Ch 16: The Rational Treatment of Cancer
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studycards24 on April 30, 2011
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Terms | Definitions |
|---|---|
 Effective therapies depend on accurate disease diagnoses | -histology: traditional -imaging: MRI (high res and non-invasive) -microarrays produce "gene signatures": allow cancers to be stratified cancers into subgroups with distinct biological properties and prognoses -outcome: tailored treatment (improves drugs used, dosing, effectiveness) |
| implications for gene array: who to treat | women whose tumors carry a good signature derive virtually no benefit from adjuvant chemotherapy |
| how do anti-cancer drugs work? | 1. induce differentiation=> enter post-mitotic state (limited success in effective drug development) 2. induce apoptosis |
| Cancer therapies that induce apoptosis | 1. block upstream signaling that induces Akt/PKB activity (pro-survival) 2. induce mitoic catastrophe -normal cells: DNA damage induces G2=> M2 block -cancer cells: cricial checkpoints gone=> residual apoptosis triggered, cells die |
| stages of drug development | 1. identify a molecular target 2. screen for inhibitors or activators 3. optimize, formulations 4. pre-clinical studies 5. clinical trials 6. regulatory approval |
| rational drug design | 1. drugs should target proteins that contribute to the disease state 2. predicted druggability of protein 3. detailed molecular structures of target proteins should inform design of drug |
| New drug development-Identifying a molecular target | low molecular weight organic compounds inhibit biochemical functions, not enhance them limits on potential protein targets 1. geatkeepers: tumor suppressor proteins 2. caretakers: genome maintenance proteins neither is realistic because need to replace missing function 3. oncoprotiens: drugs can inhibit their activity (many are signaling proteins), causing a collapse of neoplastic phenotype |
| inhibition of tumor growth by targeting downstream signaling elements | signaling from receptors can be blocked in a number of ways |
| drug and target considerations | Drugs: usually low MW organic compounds a. easier to synthesize than high MW compounds b. small molecules better penetrate interstices of tumor for greater therapeutic effect Target Protein: Is it druggable? a. identifiable enzyme function b. well-defined catalytic cleft that can bind molecules to inhibit function c.kinase vs. transcription factor (myc and fos) |
| gleevec binds catalytic cleft of fusion protein with great specificity and avidity=> disrupts protein function | ... |
| gleevec specific binding to abl catalytic cleft | -precursor compound optimized by adding and subtracting side chains to improve binding to catalytic cleft -gleevec binds via H bonds and van der waals |
| non-kinase targets | protein-protein interactions as drug targets a. cyclin-CDK pairs that drive cancer cell proliferation -unsuccessful because compound not large enough to span the multiple points of protein-protein interacting faces b. Mdm2-p53 downregulated p53 success with nutlin-2 -associates with mdm-2 binding pocket for p53 prevent mdm2-mediated p53 degradation -induces apoptosis -low micromolar concentration |
| protein-protein interactions as drug targets continued | c. Bcl2 (anti-apop) binds and neutralizes BH3 pro-apoptosis proteins drug: EGCG, found in green and black teas, bind Bcl-XL with high affinity at very low concentrations (sub-micromolar) EGCG docks in 3 adjacent hydrophobic pockets of Bcl-XL BH3 proteins are no longer sequestered=> apoptosis |
| while there are other success stores with protein-protein inhibitors, targeting kinases that function as neoplastic oncoproteins still proves the best strategy | ... |
| the human kinome | -518 genes encoding protein kinases -90 phosphorylate tyrosine residues -428 phosphorylate serine-threonine residues -all TKs and 318 seronine-threonies Ks are closely structurally related |
| structural similarity of kinases pose a problem in drug development | how can a drug be developed that affects the actions of cancer-associated kinases but does not target those required fro normal cell proliferation? similaries of 5 serine-threonine kinases and 4 tyrosine kinases: each have a catalytic cleft sandwiched between 2 major lobes |
| stages of drug development | 1. identify a molecular target 2. screen for inhibitors or activators 3. optimize, formulation 4. pre-clinical studies 5. clinical trials 6. regulatory approval |
| high-throughput screening-HTS | -test collections (libraries) of organic molecules in order to find the small number having the functional properties of the desired drug some library types: a. natural compounds b. compounds that have already been synthesized for previous drug development c. compounds generated through combinatorial chemistry (generate Ig # diff, but structurally related compounds) |
| High-throughput screening-HTS | 1. add chemical compound to plates containing biological molecule 2. did the drug produce desired response? (apoptosis of cells, kinase inhibition 3. isolate "lead compounds"-subset that have some desired function 4. optimize: chemists then create derivative by adding or subtracting chemical groups to the lead 5. newly synthesized drug may have better properties (ex. inhibit a target enzyme at lower concentrations that do not effect off-targets) |
| Stages of Drug Development | 1. identify a molecular target 2. screen for inhibitors or activators 3. optimize, formulation 4. pre-clinical studies 5. clinical trials 6. regulatory approval |
| pre-clinical drug testing I | measure a drug's relative effects on its intended target compared to its off-target effects goal: determine if drug selectively targets protein at concentrations low enough to not effect off-targets |
| assay for measuring the binding affinity of a test compound for 156 distinct kinases | binding affinity of a test drug for a kinase predicts the ability of this drug to inhibit the activity of the kinase |
| results of the binding assay for iressa, tarceva (both inhibit EGFR) and staurosporine | iressa and tarceva: both bind EGF-R with higher specificity (lower dose needed to achieve 50% inhibition) than other 155 compounds staurosporine: effectively inhibits many kinases, even at sub-nm concentraion |
| pre-clinical drug testing II | testing drug on cultured cells-is the drug selective? goal: high therapeutic index-cancer cells killed; normal cells spared ex. testing of gleevec in cell culture |
| pre-clinical drug testing III-animal models | if drug has potent killing affects on cultured cell: does its in-vitro behavior predict its action in vivo? |
| pre-clinical drug testing III-animal models | mouse models Human tumor xenografts grown in immunocompromised mouse host-presumption is that this tumor will mimic behavior of tumors in humans confounding factors 1. of mice and men 2. xenografts=human tumor cells propagated in culture for years-selection pressure for optimal proliferation 3. cultured cells that readily form established cell lines are typically from aggressively growing tumors |
| test pharmacokinetics and pharmocodynamics of a drug in mice | pharmacokinetics: does drug accumulate to significant levels in plasma or tissues for an extended period of time or only transiently? what is the cumulative drug doses experienced by cells in tumor? pharmacodynamics: gauges the ability of a drug to affect a targeted biochemcial fxn in a tumor under treatment surrogate marker: measure the response of a target with a quantifiable change e. gleevec: ideal target is bcr-abl fusion protein, easier to measure antoehr kinase it inhibits, Kit |
| mouse models: determining drug toxicities | drug concentrations needed to kill tumors may also harm organ systems: liver, kidneys, GI tract, hematopoietic kill cancer cells, spare normal cells problems 1. the 20,000 genes expressed in cancer cells are also expressed in normal cells 2. mice models often fail to predict human toxicities=> mice metabolize compounds very differently from humans |
| stages of drug development | 1. identify a molecular target 2. screen for inhibitors of activators 3. optimize, formulation 4. pre-clinical studies 5. clinical trials 6. regulatory approval |
| clinical trials | drugs that pass mouse model tests may now be promoted to a candidate for human testing who participated in a phase I clinical trial? small groups of patient volunteers who have failed to respond to other therapies |
| phase I clinical trial | 1. toxicity test: dose escalation trials yield the MTD=maximum tolerated dose -determine whether side effects at a particular does are acceptable (transient nausea vs. bone marrow depletion) -if life threatening, trial stopped, drug not further developed 2. pharmacokinetics: is the drug reaching tumor cells at a sufficient concentration over a period of time? 3. Pharmacodynamics: does the drug shut down the activity of its intended target? |
| phase II and phase III clinical trials | -enrolling patients in larger trials based on indications-tumor type, stage of progression obvious indications: use a drug that inhibits the HER2/Neu receptor molecule in the 30% breast cancer patients whose tumor cells overexpress this protein indications are often general: ex. drug may be used because it is a general inducer of apoptosis |
| phase II trials | small group of patients enrolled based on inidcations good results in phase II |
| phase III trials | large group of patients receive drug -patients usually have gone through many rounds of chemo=> unresponsive -have very aggressive tumors refractory to established therapies FDA approval: bar may not be set too high for new drug approval because drug dispatched to attack most difficult cancers |
| tumor drug resistance | common problem in cancer drug therapy: over time, cancers that once responded to a drug become refractory to the treatment cause: unstable genotype of evolving cancer accumulate mutations that confer survival |
| combating tumor drug resistance | multi-drug therapies -apply two unrelated drugs simultaneously-low likelihood of cancercells forming with ability to survive both |
| MDR: multi-drug resistance | -tumors are able to survive multiple drugs administered together evasion mechanism? upregulation of MDR1 gene: transmembrane drug efflux pump -cancer cell able to excrete variety of chemically unrelated drugs -lowers intracellular concentrations to cub-toxic levels |
| tyrosine kinase inhibitors | the gleevec story (iminatib mesylate) indication: chronic myelogenous leukemia patients: 9:22 translocations, creats the philadelphia chromsome and bcr-abl fusion protein |
| CML: philadelhia chromosome produces the bcr-abl tyrosine kinase | pathways activated by bcr-abl -ras -PI3-Akt/PKB -jak-STAT TFs: jun, fos, Nf-kb |
| specificity of gleevec | -abl kinase=42%aa homology with many kinases gleevec inhibits 4 out of 90 human TKs -binds ATP-binding pocket=> stabilizes a catalytically inactive conformation of enzyme -inhibits bcl-abl, PDGF-R, kit=> all 3 implicated in carcinogenesis |
| treatment of early state CML with Gleevec | before treatment: cytological analysis of patient's blood-many leukemia cells (large dark neuclei) after treatment: in 90% of these patients, only normal granulocytes found post-gleevec (among rbcs); relapse 5-10% |
| gleevec response in patients that have progressed to advanced stage (blast crises) | -60% respond initially, then relapse non-relapse patients: have wildtype bcr-abl (non-mutated kinase domain), respond with high specificity 29/32 relapse patients: kinase domain mutation that prevents gleevec binding to catalytic domain |
| gleevec's inhibition of PDGF-R and kit proves to be useful in treating other cancers as well | ex. myeloproliferative diseases (elevated levels of cells from myeloid lineage), hypereosoinophilic syndrome -patients have mutated PDGF-R -complete response via Gleevec treatment (eradication of eosinophils) ex. GIST-gastrointestinal stromal tumors Kit is primary mitogentic force in these tumor cells; 70% patients have tumor regression with Gleevec |
| other drugs | iressa & tarceva: EGF-receptor antagonists (block ATP-binding site) -carcinomas -partial success with NSCLC velcade: proteosome inhibitor (clogs proteosome to prevent degradation of IkB, since IkB is inhibitor of NFkB, its cannot activate anti-apoptotic gene+> apoptosis of cell -partical success with multiple myeloma (disease of B-cell lineage, immunodeficiency and death from infection) |
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