07 Targeted Cancer Therapies (Kinase Inhibitors) Flashcards Preview

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Flashcards in 07 Targeted Cancer Therapies (Kinase Inhibitors) Deck (73):

What are Targeted Cancer Therapies?

Drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. They interfere with cancer cell division (proliferation) and spread in different ways


What are the general characteristics of Kinase Inhibitors?

Very few kinases have been found mutated in human cancers (cAbl, MET, b-RAF). Several receptor tyrosine kinases are amplified in specific tumors (EGFR, ERB-B2)


What are the two classes of Tyrosine Kinase Inhibitors?

Non-Receptor Tyrosine Kinases (BRC-Abl, C-Src, Jak2). Receptor Tyrosine Kinases (VEGFR, EGFR)


What are the general characteristics of BCR-Abl Kinase?

Chromosome translocation results in fusion protein BCR-Abl. BCR-Abl kinase is constitutively active, i.e. it does not require activation by other cellular messaging proteins (always "On"). Activates a number of cell cycle-controlling proteins and enzymes, speeding up cell division and genomic unstability. Involved in Ph+ Leukemias (CML, AML)


What are the general characteristics of Imatinib (Inhibitor of BCR-Abl Kinase)?

Gleevec. 2-Phenylaminopyrimidine was found as a BCR-Abl inhibitor. Introduction of methyl and benzamide groups gave original lead enhanced binding properties, resulting in Imatinib. Imatinib binds to Tyr kinase active site


What else does Imatinib (Gleevec) inhibit?

c-Abl, c-kit, and PDGF-R, but not other known Tyr kinases (TK)


What is Imatinib used for?

Treat Leukemia and other types of cancer (notably I Stromal Tumors).


How is Imatinib administered?

Oral agent and has low toxicity


What is the PK/PD of Imatinib?

Rapidly absorbed when administered PO (BA 90%). Metabolized by liver (CYP 450). Main metabolite is a N-demethylated piperazine derivative. Mostly secreted through the bile/feces


What are the problems with Imatinib Therapy?

Many CML (Chronic Myelogenous Leukemia) patients relapse when treated with Imatinib. Sequencing of the BCR-Abl gene in resistant tumors show that secondary mutations have occurred in the ATP binding region of the kinase (TK active site)


Besides Imatinib, what are the two other oral BCR-Abl inhibitors?

Nilotinib. Dasatinib


How does Dasatinib work?

Inhibits all BCR-Abl mutants, except mutation T315l, which also confers resistance to both Dasatinib, Nilotinib, and Imatinib in vitro


What is the benefit of Nilotinib?

Shows a favorable safety profile and shows activity in cases of CML resistant to treatment with Imatinib


What potential toxicity is there with Nilotinib?

Potential heart complications


What is Vascular Endothelial Growth Factor (VEGF)?

VEGF activates VEGFR, a receptor Tyrosine Kinase (RTK). Primary mediator of angiogenesis and vasodilation. Promotes endothelial cell viability and proliferation


What is the rational for Inhibition of VEGF?

Inhibits metastasis (Blocks VEGF-induced peritumor lymph drainage. Blocks VEGF(A)-induced dysfunctional angiogenesis. Inhibits invasion of circulation by the tumor. Decreases vascular density of tumor). Increases killing of established tumors (Improves chemotherapy delivery to tumor)


What is Sunitinib (Sutent)?

Oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor. Inhibits vascular endothelial growth factor receptors (VEGFRs). Simultaneous inhibition of these targets therefore leads to both reduced tumor vascularization and cancer cell death, and ultimately tumor shrinkage


What else does Sunitinib inhibit?

Also inhibits C-kit RTK (KIT or CD117). Continuous activation of C-Kit drives the majority of GI Stromal Cell tumors. Other RTKs inhibited are: RET, CSF-1R, and flt3


What is Sunitinib used for?

Treatment of renal cell carcinoma (RCC) and Imatinib-resistant GI Stromal Tumor (GIST)


What is the PK/PD of Sunitinib?

Unaffected by food. Metabolized in liver by CYP 450. Main metabolite is N-desetylated derivative (active). Excretion fecal (61%) and renal (16%)


What are the toxicity and side-effects associated with Sunitinib?

Fatigue, diarrhea. Nausea, HTN. Anorexia. Stomatitis (inflammation of the mucous lining of any of the structures in the mouth)


Besides Sunitinibh, what are the other VEGF Kinase Inhibitors?

Sorafenib (Nexavar). Pazopanib (Votrient)


What is Her2 Receptor?

Belongs to the Epidermal Growth Factor Receptors (EGFR) family (TRK)


What does activation of Her2 Receptor do?

Activation of anti-apoptotic Ras signaling cascade (Apoptosis Inhibition). The result of gene amplification is an abnormally high cell replication response to normal levels of growth factor (increased cell replication, increased tumorigenicity)


What is Gefitinib (Iressa)?

EGFR Tyrosine Kinase Inhibitor. Inhibits Akt-mediated anti-apoptotic pathway preventing malignant cells to grow


What is Gefinitib used for?

To treat locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy


How is Gefinitib administered?

Orally (BA 59%)


What are the Toxicity and side-effects associated with Gefinitib?

Acne. N/V/D. Anorexia. Stomatitis. Gefitinib is a selective chemotherapeutic agent, its tolerability profile is far superior to previous cytotoxic agents


What is Bortezomib (Velcade)?

Ubiquitin Protease Inhibitor. Highly selective, reversible inhibitor of the 26S proteasome (used for recycling of short-lived proteins). The boron atom in bortezomib binds the catalytic site of the 26S proteasome with high affinity and specificity. May prevent Ub-mediated degradation of pro-apoptotic factors, permitting activating of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways


What is Bortezomib used for?

Treating relapsed multiple myeloma and mantle cell lymphoma


How is Bortezomib administered?



What are the toxicity and side-effects associated with Bortezomib?

Fatigue, generalized weakness. Peripheral neuropathy. N/V/D. Low platelet count


What are Chromatin Structures?

An important factor in determining whether a particular gene is expressed or not. Human genome is packaged into chromatin, which is a dynamic macromolecular complex that consists of DNA, histones, and non-histone proteins


What is Histone-Deacetylase (HDAC)?

Inappropriate transcriptional repression mediated by HDACs is a common molecular mechanism that is used by oncoproteins. Alterations in chromatin structure can impinge on normal cellular differentiation, which leads to tumor formation


What are HDAC Inhibitors used for?

Can reactivate gene expression and inhibit the growth and survival of tumor cells


What is Vorinostat (Zolinza)

Member of a larger class of compounds that inhibit HDAC. Vorinostat inhibits HDAC activity by binding to the pocket of the catalytic site. The hydroxamic acid moiety of Vorinostat (SAHA) binds to a Zinc atom in the catalytic site of HDACs


What is Vorinostat used for?

Cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after treatment with other medicines


How is Vorinostat administered?



What are the toxicity and side-effects associated with Vorinostat?

PE. GI symptoms (N/V/D, anorexia). Constitutional symptoms (fatigue, chills). Hematologic abnormalities (thrombocytopenia, anemia). Taste disorders


What is Romidepsin (Istodax)?

HDAC Inhibitor. Acts as a prodrug with the disulfide bond undergoing reduction within the cell to release a Zinc-binding thiol. The thiol reversibly interacts with a Zinc atom in the binding pocket of Zn-dependent histone deacetylase


What is Romidepsin used for?

Cutaneous T-cell lymphoma (CTCL) in patients who have received at least 1 prior systemic therapy


How is Romidepsin administered?

Intravenous infusion


What are the toxicity and side-effects associated with Romidepsin?

N/V, fatigue, loss of appetite. Blood disorders (anemia, thrombocytopenia and leukopenia). Metabolic disturbances. Altered taste perceptions


What are the general characteristics of Monoclonal Antibodies in targeted cancer therapies?

D/t their ability to specifically recognize and target antigens, antibodies have also become useful therapeutic tools


What is the downside of Monoclonal Antibodies?

Antibody secreting cells (B-cells) in culture die out after a few generations, d/t the finite growth potential of any somatic cell. In addition, the immune system does not normally just make an antibody to just ONE part of an antigen, but makes 'polyclonal antibodies' synthesized to recognize many different features of the antigen


What are the problems associated with Polyclonal Antibodies?

Lack of reproducibility (each batch could be different). Complex mixture (many different specifications, potential contaminants (e.g. viruses)). Immunogenicity (animal proteins provoke immune response, loss of efficacy and serum sickness)


What are the key properties of antibodies relevant to therapy?

Binding function (exquisite specificity, high avidity from two binding sites). Effector function (Fc receptors (ADCC), complement (CDC)). Long half life (Liver FcRn receptor, carrier function for other drugs or radioisotopes)


How are antibodies different from conventional drugs?

Large size. Potentially immunogenic


What does the "XI" stand for in Rituximab?

Chimera antibody


What does the "ZU" stand for in Alentuzumab?

Humanized antibody


What is Trastuzumab (Herceptin)?

Genetically engineered to bind specifically to HER2. Binds only to cell over-expressing the HER2 protein on the cell surface preventing dimerization of receptor and its activation. Also believed to be a mediator of antibody dependent cell-mediated cytotoxicity via natural killer cells and monocytes. Reduces growth of tumors and in some cases, has made tumors disappear altogether


How is Trastuzumab administered?

Intravenous infusion


What are the toxicity and side-effects associated with Trastuzumab?

Cardiac dysfunction. Risk of cardiomyopathy is increased when Trastuzumab is combined with anthracycline chemotherapy, for example. Treatment cost ~$70,000 per patient


What is the primary mediator of Angiogenesis?

VEGF. Blocking VEGFR pathway leads to inhibit tumor metastasis


What is Bevacizumab (Avastin)?

Blocks VEGF-A. Blocks activation of several VEGF receptors leading to both reduced tumor vascularization and cancer cell death


What is Bevacizumab used for?

Metastatic cancers, and treatment of recurring Glioblastoma Multiforme


How is Bevacizumab administered?

Intravenous infusion


Besides cancer, what else can Bevacizumab be used for?

Treat vascular-related diseases such as age-related macular degeneration (AMD) and diabetic retinopathy


What are the toxicity and side-effects associated with Bevacizumab?

Impairs wound healing, not indicated in patients that need to go into surgery (not allowed until 28 days after surgery). Bleeding complications (minor or severe). May impair fertility. GI perforations. Arterial thromboembolic events. Treatment costs ~$50k per patient


What is Rituximab (Rituxan)?

Antibody directed against CD20. CD20 is primarily found on the surface of mature B-Cells (normal and cancerous cells) and is likely involved in the regulation of B-Cell activation and proliferation


What is Rituximab used for?

Treatment of many lymphomas, leukemias, and some autoimmune disorders


How is Rituximab administered?

Intravenous infusion


What are the toxicity and side-effects associated with Rituximab?

Infusion reactions (may be severe). Cardiac arrest. Tumor lysis syndrome (acute renal failure requiring dialysis). Viral infections (progressive multifocal leukoencephalopathy, PML)


What is Cancer Radioimmunotherapy?

Combining a monoclonal (or naked) antibody with a radioactive isotope creates a radiolabeled antibody. The use of radiolabeled antibodies for treatment is known as Radioimmunotherapy (RIT)


What are the Numerous benefits of RIT compared to traditional chemo- or radio-therapy?

Less side-effects (radiation only applied to tumor cells). Can reach malignant cells that are not accessible to monoclonal antibodies or chemotherapy. Involves shorter treatment times than chemotherapy. Remission periods are typically measured in years


What is Tositumomab-I^131 (Bexxar)?

Anti-CD20 monoclonal conjugated to I^131 (B- and y-emitter)


What is Tositumomab-I^131 used for?

Treatment of follicular lymphoma, specially indicated in patients with relapsed or chemotherapy/rituxan refractory follicular lymphoma


How is Tositumomab-I^131 administered?

Intravenous infusion first naked then conjugated to I^131


What are the toxicity and side-effects associated with Tositumomab-I^131?

Severe thrombocytopenia and neutropenia (infection and bleeding)


What is Ibritumomab Tiuxetan (Zevalin)

Monoclonal antibody (IgG1) chemically conjugated to the chelator tiuxetan, to which a radioactive isotope (Y^90) is loaded


How does Ibritumomab Tiuxetan work?

Binds to the CD20 antigen found on the surface of normal and malignant B cells (but not B cell precursors). Allows radiation from attached isotope to kill targeted cell. May also mediate cell death via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis


What is Ibritumomab Tiuxetan used for?

Treat some forms of B-Cell non-Hodgkin's Lymphoma


What are the most serious side-effects of Ibritumomab Tiuxetan?

Severe and prolonged cytopenias (anemia, lymphopenia, neutropenia, thrombocytopenia)