cancer

The crab 

• Earliest known description of cancer comes from 

• Egyptian surgical manual, circa 3000 B.C.E 

• Name comes from Hippocrates = carcinos, the crab 

• Terminology: 

• – Tumour 

• – Neoplasm 

• Swelling, a mass of cells Can be benign or malignant 

• – Malignant tumour = cancer 

• Early greek/egypt called cancer crab, as tumour looked like crab under skin

Cancer has been around for as long as people have 

• Pre-historic Africa – Pleistocene (2 million to 12,000 years old) 

• Bony growth out the side of the jaw bone – bone cancer 

 

• Common in the duck- billed dinosaurs, but rare in other kinds of dinosaurs 

• Duck-billed species believed to have eaten conifer trees 

• = full of toxins 

• = damaged their DNA 

• Cancer is caused by DNA damage and mutation 

What is cancer? 

• Normal cells work together, dividing and dying in a strictly controlled and coordinated fashion.  

• This collaboration keeps each tissue at the appropriate size, shape and architecture. 

• Mutations in DNA change gene products, or change how and when genes are expressed 

• => mess up these processes 

• => cell biology goes wrong 

• an inevitable consequence of being a complex multi-cellular organisms that live in a world full of oxygen and cosmic radiation 

  

• Lots of cosmic radiation, UV radiation around that damage DNA and cause cancer 

• Some damage can be prevented (alcohol, smoking, severe sunburn) but some cannot (radiation damage) 

• 1 in 3 people in their lifetime will get cancer 

cancer proliferation

1. Dna damge happens to tissue and one cell acquires dna damage 

1. May have no impact (gene is not expressed, does use it etc) 

2. Mutation may give it advantage, help it divide 

3. Mutation may help cell get out of tissue its in, allow it to escape and spread, infecting other tissues 

4. Cells acquire more and more mutations, becoming cancer 

Cancer named for tissue of origin 

• Sarcoma – muscle, fat, bone 

• Lymphoma – lymphatic system = body’s filter 

• Leukaemia – blood (or immune) cells 

• Carcinoma – organs: eg stomach, pancreas, lung, ovary, skin 

• Other – melanoma = melanocytes; glioma = glial cell of brain; etc 

> 200 different types of cancers 

Cancer cells can metastasize to other organs, but will retain the characteristics of their tissue of origin. 

Cancer is a multi-factorial disease 

Genetic 

• the alleles you inherit from your parents 

Environmental 

• exposure to chemicals and radiation, including chemotherapy 

Medical 

• viral infection, inflammation, other diseases and treatments 

Lifestyle 

• diet, alcohol, tobacco 

• All these factors interact - damage DNA, change gene function => change cell function 

• Melanocytes: produce melanin in skin 

• Because retain tissue origin characteristics, can tell is cancer cell is from location where its been found, or metastasised there 

Mutations in Cancer 

Inherited = germline or Acquired = somatic 

• Environmental disease: exsporsure to chemicals, radiation cause dna damage (incl chemotherapy can cause dna damage) 

• Medical: chronic imflammation (consatnt immunue system activation) cause dna damage, infections can cause dna damage) 

90% of cancers = somatic mutations 

10% of cancers = germline 

• - inherited mutations 

• - predispose to cancer 

• - not a guarantee of cancer 

How do mutations arise? - mistakes

Mistakes 

• During DNA replication 

• - single base substitutions 

• deletions 

• insertions 

• - large deletions 

• - amplifications 

During mitosis 

• - improper separation of chromosomes 

• Translocater 

• Eg mitosis: spindle fibres could pull too hard and break off part of chromosome 

how do mutations arise? mutagens

Mutagens 

• Cigarette smoke 

• Radioactivity 

• Microwaves and radiowaves 

• Ultra-violet light 

• Viruses 

Chemicals 

• – DNA alkylating 

• – DNA intercalating 

• – DNA deaminating 

• *Including chemotherapy 

Mutagen=chemical that causes mutation 

Frequency of Cancer in New Zealand 

• cancer = leading cause of death for both males and females in New Zealand - nearly a third of all deaths. 

Cancer is leading cause of death in nz, often competing with heart disease (though heart disease decreasing due to healthier living) 

In 2018  

• - 9747 people had cancer as underlying cause of death 

• - 53% were male. 

• Men may be less liely to go to hospital, more likely to drink, smoke 

From 2000 to 2018 the number of deaths increased by 12.8% 

During the same period the rate of death decreased by 14.3% 

• Number of deaths increase mean population growth, but rate of death decrease mean we are better at treating (can design better drugs, new therapies, can more effectivly treat) 

Frequencies in order of highest to lowest incidence 

Highest Incidence 

• Breast (22%) and prostate (18%) 

• Colorectal cancer 

• Melanoma 

• Lung cancer 

Most common cause of death 

• Lung cancer 

• Colorectal cancer 

• Breast and prostate 

Melanoma is common, but not that deadly, can be treated easily, even if metastasised 

• Lung cancer fourth most common, but not very treatable, so most common cause of death  

• Colorectal/breast/prostate cancer easier to treat, but many types 

melanoma 

Hole in ozone layer increase uv levels that reach ground in nz/aus 

Colorectal cancer in women 

Axis title:per capita daily met consumption (grams)   

• Particularly red and processed meats (things with nitrites) Also bread 

• May also be related to how much fat in  meat (more fat, more hydrogen, leavened meat may be better) 

Prostate cancer 

• No proper explanation for why nz/aus is higher as Don’t know what causes prostate cancer 

• Something different about aus/nz is increasing our rates of cancer compared to the rest of the world, need people in nz to figure this out ( 
  no one else cares) 

Inequities in māori and pasifika health 

There are significant inequities in cancer incidence and outcome for Māori in Aotearoa

• Not only environmental/genetic effects but also social effects change rates of inccidence and outcomes 

• Much higher incidence of breast/lung cancer for māori vs non-māori 

• Lower prostate/colorectal cancer for māori 

• Bit higher rates for other types of cancer for māori 

• Mortality rate for all cancers except colorectal (matches) significantly higher for māori than non-māori 

These disparites are driven by many factors

Understanding what drives these inequities is crucial for fixing it 

• Comorbidity: diagnosed for more than 1 disease (eg diabetes increases cancer risk). Decreases likihood any one of diagnoses are going to be treated 

• Deprivation impacts access to early detection and rreatment, increase likihood of death 

• Health literacy and treatment centre location, affordability are barriers to treatment and early detection. Quality of treatment that doesn't reflect cultural health models also decreases liklihood of someone getting treatment/early detection 

How does cancer work 

• Clonal, genetic disease – one cell acquires a mutation that gives it a functional advantage 

• Better survival, more proliferation 

A daughter cell acquires more mutations and more advantage 

• Out survives and out proliferates other cells 

 

• Cancer cell: a mutated cell that has outlived and out-proliferated competition, can overwhelm immune system  

• Combination of mutation gives cancer cell more advantage of normal cells 

Cancers progress in stepwise changes 

• Some factor led to a mutation in a cell 

• -  If that mutation made that cell divide faster, that is a problem 

• Mutated proliferating cells get more opportunities to get more mutations 

• - If the next mutation stops the cell from dying, or helps it divide faster, the progeny of that cell will expand 

• More cells, more opportunity for more mutations 

The more you proliferate, more opportunities for mutation. Cells become more abnormal, as accumulate more and more mutations 

Cancer Treatments 

• Some treatments target the rapidly dividing cells 

• Some treatments target a particular mutation 

• Some treatments target the support network 

• Some treatments target the immune system 

Target rapidly dividing cells 

Cytotoxic treatments (cyto = cell) 

Based on the fact Normal cells can repair faster than cancer cells. Idea is cause so much damage cancer cells cannto cope and die, but normal cells hopefully survive (must find balance between killling cancer cells and keeping normal cell 

• DNA damage (genotoxic) 

• Radiation 

• Chemotherapy 

• Block mitosis 

• Mess up microtubule function 

• By blocking mitosis, the cell cant divide and cant survive 

• Block DNA replication 

• Nucleotide analogs that mess up DNA replication 

• Inhibitors of enzymes important for DNA replication 

• Block replication prevents metastasising 

Most of these methods are cytotoxic, any rapidky dividng cell will be affecting (hair, skin, gut lining) tehrefore side affects of these teatments incl hair loss, ulcers etc due to damage to these cells 

Targeting cancer mutations 

Specific to the cancer cell, such as: 

Herceptin for breast cancer 

• if the cancer cells express a protein called Her2 

Erlotinib or cetuximab for lung cancer 

• If the cancer cells have a mutation that activates EGFR 

Olaparib or niraparib for ovarian cancer 

• If the cancer cells have a defect in double strand DNA break repair 

Targeting the support network 

Cancers need a blood supply for O2, nutrients, waste removal 

• Block the factors released by the cancer that cause blood vessels to grow into the cancer 

• Vascular endothelial growth factor (VEGF) inhibitors 

Target the immune system 

The immune system can recognize when a cancer cell has started making mutant/abnormal proteins, and can kill it 

• Improve the recognition of the cancer cell 

• Improve the killing by the immune cells 

The cancer can shut down the immune system, to allow the cancer to survive and proliferate 

To understand the biology of cancer, ask 

Who gets cancer? Are there ethnic/geographic/socioeconomic patterns? 

What caused the mutations to form? 

• – Genetic? 

• – Environmental exposure? 

• – Bad luck? 

What are the mutations that drive the cell to behave abnormally? 

• - sequence the DNA of the cancer 

Can the impact of those mutations be altered? 

• – are there drugs that can target the mutation? 

• – Is the immune system alert to the presence of the cancer? 

• – Can the cancer be starved? Or obliterated with cytotoxic therapy? 

Cancer mutations 

Mutations can be classed multiple ways 

• – Loss of gene function = brakes on the cell 

• – Gain of gene function = accelerator on the cell 

Mutations – accelerators and brakes 

Normal cell behaviour requires both accelerators and brakes 

• Signals that push a cell to divide, or keep it alive 

• Signals that stop it dividing, or cause it to die 

• If mutation hits cell is tumour suppressor, must induce a loss of function in order to cause cancer  

Abnormal acceleration => oncogene mutation 

• Gain of function, protein activity is enhanced by mutation 

Abnormal loss of brake => tumor suppressor mutation 

• Loss of function, protein activity is reduced or lost by mutation 

Abnormal Accelerators – Oncogenes 

Proto-oncogenes - positively influence cell division, cell survival 

• accelerator, increase cell division and cell survival 

High evolutionary conservation across species 

• proto-oncogenes regulate fundamental processes 

Oncogene is a mutated proto-oncogene 

Mutation does not stop the function of the protein 

• increases the activity of the protein 

Oncogenes 

Oncagene: gene that normally cause cell to divide 

• If mutation is gain of fucntion, more cell division, more cancer 

First discovered in chickens in 1910 by Dr Peyton Rous 

• Chicken retrovirus carried over-active version of a chicken proto-oncogene, so chickens reasonably prone to getting cancer

• “Rous sarcoma virus” infection caused sarcoma 

• Sarcoma could be transmitted to other chickens by infecting with virus 

• This normal proto-oncogene is now called Src, found in most/all vertebrates 

• Other viruses can also cause sarcoma in other animals 

• All have mutated version of different host proto-oncogenes 

• Rat sarcoma virus = RAS 

Viruses stimulate host cell to divide as most effect way for virus replication, but has conseuqenc eof making cell proliferative, makes it easy to acquire new mutation and become cancer 

Oncagenes and cancer 

Mutation is always a gain of function 

• – More cell division 

• – Less cell death 

A mutant allele can over-ride the normal allele 

• only one allele needs to be mutated 

Mistakes causing oncagene 

• Small deletions/insertations causes frameshift mutation, likely to give non-working protein  

• Single base substitution can sometimes generate gain of function 

•  Amplification of dna most likely to generate gain of function 

• Reasonably uncommon for a random mutation to give gain of function 

Abnormal brakes - Tumour Suppressors 

tumour suppressor genes 

• slow down/prevent cell division 

•  induce cell death 

• ‘brakes’ on cell division/ 

High evolutionary conservation across species 

• Tumor suppressors regulate fundamental processes 

Combination of oncagene gain of function and tumour suppressors loss of function is needed for cell to become cancerous 

• Genes that induce apoptosis are tumour suppressor genes, apoptosis happens when cell is pushed to divide 

Discovery of Tumour Suppressor Genes - retinoblastoma (rare paediatric cancer in children under 5)

Alfred Knudson was studying retinoblastoma, a rare pediatric cancer of the retina. (Discovered 1970s in rare pediatric cancer found in children under 5) 

• Both inherited and sporadic cases 

• Some kids had tumours in both eyes (bilateral) 

• Some had one eye affected (unilateral) 

Knudson compared this data with age of onset 

• Compared if have bilateral tumour, multiple tumours, inherited against age of onset 

Retinoblastoma findings 

• About 40% cases were inheirted, and of that about 25-30% of cases were bilateral. If no familiy history, did not have bilateral cancer  

• Unilateral cases are combo on hereditary and not, but took longer to develop. Bilateral cases were only hereditary, and much faster onset, 

Knudson’s two-hit hypothesis, 1971 

Retinoblastoma is caused by a recessive mutation in a single gene: 

• - both alleles need to be mutated 

• - mutation rate should be the same for each allele. 

option a) Inherited mutation in one allele (familial) 

• only need single mutation in the remaining normal allele. 

option b) No inherited mutation (sporadic) 

• cell would need to accumulate two mutations, one in each allele 

• process would be slower. 

• In 1986, the mutated gene was identified in the families - called Rb, the retinoblastoma gene 

• Families with inherited high risk of retinoblastoma had one mutant copy and one wild-type copy 

• All retinoblastoma had mutations in both copies 

• Quicker to get retinoblastoma if already had one non-functioning allele (mutated) as only needed one mutation in normal allele to cause disease 

 

Mistakes causing tumour suppressor loss of function 

• Everything except amplification of dna can easily result In loss of fucntion, therefore loss of funciton easier to achieve through random mutations can gain of fucntion in oncagene  

• Messing something up is easier than enhancing it 

Inherited cancer risk = TS gene mutations 

Being born with one mutant allele in every cell may have an effect 

• Loss of second allele necessary for cancer 

BRCA1 and Breast Cancer 

BRCA1, BRCA2 = breast cancer susceptibility genes 

• Cloned in 1994 by linkage analysis and positional cloning 

Mutations in these 2 genes associated with ~70% of early onset familial breast & ovarian cancer 

• Most mutations are single insertions or deletions that cause frameshift 

• Truncated protein, likely cause complete loss of function 

Typical tumour suppressor gene 

• Loss of wild-type allele seen in affected individuals from pre- disposed families 

Prevalence of disease = average 85% for breast cancer 

• Risk of disease is different based on mutated allele, status of modifier genes, environmental and hormonal exposure. 

• About 85% of people who have inherited gene, will develop cancer, as about 85% risk of losing wild type allele function 

• Where most case of breast cancer in males is form 

E-cadherin and hereditary diffuse gastric cancer\ 

E-cadherin (CDH1) is a cell adhesion molecule that maintains integrity of cell-cell contact in epithelium 

• Signals through the b-catenin / WNT signaling pathway to regulate gene expression 

Loss of E-cadherin in cell layers can drive cancer development 

• gastric cancer 

• breast cancer  

Helps cell know which way is up, connect cells to actin skeleton 

• Lose e-cadherin cells cannot hold on to eachother, lose ability to know when to stop dividing, as job is to maintain layer, so when lose contact, cell shape changes and become proliferative 

• Particularly important and devastating in lining of stomach and breast globules 

Gastric cancer causes

Cancer of the stomach can be caused by 

Helicobacter pylori 

• h.Pylori causes ulcers, causes inflammation, cause dna damage and mutations, increases chance of loss of ts, gain of oncagene 

Infection 

•  ulcer  

• inflammation  

• DNA damage 

Diet 

• Nitrites in processed meat, dairy? – DNA damage 

• Some foods cause increased dna damage, eg nitrites 

Inherited risk 

• Mutation in something 

• Inherited risk from mutation in e-cadherin gene 

E-cadherin and hereditary diffuse gastric cancer discovery 

McLeod whānau of Tauranga had a long family history of stomach cancer 

• For generations, lots of whānau died in their 20s and 30s 

• Stories of people moving away, changing their names, adopting their children out to avoid the makutu that was on the area/family 

• In 1993 Maybelle McLeod and Pauline Harawira, nurses at Kimi Hauora Health clinic, decided to find out what was happening 

• Convinced kaumatua they needed to find answers 

• Given contact details for the Cancer Genetics Lab at Otago University 

Professor Tony Reeve and Dr Parry Guilford made many trips to Mangatawa marae in the BoP 

• Build reciprocal relationship that led to trust - McLeod whakapapa with affected and non-affected whānau 

• Blood and tissue samples 

• Kaumatua came to the lab  - Tikanga for samples 

18 months of analysis, looking for sequences of DNA that correlated to affected vs non-affected whānau 

• Mutation in one allele of e-cadherin gene – CDH1 

• Chance of developing gastric cancer = 55-70% 

• Different families had different mutations but in the same gene 

• Second allele lost when tumours formed 

• Returned the data to the McLeod whānau 

• Whānau set up screening – find people carrying gene before the cancer formed 

Cancer Treatments 

• Some treatments target the rapidly dividing cells 

• Some treatments target a particular mutation 

• Some treatments target the support network 

• Some treatments target the immune system 

Target rapidly dividing cells 

Cytotoxic treatments 

methods 

• DNA damage (genotoxic) 

• Block microtubule 

• Block DNA replication 

idea behind cytotoxic treatments

• Idea with cytotoxic treatments is to push cancer cell to be unable to repair damage and die compared to noral cell 

• (normal cells better at repair than cancer cell, as cncer cell already damaged)  

• Therefore cancer cell should die at higehr rate than normal cell (therapeutic index is window where cancer cell die and normal cells live) 

• Sometime index can be really small, creates guesswork when tumour cells are dying at a goven dose, but normal cells are affected at only slightly higher dose (mus tbe very careful to kill cancer cell but also leave normal cell alive) 

dna damage/genotoxic treatment

• Genotoxic: toxic to cell 

• Radiation 

• Chemotherapy 

• Radiation and chemotherapy can also cause single strand break which cell has to deal with or double strand break creates DNA fragments 

blocking microtubule treatment

• Mess up mitosis 

• Normal cell activity lost 

• Blocking microtubules messes up mitosis process, destroys normal cell activity, 

• Proteins on microtubule exert force to separate chromosomes, lots of drugs are capable of messing up this process. 

•  Messing with microtubules can severely mess with activity of cells 

blocking dna replication treatment

• Nucleotide analogs that mess up DNA replication 

• Inhibitors of enzymes important for DNA replication 

• Blocking can happen via nucleotide analog or inhibitors of enzymes 

• Inhibiting these critical enzymes means dna replication cannot occur properly, as replication is a very complicated process, a drug targeting any one of these enzymes will block replication 

side effects of targeting rapidly dividing cells/cytotoxic treatments

• Hitting other cell types, anything that is replicating (as cannot target only cancer cells) 

•  Treatments are very non-specific, so anything that acts on cancer cell with also damage normal cell 

Targeting cancer mutations 

“Precision Medicine” 

• designed for specific person via genome sequencing 

•  Prevents cancer drugs from also damaging normal cells 

 

DNA sequencing of the genome in the cancer cell 

• Find mutations specific to each individual’s cancer 

• Not all cancers of the same tissue have the same mutations (because mutations are random) 

Cancers in different tissues can have the same mutation 

• Understanding biology of cancer is critical for treatment 

Breast cancer targeting (targeting cancers w/ different mutations) 

Estrogen receptor positive ER+ / Progesterone receptor positive PR+ 

• express the estrogen/progesterone receptors 

• tamoxifen = estrogen analog 

• hormone receptor positive cancer type: if see cancer cell expresses one of these hormone receptors, can block receptor and stop signalling, kill cell 

• stops estrogen signalling, blocks cell survival 

Her2 positive 

• Herceptin = antibody that binds to Her2 

• blocks signal that supports cell survival and proliferation 

• herceptin binds to Her2 on surface of cell if expressed by cancer cell, takes away survival advantage 

Triple negative (everything else) 

• No specific treatments, DNA damaging chemotherapy 

• umbrella term for everything else. For long time just got cytotoxic treatment, chemotherapy 

• Triple negative: not estrogen/progesterone receptor positve or her2 positve 

Estrogen receptor positive ER+ / Progesterone receptor positive PR+ 

• express the estrogen/progesterone receptors 

• tamoxifen = estrogen analog 

• hormone receptor positive cancer type: if see cancer cell expresses one of these hormone receptors, can block receptor and stop signalling, kill cell 

• stops estrogen signalling, blocks cell survival

Her2 positive BC

• Herceptin = antibody that binds to Her2 

• blocks signal that supports cell survival and proliferation 

• herceptin binds to Her2 on surface of cell if expressed by cancer cell, takes away survival advantage 

triple negative BC

• No specific treatments, DNA damaging chemotherapy 

• umbrella term for everything else. For long time just got cytotoxic treatment, chemotherapy 

• Triple negative: not estrogen/progesterone receptor positve or her2 positve 

Precision Medicine for Triple Negative BC 

• Sequence DNA and RNA 

• subset of TNBC express HER2 (erbb2) 

• lots of people worked to sequence DNA and RNA from triple negative breast cancer to find precision treatment. 

•  By sequencing mRNA, find mutations and genes that arent supposed to be active (abnormal gene expression 

•  Found subset of Triple negative BC (LAR in purple) had mutation in HER2 (erbb2), means could treat with Herceptin 

•  With precision medicine approach, can give targeted therapies even more triple negative BC 

Targeting cancers with the same mutation

• Epidermal growth factor receptor = EGFR 

• EGFR expressed on sruface of cell: when growth factor binds, induces hallmarks of cancer (evasion of apoptosis, sustained angiogeneis, resistance to antigrowth signals, invasion and metastasis, self-suffiecent in growth signals) 

•  Therefore can target these mutations, can use same drug to treat many different types of cancer 

Mutations in lung cancer, but also 

• breast 

• colorectal/bowel 

• head-and-neck cancers 

• glioblastoma 

• melanoma 

• B-cell lymphoma 

can treat all these different cancer types with same drug if expressed same proteins/receptors/mutation 

Side effects of precision medicine 

very targetted, so very few side effects as only affect cells expressing mutation, which normal cells should not (if do, are cancer cells or will become cancer cells) 

Targeted Therapies – Tumour Suppressors 

How do you stop a cancer with a mutant tumour suppressor gene? mutant tumour supressor: loss of function, cannot inhibit something that is not there, so how do treat? 

• • Example in TNBC is p53 – lost in many cancers 

• • CDH1 – e-cadherin is lost in hereditary diffuse gastric cancer 

How do you stop a cancer with a mutant CDH1 gene? 

• try prevent loss of wild-type allele (as cannot get cancer if protected by normal wild-type allele) 

• In practicallly was not efficent, needed to higha  dose to be practical 

•  Try kill cancer another way 

• Target the CDH1 cells with drug that doesn't healthy cells 

Target the support network 

Cancers need a blood supply: mutations that lead to the activation of blood vessel formation = vascular endothelial growth factor, VEGF 

•  cancer need blood, so cannot get bigger or spread if no blood 

• Angiogenesis: process of making new blood vessel.  

Tumours must find a way to activate growth of blood vessel, normally by turnig on gene VEGF, auses blood vessels to grow towards where signal coming fro (cancer cell), bringing blood and oxygen/nutrients needed to grow 

•  VEGF is a gain of function, therefore an oncagene, therefore is easeit to treat, inhibitor of VEGF, blocks growth factor of blood vessels, stops tumours from getting bigger and spreading 

Targeting VEGF 

Block VEGF activity 

• Anti-angiogenic therapy 

• Vascular endothelial growth factor (VEGF) inhibitors 

Side effects of targeting support netowkr (VEGF) 

• side effects: cannot grow more blood vessels, detrimental for if get injury (though effects are subtle) 

•  VEGF is important during embryo development and small children, but not so much in adults, so good for use on adults 

target the immune system 

• The immune system can recognize when a cancer cell has started making mutant/abnormal proteins, and can kill it  

BUT 

• The cancer can shut down the immune system, to allow the cancer to survive and proliferate. 

How can cancer turn immune system to its benefit? 

• when cancer cell picks up mutations and becomes abnormal, should be enough for immune cells to become alerted to non-self and target cancer cells 

•  TAA: tumour associted antigen.  

• Once APC pick up TAA, initate immune response and immune cells can kill tumour cell 

•  However tumour cell can convert normal immune cells to become pro-tumour. Can also create suppressor cells to kill immune cell, reverses immune repsonse from anti0tumour to pro-tumour, changes immune response 

•  Tumour doesn't actually develop until immune system is pro-tumour and no longer fighting 

How to target immune system 

Improve the recognition of the cancer cell by the immune system 

Improve the killing by the immune cells 

• Immune checkpoint inhibitor 

• CAR-T cells 

  therapies incl. trying to improve recognition or improve killing ability 

•  Most therapies idea is to improve killing of cancer cell but immune cell 

Immune checkpoint Inhibitors 

• mmune checkpoints are a normal part of the immune system. They prevent an immune response from being so strong that it destroys healthy cells. 

• Cancer cells will activate the immune checkpoint pathway to turn off the T- cells 

• This interaction can be blocked with a drug 

• Immune checkpoint inhibitor rely on fact turn on immune response is normal process (why T cell have off switch).  

• By cancer cell expressing portiens that interact with immune checkpoint, can turn off T cell. If block interaction with drug, T cell cannt be turned off 

Side effect of immune checkpoint inhibitors 

T cell cannot be turned off, immune response cannot be stop, causes cytokine storm, pateints must be hospitalised as get very ill. However, very effective for killing tumour cells 

Use of immune checkpoint inhibitors nz 

very good for metastatic melanoma, greatly increased probability for survival (from almost certaindeath for 50% survival) 

• advanced/metastatic melanoma 

• • recurrent/metastatic head and neck cancer 

• • unresectable/metastatic bowel cancer 

• • advanced bladder cancer 

• • relapsed Hodgkin lymphoma 

• • advanced kidney cance 

drugs 

• atezolizumab (also called Tecentriq) 

• • durvalumab (also called Imfinzi) 

• • ipilimumab (also called Yervoy) 

• • nivolumab (also called Opdivo) 

• • pembrolizumab (also called Keytruda). 

Precision medicine in ICI use 

Bc inhibits immune checkpoint, so must make sure cancer cell is actually expressing protein, otehrwise patient does not respond and nothing happens 

CAR-T cells 

• Chimeric Antigen Receptor on a T-cell 

• working to use to treat lymphoma 

• Genetically modify T cell (take out, modify and put back). 

Recognition sequence for an antigen on the cancer cell PLUS T-cell activation signal 

• find antigen, attach to patient T cell, so when T cell are reintroduced to body, T cell can find and indentify antigen and kill  

•  Precision medicine approach is make sure engineered cell expresses antigen that can be recognied, 

CAR-T cells and genetic modification 

• Effective against blood cancers, less effective in ”solid cancers” 

• Still an experimental therapy – customized and very expensive (~600,000 NZD) 

• Doesn’t account for the other half of the equation 

still have supressive immuen response that must treat 

Teh cancer research continuum 

Understand biology 

• identify causes --> prevention 

• Patterns in big datasets, epidemiology 

Find important steps in processes --> new targets for treatment 

• Genetics, cell biology and immunology 

• Chemistry = make compounds to block oncogenes 

• Test new treatments 

Clinical trials 

• Phase 1, 2, 3 

• Understand the impact of the “cancer journey” 

Symptoms - diagnosis - treatment - outcome 

• Patients and families 

• Prehabilitation and rehabilitation - exercise, diet, lifestyle