Targeted Therapy in the Treatment of Cancer – Flashcards
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The targeted drug may interfere with two things:
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cell communication and growth and may prevent tumor growth specific molecules involved in carcinogenesis and tumor growth
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Standard chemotherapy disadvantages
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primarily interferes with synthesis or activity of DNA to mainly kill rapidly dividing cells non-specific, affects normal and malignant cells many adverse effects
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Targeted therapy advantages
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designed to interact with specific molecules that are part of a system or process in cancer cells, that allow cells to grow, reproduce, and progress specific effects may produce less systemic toxicity
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What is the function of growth factors in normal cells?
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control growth/function bind to extracellular receptors, activate receptors, send a signal through the receptor into the cell to activate intracellular proteins - signaling pathways
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How are these signaling pathways activated chemically?
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phosphorylation
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The activated pathways send messages to do what?
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foster or inhibit cell growth and reprodution
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Kinases
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receptors and other proteins involved in phosphorylation
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What is the structure of tyrosine kinases?
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receptor TKs are transmembrane glycoproteins that are present within the cell membrane
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What are the three sections of tyrosine kinases and their functions?
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extracellular - contains ligand-binding area transmembrane - anchors protein in place intracellular - a catalytic domain
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What is the function of receptor kinases?
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extracellular domain = receptor ligand binding --> dimerization and signal transmission through transmembrane section to intracellular domain TKs transfer phosphate from ATP to tyrosine resides in polypeptides, initiating cascade of actions
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Cancer cells have uncontrolled growth.
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Growth factors can bind to extracellular receptors Some cancer cells can make their own growth factors Cancer cells can make extra growth factors - overexpression Gene mutations -> abnormal receptors that remain on w/o a growth factor Intracellular mutations can activate growth processes without receptor involvement Cancer cells can ignore signals to stop growth
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VEGF
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vascular endothelial growth factor plays a major role in angiogenesis secreted by cancer cells to stimulate new blood vessels to grow out to the tumor, increasing tumor size
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What is angiogenesis and its role in cancer?
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all tumors need blood vessels for nourishment cancer cells secrete VEGF to stimulate new blood vessels --> larger tumors
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What is apoptosis and its role in cancer?
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cell suicide; programmed cell death; controlled by genetics cancer cells can avoid it
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What are the therapy targets (cell processes) in cancer cells?
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increased signaling for cell growth increased blood vessel formation evasion of cell death (apoptosis)
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What are the types of targeted therapy?
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monoclonal antibodies (Mabs) small molecules (tyrosine kinase inhibitors, immunomodulators, misc) vaccines
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What are the three mechanisms of monoclonal antibodies?
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block extracellular receptors (rituximab, trastuzumab) Act as carriers of toxic substances to cancer cells (ibritumomab and tositumumab carry radiation; brentuximab carries microtubule disrupting agent) Attach to cells and trigger immune responses (rituximab)
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What do B cells produce?
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antibodies in response to antigenic stimulation
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Endogenous antibodies
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immunoglobulins IgG, IgA, IgM, IgD, IgE
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Exogenous antibodies
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produced outside body rituximab, trastuzumab, cetuximab, etc.
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How are monoclonal antibodies produced? What do hybridomas do?
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by fusing an AB-producing cell with a tumor cell to produce a hybridoma Hybridomas produce a large supply of the AB
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Why are the ABs monoclonal?
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all of the ABs are produced from a cloned population of cells derived from the original cell
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Murine Mabs
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mouse origin --> omab e.g. ibritumomab, tositumomab
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Chimeric Mabs
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human (65%) and mouse origin --> ximab e.g. rituximab, cetuximab, brentuximab
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Humanized Mabs
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95% human --> zumab e.g. alemtuxumab, pertuzumab, bevacizumab
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Fully human Mabs
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100% human --> umab e.g. panitumumab, ofatumimab, ipilitumumab
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Small molecules
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pass through cell membranes, interact with intra and extracellular proteins suffix = ibs (with inhibitory properties)
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Tyrosine kinases inhibitors (TKIs)
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"nibs" in cancer cells, TKs may be too abundant or active TKIs block action of enzymes, tyrosine kinases, which are involved in cell growth /division
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Misc. activities of TKIs
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induce apoptosis block specific enzymes / growth factors modify function of regulatory proteins act as immunomodulators
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Tyrosine kinases are either receptor or non-receptor
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receptor - transmembrane glycoproteins non-receptor - various locations including nucleus, maintained inactive by intracellular inhibitory proteins, activated by various intracellular signals
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What happens when a TK becomes fused with another protein after a chromosomal translocation?
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overcomes autoinhibition within the cell autophosphorylation without a signal cell becomes hyperactive and does not respond to regulation 95% of CML and 15-30% of ALL
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Philadelphia Chromosome
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CML - translocation of chromosome 9 and 22 results in the formation of the BCR-ABL tyrosine kinase Abl tip from 9 and bcr from 22
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Which chromosomes are fused to produce the Philadelphia chromosome? Which tips?
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Chromosomes 9 and 22 9 - ABL 22 - BCR
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What happens when there is an increased expression of receptor TK?
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leads to proliferation due to increased signaling
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Breast cancer
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some types involve overexpression of HER-2 receptors, which are present in normal cells to certain extent but lead to proliferation in overabundance
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EGFR
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epidermological growth factor receptor in solid tumors
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What is the difference between MABs and Nibs on the EGFR axis?
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MABs block external receptor (no signal, no phosphorylation) NIBs act inside to prevent autophosphorylation
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Pharmacological inhibition by MABs
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antibodies bind to external receptors block the receptor in the place of the ligand or neutralize the ligand
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Herceptin (Trastuzumab)
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a MAB that binds HER-2 receptors so normal signaling molecule can't access to stimulate; inhibits proliferation
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Mechanism of ibritumomab and tositumomab
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cytotoxicity by a substance carried by the AB radiation harm to all cells
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Mechanism of Brentuximab
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delivers antimicrotubule substance to cells
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Rituximab (Rituxan) Mechanism
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binds to B (bad) cells and causes cell lysis in two ways - antibody-dependent cellular toxicity (ADCC) and complement-induced cell death (CDC)
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Rituximab Antibody-Depedendent Cellular Toxicity (ADCC)
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immune system sends T cells and macrophages to kill b cells, causing cell lysis
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Rituximab Complement-Induced Cell Death (CDC)
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binding of the antibody to the cells calls complement proteins, which punch holes in the cell membrane, flooding the cell and leading to cell lysis
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CTLA-4 cytotoxic T-lymphocyte antigen-4 (CTLA-4)
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a negative regulator of T-cell activation
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Implimumab (Yervoy)
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binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligand CD80/CD86 blockade of CTLA-4 has been shown to augment T-cell activation and proliferation
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Tyrosine Kinase Inhibitors Mechanism
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act inside to prevent phosphorylation inhibit abnormal signals that lead to the formation of neoplastic cells Bind to and block ATP-binding site on tyrosine kinases Proteins are unable to phosphorylate tyrosine resides located on their cytoplasmic domains and effector proteins
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What may the neoplastic cells do once inhibited by TKIs?
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may stop abnormal replication and/or undergo apoptosis
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What do all TKIs have in common?
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all are PO form
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What is the most common adverse effect of tyrosine kinase inhibitors?
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rash - face, neck, trunk may indicate response to therapy prevent with self-care
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Why does a rash occur with tyrosine kinase inhibitors?
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epidermal growth factor receptor is found on the skin; drugs interfere with it, reducing skin growth that maintains skin surface skin is also sustained by vasculature (VEGF receptors)' blocking receptors interferes with blood vessels in skin
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What other dermatological adverse effect is seen with tyrosine kinase inhibitors?
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hand and foot syndrome
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What other side effects are seen with tyrosine kinase inhibitors?
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hypertension, marrow suppression, diarrhea, fatigue, hepatotoxicity, QT prolongation, interstitial lung disease, interactions with enzyme inducers/inhibitors
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Diarrhea with tyrosine kinase inhibitors
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seen with all TKIs, 1 out of 2 patients, treat with loperamide or reduce dose
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QT prolongation with NIBs
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uncommon, black box with nilotinib, avoid low K and Mg
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Interstitial lung disease with NIBs
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rare but potentially life-threatening (cough, fever, shortness of breath), hold tx EGFR may have role in repairing lung damage
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Use cautions with NIBs and interactions with enzyme inducers/inhibitors
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agents inducing CYP3A4 metabolism may increase drug clearance agents inhibiting CYP3A4 metabolism may decrease drug clearance
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Targeted therapy may interact with several factors
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intracellular signaling pathway specific protein or growth factor needed for cell growth (e.g. BCR-ABL) angiogenesis apoptosis
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Cancer therapies that target angiogenesis
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block VEGF e.g. Bevacizumab, sorafenib, sunitinib
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Bevacizumab MOA
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attaches to VEGF and prevents it from binding to the receptor blood vessels shrink away from tumor and new blood vessels prevented from forming
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How do certain therapies target apoptosis?
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signaling pathway can turn apoptosis on/off, and normal cells respond and die. Cancer cells can avoid/ignore apoptosis Targeted agents affect specific molecules to induce apoptosis. "Turn off and restart apoptosis gene" e.g. rituximab
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What is the chromosomal translocation responsible for chronic myelogenous leukemia?
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philadelphia chromosome
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Targeted therapies for CML and their MOA
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imatinib, nilotinib, and dasatinib interact with intracellular signaling pathway interact with specific protein or growth factor needed for cell growth e.g. Imatinib blocks BCR-ABL protein in patients with CML
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How effective are targeted therapies for CML and how do they compare to IFN?
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highly effective treatment but not curative; produce long-term disease control imatinib has higher response rates than IFN and more durable responses and less toxicity they have replaced IFN as standard of therapy
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Targeted therapies for renal cell carcinoma
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target proteins involved in causing excessive proliferation sutinib, sorafinib, pazopanib, axitimib meaningful improvement over chemo in terms of less toxicity and better overall survival
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Which targeted therapy is used against hepatocellular carcinoma?
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Sorafenib FDA-approved for unresectable disease clear survival advantage over previously available drug major ADRs: diarrhea, hand/foot, fatigue
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Which targeted therapy is used against malignant melanoma?
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vemurafenib
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Vemurafenib MOA
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inhibition of BRAF with V600 mutation this pathway does not need external growth for proliferation more effective than chemo - more survival
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Vemurafenib ADRs
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arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritis, and skin papilloma cutaneous toxicity - squamous cell and photosensitivity
