Lecture 22- Cancer treatments
• 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
• 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
• 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
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
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
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
In vivo testing
• Involve inducing a clinical condition in the animal to produce observable systems.
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)
• 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
• 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
• 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,
• File Investigational New Drug (IND) Application submitted to FDA, Health Canada
• 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 ClinicalTrials.gov
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
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