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Lecture 22

BMS 860 Lecture 22: Cancer Notes 22

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Biomedical Sciences
BMS 860

Lecture 22- Cancer treatments Translational Research • The process of applying new knowledge, mechanisms and techniques generated by advances in basic science research into new approaches for prevention, diagnosis, and treatment of disease. Model for translational research • Basic research includes drug development and study of disease mechanisms • Patient oriented research is research that is used to affect the clinical practice • Population based research- epidemiology, public health policies, cost effective options Canadian Institute for Health Research (CIHR) Pillars • 4 pillars: biomedical research, clinical research, health systems and services research, social/cultural/environmental population health research • ex. of Social, Cultural, environmental and population health = Enhancing HPV prevention among indigenous populations – HPV infections and hence cervical cancer Drug Development Pipeline • Starts with basic research question, drug discovery, preclinical studies where drugs are tested on experimental models • Clinical trials- 3 phases, positive results leads to FDA review, phase iv is post marketing trials • How much does it cost to bring a new drug to the market? 1.4 billion dollars • What percentage of total healthcare is spent in pres drugs in Canada? 13.4% • What percent of compounds in phase I make it to the market? 10% • For every 100 pres written, what % are filled and taken appropriately? 20% Drug discovery phase • basic research and drug discovery can take 2-10 years 1. Choose a disease 2. Choose a drug target- protein, pathway 3. Choose a “bioassay” to validate the target/drug 4. Find a lead compound 5. Preclinical testing of lead compounds Choosing a Disease • Pharmaceutical companies are commercial enterprises • Pharmaceutical companies tend to avoid products with a small market (i.e. rare cancers) • Pharmaceutical companies will also avoid products that would be consumed by individuals of lower economic status (i.e. a disease which only affects third world countries) • Most research is carried out on diseases which afflict “first world” countries: (e.g. cancer, cardiovascular diseases, depression, diabetes, flu, migraine, obesity). The Orphan Drug Act • The Orphan Drug Act of 1983 was passed to encourage pharmaceutical companies to develop drugs to treat diseases which affect less than 200,000 people in the US- addresses rare diseases • Under this law, companies who develop such a drug are entitled to market it without competition for seven years. • This is considered a significant benefit, since the standards for patent protection are much more stringent. • resulted in extremely high prices for drugs- Gleevec costs 20k per year per patient • Designation of rare disease: o Prevalence (less than 200K)- ex. sickle cell disease o If disease is common (more than 200K) but subset of all persons with the disease are expected to benefit from the drug- ex. common disease (NSCLC); orphan subset (EGFR mutations) o Many cancer molecular targeted therapies fall under orphan drug act Choosing a drug target • Drug target is a specific macromolecule, or pathway, which the drug will interact with (e.g. EGFR pathway in NSCLC) • Drug target must be “druggable” or accessible to the putative drug molecule • Drug targets can be identified: o Data mining (genome, transcriptome, epigenome) o Functional genomics or phenotypic screening Choosing a “bioassay” • Drug targets are validated using “bioassays” o Live systems to measure the effects of a drug: cell or tissue culture system or in vivo model. o Assay should be simple, quick and relevant as there are usually a large number of compounds to be analyzed. ▪ In vitro (cell lines and organoids) ▪ In vivo (animal models) In vitro testing • Advantages: o fast, requires relatively small amount of compounds, possible to analyze thousands of compounds in a single day (high throughput screening) • Disadvantages: o Results do not always translate in vivo. o Heterotypic interactions not represented o Established cell lines have evolved in culture far beyond the ancestral cells that were originally removed from actual human tumours. ▪ Tumors have been propagated for a long time- many alterations have been made since the original tumor ▪ Now studies use cell lines form patients but they don’t go for more than 10 passages In vivo testing • Involve inducing a clinical condition in the animal to produce observable systems. • Disadvantages: o Slow and causes animal suffering. o Pharmacokinetics different in animals than humans. o Pharmacokinetics measures: ▪ How the drug is absorbed into the circulation? ▪ How is the drug distributed throughout the body? ▪ How it the drug metabolized? ▪ How is the drug excreted? Finding a lead compound • Once a target and testing models have been chosen, the next stage is to find a lead compound. • Compound which shows the desired pharmaceutical activity. • the lead compound provides a start for the drug design and development process. Lead compound screening strategies: • Screening of natural products- natural products are a complex of compounds, difficult to extract components and figure out which one is targeting • Screening synthetic compound “libraries” • Screening with existing drugs used for other treatments • Focused screen (compounds previously identified as hitting specific classes of targets and compounds with similar structures) • Virtual screening (interrogation of virtual compound library with the X-ray structure of the protein. High throughput screening (HTS) • Process by which large number of compounds are rapidly tested for their ability to modify the properties of a selected biological target. • It involves testing a large number of compounds versus a large number of targets. • The test should produce easily measurable effect. o Cell proliferation, apoptosis, cell morphology (microscopy) Lead optimization • If the lead compound is a mixture of other compounds it has to be isolated and purified. • Structure of unknown lead compound needs to be determined (X-ray cystallography, NMR spectroscopy etc.) • Structure identification can aid in identification of the “pharmacophore” = the structural features directly responsible for activity/pinpoint part of drug that targets molecule • Drug can be optimized to improve interactions with target. • Drug can be optimized to improve potency and selectivity • Can create drug that only contains the pharmacophore Pre-clinical testing • To establish the safe and toxic dose ranges for future testing in humans. • Determine drug toxicity and efficacy. • Determine pharmacodynamics and pharmacokinetics of the drug. o Dynamics- measures what the drug does to the body- concentration of drug that is needed to get a certain outcome o Kinetics- what the body does to the drug- ADME (absorption, distribution, metabolism, elimination) • File Investigational New Drug (IND) Application submitted to FDA, Health Canada Clinical Trials • Clinical trials involving new drugs are classified into four phases (I, II, III, IV). • Each phase is treated as a separate clinical trial. • Clinical trials are registered in o Run by National Institutes for Health o Largest clinical database Ethics in Research Involving Human Subjects • Nazi Medical War Crimes (1939–1945) o 23 German physicians performed devastating tests on prisoners after second world war • Tuskegee Syphilis Study - Alabama 1932-1972 o Recruited 600 low-income African-American males (400 infected with syphilis) – monitored for 40 years o Subjects were given free medical examinations o Subjects were NOT told about the disease even though a proven cure (penicilin) became available in the 1950s. o Many subjects died of syphilis during the study. • Willowbrook State Hospital in New York 1972 o Retarded children were deliberately infected with viral hepatitis to study its natural history. The Nuremberg Code: 1948 • As the result of the trial against Nazi’s experimentation on humans • The first international document which advocated voluntary participation and informed consent • The Nuremberg Code: o Voluntary informed consent o Likelihood of some good resulting o Based on prior research (animal models) o Avoidance of physical or physiological injury or harm o Benefits sh
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