with over 1.7 million new cases diagnosed globally in 2012. Several new therapeutic targets and agents are in development to treat metastatic breast cancer and its subtypes. These include agents targeting intra-tumoral drivers like HER2, IGF, HGF, PI3K/AKT/mTOR, PARP, and AR. Agents also target the tumor microenvironment, such as anti-angiogenics targeting VEGF and agents targeting immune cells. Many of these novel agents are currently in Phase II or III clinical trials alone or in combination with standard therapies. Developing strategies to optimize targeted treatments and combinations holds promise to improve outcomes for patients with advanced breast cancer.
This document discusses tyrosine kinase inhibitors and their role in cancer therapy. It begins by introducing tyrosine kinases and their importance in cellular signaling pathways. Tyrosine kinases are implicated in cancer development and progression. The document then discusses the classification, structure, and mechanisms of tyrosine kinase receptors. It provides examples of FDA-approved tyrosine kinase inhibitors for various cancers. The document discusses strategies for inhibiting EGFR signaling, including monoclonal antibodies and small molecule tyrosine kinase inhibitors. It also provides information on trastuzumab and its role and use for HER2-positive breast cancer.
The Cytotoxic and Antimigratory Activity of Brazilin-Doxorubicin on MCF-7/HER...UniversitasGadjahMada
Breast cancer cells with overexpression of HER2 are known to be more aggressive, invasive, and resistant to chemotherapeutic agent. Brazilin, the major compound in the Caesalpinia sappan L. (CS) heartwood, has been studied for it's anticancer activity. The purpose of this study was to investigate the cytotoxic and antimigratory activity of brazilin (Bi) in combination with doxorubicin (Dox) on MCF-7/HER2 cells. Cytotoxic activities of Bi individually and in combination with Dox were examined by MTT assay. Synergistic effects were analyzed by combination index (CI). Apoptosis and cell cycle profiles were observed by using flow cytometry. Migrating and invading cells were observed by using a Boyden chamber assay. Levels of MMP2 and MMP9 activity were observed by using a gelatin zymography assay. Levels of HER2, Bcl-2, Rac1, and p120 protein expression were observed by using an immunoblotting assay. The results of the MTT assay showed that Bi inhibited MCF-7/HER2 cell growth in a dose-dependent manner with an IC50 of 54 ± 3.7 μM. Furthermore, the combination of Bi and Dox showed a synergistic effect (CI <1). Flow cytometric analysis of Bi and its combination with Dox showed cellular accumulation in the G2/M phase and induction of apoptosis through suppression of Bcl-2 protein expression. In the Boyden chamber assay, gelatin zymography, and subsequent immunoblotting assay, the combination Bi and Dox inhibited migration, possibly through down regulation of MMP9, MMP2, HER2, Rac1, and p120 protein expression. Hence, it was deduced that Bi enhanced cytotoxic activity of Dox and inhibited migration of MCF-7/HER2 cells. Therefore, it is believed that it has strong potential to be developed for the treatment of metastatic breast cancer with HER2 overexpression.
Thanks to Prof. Chavdar Pavlov, MD, PhD, MScD - Department Head of Therapy, Head of the Centre for Evidence-Based Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia for helping organizing this event in Moscow.
Hallmarks of cancer and radiopharmaceuticalsAlice Viana
In this presentation I review the article Hallmarks of cancer: next generation, from Hanahan and Weinberg, and make a parallel with potential and current targets of radiopharmaceuticals for diagnosis and treatment.
Cancer genes can be divided into two main classes: oncogenes and tumor suppressor genes. Oncogenes promote cell growth and proliferation when activated by mutations, while tumor suppressor genes normally inhibit cell growth and their inactivation allows for unchecked cell division. Dysfunction of multiple cancer genes is typically required for malignant transformation, as an imbalance between oncogene and tumor suppressor gene activity leads to cancer development. Common oncogenes include ras, myc, and HER2, while tumor suppressor genes include RB, p53, and APC. Mutations in DNA repair genes can also contribute to cancer by allowing genetic errors to persist.
8. newer chemical entities for cancer treatmentAiswarya Thomas
discussed about newer chemical entities in the cancer treatment such as ibrutinib, avastin, nolvadex, mozobil, xeloda, jevtana,femara,letrozole,sutent etc and mechanism of action of various drugs used under there categories.
Trophoblast Glycoprotein (TPGB5T4) A New Target For ADC Drugs.pdfDoriaFang
The more popular targets in ADC drugs include HER2, TROP2, EGFR, CLDN18.2, c-Met, CD19, PSMA, Muc1, BCMA and PDL1. Here we will introduce a new ADC target trophoblast glycoprotein (TPBG).
Effectiveness of Resveratrol on Metastasis: A Reviewiosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
FRα Targeting ADCs for Ovarian cancer.pdfDoriaFang
This article introduces FRα targets and FRα ADCs in clinical trials. There is only one FRα targeting ADC for ovarian cancer - mirvetuximab soravtansine-gynx (Elahere) and a few in clinical trials.
Progesterone receptor (PR) plays an important role in breast cancer progression and response to hormone therapy. PR exists as two isoforms, PR-A and PR-B, which act as transcription factors. PR signaling can occur through both nuclear and non-nuclear pathways. While PR expression correlates with better outcomes from hormone therapy, loss of PR is a mechanism of resistance. Targeting the PR pathway through drugs like anti-RANKL agents may be a preventative strategy, while newer endocrine therapies aim to overcome resistance.
This presentation (in English) made at ONCOTRANS in Besançon on Friday 3rd 2017 reviews the potential for TGF-beta inhibition in hepatocellular carcinoma based on preclinical and clinical data.
Impact of genetic targets on cancer therapySpringer
This review discusses genetic targets in breast cancer. It summarizes that breast cancer is the most commonly diagnosed cancer in women in the US, with over 178,000 new cases diagnosed in 2007. While the death rate has decreased over time due to improved treatments, it is still the second leading cause of cancer death among women after lung cancer. The review discusses several important molecular targets in breast cancer, including HER2, IGF, and cancer stem cells. It focuses on examples of molecular pathways and targets that have potential for personalized treatment approaches.
Impact of genetic targets on cancer therapySpringer
This review discusses genetic targets in breast cancer. It summarizes that breast cancer is the most commonly diagnosed cancer in women in the US, with over 178,000 new cases diagnosed in 2007. Molecular subtyping of breast cancer focuses treatment on specific targets like hormone receptor status and HER2 expression. Understanding genetic drivers of tumorigenesis has led to personalized, more effective treatments. The review discusses HER2 and IGF as molecular targets, treatments that target them like trastuzumab and lapatinib, and mechanisms of resistance. It also summarizes the roles of cancer stem cells and the tumor microenvironment in breast cancer.
This document describes a study investigating the role of the protein Morgana in breast cancer metastasis. The study found that knocking down Morgana impaired migration, invasion, and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, Morgana was found to increase the transcriptional activity of NF-κB, leading to increased expression of metastasis-promoting genes like MMP-9. Overexpressing Morgana had the opposite effect of increasing NF-κB target gene expression. Therefore, Morgana appears to promote breast cancer metastasis by activating the NF-κB pathway and increasing expression of pro-metastatic genes.
A 13-year-old girl presented with pain in her right lower limb for two months. An FDG PET-CT scan found tumors in her right lung, left lung, diaphragm, and a large tumor encasing her right tibia. A biopsy of the tibia tumor confirmed Ewing's sarcoma. Further tests found the cancer had spread to her bone marrow and lungs. She received 15 weeks of chemotherapy with VAC-IE. A follow up PET-CT then showed minimal residual disease in her tibia with complete resolution of the lung and node tumors, indicating positive treatment response.
A 50-year-old man presented with a lesion on his tongue that was biopsy and found to be poorly differentiated squamous cell carcinoma. He underwent a partial glossectomy and neck dissection at a private hospital. The post-op analysis found the tumor was 1.4x1.5cm in size and had clear margins, with no lymph node involvement. A follow up MRI found a possible residual lesion in the operation site that did not invade surrounding areas.
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Gene expression profiling in breast carcinomaghoshparthanrs
This document discusses gene expression profiling in breast cancer and its use in classifying tumor subtypes. It describes how gene expression profiling analyzes thousands of genes simultaneously to more accurately classify tumors. Breast cancer is classified into clinical subtypes based on receptor expression, including luminal, HER2-enriched, and basal subtypes. Gene signatures can provide prognostic information to help guide treatment decisions for early-stage breast cancer patients. Tests like Oncotype DX and Mammaprint analyze gene expression from tumor samples to predict the risk of recurrence.
Summary of Approved HER2 ADCs on The Market & in Clinical Trials.pdfDoriaFang
This document summarizes approved and investigational HER2-targeted antibody-drug conjugates (ADCs). Currently, three HER2 ADCs are approved: T-DM1, T-DXd, and RC48. T-DM1 and T-DXd are both comprised of the antibody trastuzumab linked to cytotoxic payloads (DM1 for T-DM1 and DXd for T-DXd). RC48 uses a different HER2-targeting antibody linked to MMAE. Many other HER2 ADCs are in clinical trials, including SYD985 which recently had its BLA accepted by the FDA. While some HER2 ADCs have been approved or shown promise, others like TAA013
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Metastatic breast cancer remains a major unmet medical need, with over 1.7 million new cases diagnosed globally in 2012. Several new therapeutic targets and agents are in development to treat metastatic breast cancer and its subtypes. These include agents targeting intra-tumoral drivers like HER2, IGF, HGF, PI3K/AKT/mTOR, PARP, and AR. Agents also target the tumor microenvironment, such as anti-angiogenics targeting VEGF and agents targeting immune cells. Many of these novel agents are currently in Phase II or III clinical trials alone or in combination with standard therapies. Developing strategies to optimize targeted treatments and combinations holds promise to improve outcomes for patients with advanced breast cancer.
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The Cytotoxic and Antimigratory Activity of Brazilin-Doxorubicin on MCF-7/HER...UniversitasGadjahMada
Breast cancer cells with overexpression of HER2 are known to be more aggressive, invasive, and resistant to chemotherapeutic agent. Brazilin, the major compound in the Caesalpinia sappan L. (CS) heartwood, has been studied for it's anticancer activity. The purpose of this study was to investigate the cytotoxic and antimigratory activity of brazilin (Bi) in combination with doxorubicin (Dox) on MCF-7/HER2 cells. Cytotoxic activities of Bi individually and in combination with Dox were examined by MTT assay. Synergistic effects were analyzed by combination index (CI). Apoptosis and cell cycle profiles were observed by using flow cytometry. Migrating and invading cells were observed by using a Boyden chamber assay. Levels of MMP2 and MMP9 activity were observed by using a gelatin zymography assay. Levels of HER2, Bcl-2, Rac1, and p120 protein expression were observed by using an immunoblotting assay. The results of the MTT assay showed that Bi inhibited MCF-7/HER2 cell growth in a dose-dependent manner with an IC50 of 54 ± 3.7 μM. Furthermore, the combination of Bi and Dox showed a synergistic effect (CI <1). Flow cytometric analysis of Bi and its combination with Dox showed cellular accumulation in the G2/M phase and induction of apoptosis through suppression of Bcl-2 protein expression. In the Boyden chamber assay, gelatin zymography, and subsequent immunoblotting assay, the combination Bi and Dox inhibited migration, possibly through down regulation of MMP9, MMP2, HER2, Rac1, and p120 protein expression. Hence, it was deduced that Bi enhanced cytotoxic activity of Dox and inhibited migration of MCF-7/HER2 cells. Therefore, it is believed that it has strong potential to be developed for the treatment of metastatic breast cancer with HER2 overexpression.
Thanks to Prof. Chavdar Pavlov, MD, PhD, MScD - Department Head of Therapy, Head of the Centre for Evidence-Based Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia for helping organizing this event in Moscow.
Hallmarks of cancer and radiopharmaceuticalsAlice Viana
In this presentation I review the article Hallmarks of cancer: next generation, from Hanahan and Weinberg, and make a parallel with potential and current targets of radiopharmaceuticals for diagnosis and treatment.
Cancer genes can be divided into two main classes: oncogenes and tumor suppressor genes. Oncogenes promote cell growth and proliferation when activated by mutations, while tumor suppressor genes normally inhibit cell growth and their inactivation allows for unchecked cell division. Dysfunction of multiple cancer genes is typically required for malignant transformation, as an imbalance between oncogene and tumor suppressor gene activity leads to cancer development. Common oncogenes include ras, myc, and HER2, while tumor suppressor genes include RB, p53, and APC. Mutations in DNA repair genes can also contribute to cancer by allowing genetic errors to persist.
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discussed about newer chemical entities in the cancer treatment such as ibrutinib, avastin, nolvadex, mozobil, xeloda, jevtana,femara,letrozole,sutent etc and mechanism of action of various drugs used under there categories.
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This review discusses genetic targets in breast cancer. It summarizes that breast cancer is the most commonly diagnosed cancer in women in the US, with over 178,000 new cases diagnosed in 2007. While the death rate has decreased over time due to improved treatments, it is still the second leading cause of cancer death among women after lung cancer. The review discusses several important molecular targets in breast cancer, including HER2, IGF, and cancer stem cells. It focuses on examples of molecular pathways and targets that have potential for personalized treatment approaches.
Impact of genetic targets on cancer therapySpringer
This review discusses genetic targets in breast cancer. It summarizes that breast cancer is the most commonly diagnosed cancer in women in the US, with over 178,000 new cases diagnosed in 2007. Molecular subtyping of breast cancer focuses treatment on specific targets like hormone receptor status and HER2 expression. Understanding genetic drivers of tumorigenesis has led to personalized, more effective treatments. The review discusses HER2 and IGF as molecular targets, treatments that target them like trastuzumab and lapatinib, and mechanisms of resistance. It also summarizes the roles of cancer stem cells and the tumor microenvironment in breast cancer.
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A 50-year-old man presented with a lesion on his tongue that was biopsy and found to be poorly differentiated squamous cell carcinoma. He underwent a partial glossectomy and neck dissection at a private hospital. The post-op analysis found the tumor was 1.4x1.5cm in size and had clear margins, with no lymph node involvement. A follow up MRI found a possible residual lesion in the operation site that did not invade surrounding areas.
A 42-year-old female patient from Bhopal, India presented with an abdominopelvic mass in January 2023. Various tests found elevated LDH and a large cystic pelvic mass. She underwent surgery which revealed a mucinous borderline tumor with microinvasion of the left ovary, classified as stage IA. The tumor board must now determine the appropriate next steps for treatment and follow-up care.
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- The patient is a 1 year and 10 month old male who presented with a fever for 6 months and a painless abdominal lump for 5 months.
- Imaging found a large solid mass in the right suprarenal region measuring 9.3 x 8.8 x 10 cm with enlarged lymph nodes. Biopsy confirmed a malignant small round cell tumor.
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This document provides information on low grade gliomas (LGG), including their classification, clinical presentation, imaging, molecular markers, and treatment. LGGs are slow-growing primary brain tumors that originate from glial cells. They are graded I-II by the WHO based on their morphology and malignancy. Common symptoms include seizures, which correlate with better survival. Imaging with MRI is used to identify non-enhancing lesions. Surgery aims to resect as much tumor as possible while preserving function. For higher risk patients, adjuvant radiation and chemotherapy such as PCV or temozolomide have been shown to improve survival outcomes compared to radiation alone. Close monitoring after treatment involves serial MRI and clinical exams.
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Healthy Eating Habits:
Understanding Nutrition Labels: Teaches how to read and interpret food labels, focusing on serving sizes, calorie intake, and nutrients to limit or include.
Tips for Healthy Eating: Offers practical advice such as incorporating a variety of foods, practicing moderation, staying hydrated, and eating mindfully.
Benefits of Regular Exercise:
Physical Benefits: Discusses how exercise aids in weight management, muscle and bone health, cardiovascular health, and flexibility.
Mental Benefits: Explains the psychological advantages, including stress reduction, improved mood, and better sleep.
Tips for Staying Active:
Encourages consistency, variety in exercises, setting realistic goals, and finding enjoyable activities to maintain motivation.
Maintaining a Balanced Lifestyle:
Integrating Nutrition and Exercise: Suggests meal planning and incorporating physical activity into daily routines.
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3. Targeted Cancer Therapies
Drugs or other substances that block the growth and spread of cancer by
interfering with specific molecules involved in tumor growth & progression.
Most researchers consider it as new approach to treating breast cancer that
targets the cell signaling pathways of cancer cells.
More selective for cancer cells.
Blocking of signals help to stop cancer progression and may induce cancer cell
death through apoptosis.
The development of targeted therapies requires the identification of good
targets.
3
4. In this seminar, we are going to study breast cancer therapies which are targeted
for following targets:
Tyrosine Kinases Receptors
Steroid Receptor Coactivators (SRC)
Mammalian Target of Rapamycin (mTOR) & Phosphoinositide 3-kinase
(PI3K)
Poly-{adenosine diphosphate (ADP)-ribose} polymerase (PARP)
4
5. Class of enzymes which are responsible for phosphorylation of tyrosine residue on
targeted proteins.
Stimulate multiple signaling pathways responsible for basic cells functions.
Several oncogenic tyrosine kinases have been detected in human malignancies. There
are two families of tyrosine kinases- Transmembrane receptor kinases & Cytoplasmic non-
receptor kinase
a) Transmembrane kinases receptor :
Human Epidermal Receptor (HER)
Insulin like Growth Receptor (IGFR)
Fibroblast Growth Factor Receptor (FGFR)
Vascular Endothelial Growth Factor Receptor (VEGFR )
Platelet-derived Growth Factor Receptor (PDGFR)
b) Cytoplasmic non-receptor kinase: Steroid Receptor Coactivators (SRC)
Tyrosine Kinases (TKs)
5
6. Multiple signaling pathways involved in the development, growth, and survival of breast
cancer cells
mTOR/PI3K/Akt
Pathway
IP3/DAG Pathway
Ras/MAPK
Pathway
6
7. o ErbB proteins are a four-member family of highly homologous receptor tyrosine kinases
comprised of ErbB1 (EGFR, HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).
o It is also known as ErbB1/HER1, is essential for growth and differentiation of epithelial
cells.
o The expression of EGFR, ligands, and their activating proteases in breast cancers has
been intensively studied.
Epidermal Growth Factor Receptor Targeting Monoclonal Antibodies:
Agent Class of compound Stages
IMC-C225 mAb Phase II
ABX-EGF mAb Phase II
Human Epidermal Receptors (HER)
Epidermal Growth Factor Receptor (EGFR)
7
8. The HER2 gene is amplified in approximately 20%-30% of breast cancers.
Overexpression HER2 found in breast cancer cells which has also been associated with
resistance to chemotherapy and hormone therapy.
HER2 target is present in a very high proportion of tumor cells
Human Epidermal Receptor 2 Targeting Monoclonal Antibodies:
Agent Class of compound Stages
Trastuzumab mAb Approved
Trastuzumab–DM-1 mAb-toxin conjugate Approved
Human Epidermal Receptor 2(HER2)
8
10. Compound Selectivity invitro IC(Nm) Stages
EGFR HER2
ZD1839, Gefitinib 27 3700 Marketed
OSI-774, Erlotinib 2 350 Marketed
GW572016, Lapatinib 11 9 Marketed
CP-724714 4300 8 Phase II
Arry-334543 7 2 Phase II
CI-1033, PD183805,
Canertinib
0.8 19 Phase II
BIBW-2992 0.5 14 Phase II
AV-412, MP-412 1 18 Phase I
AEE788 6 6 Phase II
EKB-569, Pelitinib 39 1200 Phase II
HKI-272, Neratinib 92 59 Phase II
BMS-599626 22 32 Phase I
Selected HER Family Tyrosine Kinase Inhibitors:
10
11. IGF system is composed of
↑ circulating levels of IGF-I are associated with a greater risk of breast cancer
in premenopausal women, with an especially high risk among those younger than
50 years.
↑ IGFs resists apoptosis in response to chemotherapy and radiation.
IGFBPs is activated by the estrogen, which itself activates expression of IGF-I.
Insulin-like Growth Factor Receptor (IGFR)
IGF
system
Ligands
IGF1 IGF2
Receptors
IGF1R IGF2R
Binding
Proteins
6 IGFBPs
11
12. Insulin-like growth factor 1 receptor (IGF-1R) Targeting Agents:
Agents Regimen Stages
IGF-1R Antibodies
CP-751,871 Docetaxel Phase II
Exemestane Phase II
Single agent Phase I
AVE1642 / EM164 Faslodex Phase II
IMC-A12 (Cixutumumab) Temsirolimus Phase I/ II
Capecitabine and Lapatinib Phase II
AMG 479 Exemestane or fulvestrant Phase II
MK-0646/h7C10
(Dalotuzumab)
Single Regimen Phase II
Ridaforolimus Phase II
Ridaforolimus and exemestane Phase II
Dual IGF-1R–insulin receptor inhibitor
BMS-754807 Trastuzumab Phase I/ II
Letrozole Phase II
12
13. The fibroblast growth factor (FGF) consist of 18 ligands.
FGF1 & FGF23 signal through four high affinity fibroblast growth factor
receptor (FGFR1 to FGFR4).
Under physiological conditions, the highly complex FGF signaling pathway is
tightly regulated.
The deregulation of FGF signaling to development of cancer, promoting
cancer cell proliferation, survival and migration.
Fibroblast Growth Factor Receptor (FGFR)
13
14. Drug class Drug name Target Stages
1st generation
TKIs
TKI258 (Dovitinib) FGFR, PDGFR &
VEGFR
Phase III
BMS54021 (Brivanib) FGFR & VEGFR Phase II
BIBF 1120 FGFR, PDGFR &
VEGFR
Phase III
Ponatinib ABL, FGFR,
PDGFRα, FLT3 &
VEGFR2
Phase II
E7080 FGFR, PDGFR,
VEGFR, KIT, RET
Phase I
E3810 FGFR1& VEGFR1
to VEGHR3
inhibitor
Phase I
Sulfatinib FGFR & VEGFR
inhibitor
Phase I
Fibroblast Growth Factor Receptor Targeting Agents:
14
15. Drug class Drug name Target Stages
2nd generation
TKIs
AZD 4547 Selective FGFR1,
FGFR2 & FGFR3
inhibitor
Phase II
BGJ398 Selective pan- FGFR
inhibitor
Phase I
FGFR antibodies IMC-A1 FGFR1-IIIc-specific
antibody
Preclinical
GP369 FGFR2 blocking
antibody
Preclinical
PRO-001 FGFR3-specific
blocking antibody
Preclinical
R3Mab FGFR3-specific
antibody
Preclinical
FGFR ligand
traps
FP-1039 FGF ligand traps
(blocks multiple FGFs)
Phase I
Fibroblast Growth Factor Receptor Targeting Agents:
15
16. VEGF overexpression is common in breast cancer.
Bevacizumab (Avastin; Genentech), a humanized monoclonal antibody against VEGF,
was granted accelerated approval in the US for the first-line treatment of MBC in
combination with Paclitaxel in 2008.
1st generation tyrosine kinase inhibitor; which also targets VEGFR are shown in
previous table.
Selected additional VEGF-targeted therapies:
Aflibercept or VEGF Trap is an antiangiogenic peptide-antibody fusion containing
portions of human VEGF receptor 1 and 2.
Vascular disrupting agents (eg, Ombrabulin; Sanofi-Aventis) another class of
antiangiogenic therapy, are under clinical trials for MBC.
Vascular Endothelial Growth Factor (VEGF)
16
17. PDGFR is expressed in most breast tumors.
The individual PDGF chains have different affinities for the two receptors- PDGFR α &
PDGFR β.
PDGFR α has high affinity for PDGF -A, -B, and -C, whereas PDGFR β has high
affinity for PDGF -B and –D.
Induces angiogenesis by up-regulating VEGF production.
1st generation TKs; which also targets PDGFR are shown in previous table.
Platelet Derived Growth Factor (PDGFR)
17
18. SRCs are small proteins of 160 kDa non-receptor tyrosine kinase and include SRC-1,
SRC-2/transcription intermediary factor-2 (TIF-2) and SRC-3.
SRC may play a significant role in tumor progression and spread.
SRC interact receptor tyrosine kinases (e.g. HER family), integrins, steroid hormone
receptors, including the estrogen receptor.
Steroid Receptor Coactivators (SRC) Inhibitors:
Agents Stages Regimen
Dasatinib Phase I/II Fulvestrant and MK-0646
Bosutinib Phase II Single Agent
Saracatinib Phase II Vs Zoledronic
Steroid Receptor Coactivators (SRCs)
18
19. mTOR is a member of the cellular mTOR/PI3K/Akt pathway. A high proportion of breast
tumors exhibit constitutive activation of the mTOR pathway.
Rapamycin is a macrolytic lactone produced by Streptomyces hygroscopicus, which has
immunosuppressive, antimicrobial, and antitumor properties. Rapamycin targets a
principal protein that was named mTOR.
Two mTOR complexes have been identified: mTORC1 and mTORC2 of cell growth and
proliferation, cell metabolism, angiogenesis, and apoptosis.
New agents are being developed that can inhibit both mTORC1 and mTORC2.
Mammalian Target of Rapamycin (mTOR)
Phosphoinositide 3-kinase (PI3K)
Three classes of PI3K enzymes, designated I to III, have been identified; members of
PI3K class I have been implicated in the mTOR pathway
PI3K can be key target that, if effectively inhibited, could improve outcomes.
19
21. Drug Drug class Stage of development
Sirolimus
(Rapamycin)
mTOR inhibitor Approved
Everolimus
(RAD001)
mTOR inhibitor Approved in 2012 for postmenopausal
women with advanced HR+/HER2- breast
cancer in combination with exemestane
after failure of treatment with letrozole or
anastrozole
Ridaforolimus
(deforolimus)
(AP23573)
mTOR inhibitor Phase III clinical trials
PP242 mTOR inhibitor Preclinical
BN107 mTOR inhibitor Preclinical
mTOR inhibitors:
21
23. PI3K selective inhibitors:
Agents Company Stage
PX-866 Oncothyreon Inc Phase I
GDC-0941 Genentech Inc Phase II
XL-147 Exelixis Phase I/II
BKM-120 Novartis Phase I
23
24. Drug Drug class Stage of development
PI-103 Dual kinase inhibitor Preclinical
LY294002 Dual kinase inhibitor Preclinical
NVP-BEZ235 Dual kinase inhibitor Phase I/II clinical trials
SF1126 Dual kinase inhibitor Phase I/II
XL765 Dual kinase inhibitor Phase I
BGT226 Dual kinase inhibitor Phase I/II
Dual kinase (mTOR &PI3K) inhibitors:
24
25. DNA damage, double strand breaks are highly toxic to cells
Homologous recombination is DNA repair mechanism.
Homologous recombination is dependent on functional BRCA 1 and 2 pathways.
Germline mutations in either the BRCA1 or BRCA2 genes are associated with a high
risk of developing a number of breast cancers.
When the BRCA-associated DNA repair pathway (homologous recombination) – is lost
or dysfunctional, repair shifts toward alternate DNA repair mechanisms dependent on a
unique class of enzymes, Poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP).
Poly-{Adenosine diphosphate (ADP)-Ribose} Polymerase (PARP)
25
26. PARP-inhibitors in clinical development:
Agent Company Stages
Olaparib (AZD2281) AstraZeneca/KuDOS Phase I/II
Veliparib Abbott Phase I/II
BS1-201 BiPar/SanofiAventis Phase II/III
AG014699 Pfizer Phase I/II
MK482 Merck Phase I
INO-1001 Inotek Phase I
CEP9272 Cephalon Phase I
26
27. Targeted cancer therapies hold the promise of being more selective, reducing side
effects, and improving quality of life.
Targeted therapies may work best in combination, either with other targeted therapies
or with more traditional therapies. Researchers are working to find new ways to target
cancer cells as part of treatment.
Various targeted therapies are being studied in clinical trials to see how well they
work in treating breast cancer.
As more targets are identified and therapies are developed, doctors will be able to
offer patients treatment that works best for their type of breast cancer.
In future, metastatic breast cancer, triple negative breast cancer can be well treated.
Conclusion
27