What % of patients with cancer can be cured?
Why is prevention better than cure in terms of treatment?
It can be unpleasant, ineffective, and extremely expensive
Who does cancer have a huge impact on?
What are the main modifiable risk factors of cancer?
- Bad diet
- Occupational exposures
What has shown the importance of lifestyle and environment in cancer?
Immigration studies, showing the decreased incidence of stomach cancer in Japanese populations who immigrated to Hawaii
What recommendations were made in 2007 by the WCRF/AICR expert report to prevent cancer?
- Be as lean as possible without being underweight
- Be physically active for at least 30 minutes per ady
- Avoid sugary drinks. Limit consumption of energy-dense foods (particularly processed foods high in sugar, or low in fibre, or high in fat)
- Limit consumption of red meats and avoid processed meats
- If consumed at all, limit alcoholic drinks to 2 for men and 1 for women a day
- Limit consumption of salty foods and food processed with salt
- Don't use supplements to protect against cancer
The use of natural or synthethic compounds to reverse, suppress, prevent or delay carcinogenic progression to invasive cancer
What characteristics should an ideal chemoprevention agent have?
- High efficacy
- No or low toxicity
- Known mechanism
- Acceptable by humans
- Oral formulation
- Low cost
What is the result of chemoprevention agents needing to have no or low toxicity?
Novel agents are not an option
Why are novel agents not an option in chemoprevention?
Because when you develop a new drug, it can take 20/30 years to find side effects
If novel agents can't be used for chemotherapy, what can?
Repurposed drugs, such as aspirin and metformin, or dietary compounds
When in carciongenesis can cancer be prevented?
Anywhere before the cancer becomes malignant - gives a big window for prevention
What are blocking agents?
Compounds which inhibit carciogenesis by preventing carcinogens from being created, or from reaching, or reacting with, critical target sites in tissues
What are suppressing agents?
Compounds which act after carcinogenic exposure by suppressing the expression of neoplasia
What is true of the mechanism of action of most chemoprotective drugs?
They have many mechanims, and so often act as blocking agents and suppressing agents
Give 6 mechanisms of action of blocking agents
- Scavenging free radicals
- Antioxidant activity
- Induction of phase II drug metabolising enzymes
- Inhibition of phase I drug metabolising enzymes
- Induction of DNA repair
- Blockage of carcinogen uptake
Give 5 mechanisms of action of suppressin agents
- Alteration in gene expression
- Inhibition of cell proliferation or clonal expansion
- Induction of terminal differentiation or senescence
- Induction of apoptosis in preneoplastic lesions
- Modulation of signal transduction
How can modulation of signal transduction be achieved?
- Inhibition of arachidonic acid cascade
- Inhibition of tyrosine kinase activity
- Induction of phosphatases
- Modulation of hormone/growth factor activity
- Induction of ornithine decarboxylase activity
- Induction of gap junction communication
What is primary chemoprevention?
Giving chemoprevention to a healthy patient, or one with a genetic predisposition
Give two examples of primary chemoprevention
- Low dose aspirin to prevent colorectal cancer
- Tamoxifen to prevent breast cancer
What is secondary chemoprevention?
Giving chemoprevention to patients with preinvasive dysplasia or preneoplastic lesions
Give an example of secondary chemoprevention
Use of valrubin in bladder cancer in situ
What is tertiary prevention?
Using chemopreventive agents to prevent relapse or the development of a new primary cancer
Give an example of tertiary chemoprevention
SERMs for prevention of breast cancer recurrence/mets
How does the acceptibility of toxicity differ in primary and tertiary chemoprevention?
Increased toxicity and side effects acceptable in tertiary
What are the challenges of chemoprevention research?
- When researching a treatment, you have a population who are all of interest, and get a result in months. In chemoprevention, need a very large population, only a few of which would get cancer, and it takes decades to see if it works.
- Hard to get funding, as not sponsered by pharmaceutical companies
What can be used to overcome the problem of chemoprevention research taking a very long time?
What do surrogate endopoint biomarkers allow?
- Smaller trials
- Quicker assessment of efficacy without waiting for tumours
What do surrogate endopoint biomarkers require?
- A detailed understanding of the cancer process in any given issue
- Requires a detailed understandin of the mechanism of action of chemopreventive agents
What is the difference in dosages between chemotherapy and chemoprevention studies?
Chemoprevention has to minimise the dose and maximise the safety. Chemotherapy has to maximise the dose, and emphaise efficacy
What problems with chemopreventative agents must be considered before approving for public use?
- Some agents inhibit carcinogenesis in one experimental setting, but enhance the process in another
- Some agents may be beneficial to some individuals and harmful in others
What is the importance of genetic polymorphisms in chemopreventative agents?
They influence the response of the host to endogenous or exogenous carcinogenic factors
What molecules might have drug polymorphisms that are important to consider in chemoprevention?
- Drug metabolising enzymes
- Repair enzymes
- Receptors, kinases, and transcription factors
Give two examples of where genetic polymorphisms in drug metabolising enzymes may be important
- Susceptibility to carcinogenic effects of cigarette smoke
- Altered response to chemopreventive agents which require metabolism
What are the potential pharmacokinetic problems to be considered with chemoprevention?
- Cell-type specificity
- Cancer subtypes
- Concentration effects
- Primary targets
What is the advantages of using dietary derived agents in chemoprevention?
- Need agents where there is existing evidence of safety
- Often consumed in the diet regularly, so they are considered to be relatively safe
- They are multi-targeted in than they can interfere with many pathways involved in carciogenesis
What are the steps in the chemopreventative agent development process?
- Look for chemopreventative activity
- Look for efficacy/PK in rodent models
- Phase 1 pilot studies, looking at PK, PD, safety, and tolerability
What methods can be used to look for chemopreventive activity?
- In vitro
- Ex vivo
- Stem cell models
What are the types of rodent models in carcinogenesis/chemoprevention?
- Mutant or genetically engineered models
What happens in chemical rodent models of carciogenesis?
Tumours in rodents induced by chemical carcinogens
Describe tumour development in chemical rodent models of carciogenesis
- Localisation and nature of tumoru dependant on dose, strain of rodent etc
What happens in mutant or genetically engineered rodent models of carciogenesis?
Rodents carry mutations in genes implicated in initiation or progression of cancer, or the genes are knocked out or mutated
What kind of drug is tamoxifen?
A selective oestrogen receptor modulator (SERM)
What is the action of tamoxifen?
- Primary action is in breat tissue, as an antioestrogen
- Partial oestrogen agonist properties in other tissues
What effect does tamoxifen have in breast cancer?
- It decreases the growth of human breast cancer cells
- 40% decrease in new tumours in contralateral breast
By how much does tamoxifen reduce the incidence of breast cancer in high risk women?
38% (48% decrease in OR+ cancers)
What are the serious adverse effects of tamoxifen?
- Endometrial cancer risk
- Risk of venous thromboembolic events
How does raloxifene compare to tamoxifen?
- Nearly as effective in preventing invasive breast cancer
- Caused half as many uterine malignancies, 20% fewer pulmonary emboli, and 28% fewer deep vein thrombi
Why is the inhibition of COX enzymes a target for chemoprevention?
Because COX-1 and COX-2 are required in the synthesis of PGH2 from arachidonic acid, which then produced prostaglandins which lead to inflammation neoplasia
What drugs target COX-1 in chemoprevention?
What drugs target COX-2 in chemoprevention?
Give two examples of coxibs?
What are the adverse effects of coxibs?
How do coxibs cause cardiovascular risk?
Endothelial prostacyclin (COX-2) inhibits platelet aggregation, causes vasodilation, and prevents vascular proliferation. Thromboxane (COX-1) causes platelet aggregation, vasoconstriction, and vascular proliferation - coxibs cause an imbalance
By how much does daily aspirin use for 5 years reduce 20 year colorectal cancer mortality?
What aspects of aspirin as a chemopreventative agent are unknown?
- Risk vs benefit balane
- Optimal dose for prevention
- Mechanism of action
What happened with ß-carotene?
Epidemiology suggested that it would be a useful chemopreventive agent for lung cancer, however two large clinical trials actually demonstrated an adverse effect in heavy smokers.
Why may ß-carotene not have been as successful as epidemiology might have suggested?