precision medicine and oncology

What is precision medicine?

Delivering the right treatment to the right patient at the right dose and time.

How does precision medicine differ from traditional medicine?

Traditional medicine:

• Uses population averages

• Often applies the same treatment to all patients

• Relies heavily on trial-and-error prescribing

Precision medicine:

• Stratifies patients biologically

• Uses biomarkers and genetic profiling

• Predicts treatment response before therapy begins

What is the main goal of precision medicine?

• Maximise therapeutic efficacy

• Minimise adverse effects

• Avoid ineffective therapy

• Improve clinical outcomes

What is personalised medicine?

Completely individualised healthcare tailored uniquely to one patient

What is stratified medicine?

dividing patients into groups according to relevant characteristics, such as genetic or biomarker information, so that particular groups can receive treatments most appropriate to them.

Why is “precision medicine” considered a more accurate term than “personalised medicine”?

Patients are grouped into biologically similar categories that respond similarly to treatment rather than designed for one person.

What is pharmacogenetics?

The application of genetic analysis to predict drug response, efficacy and toxicity.

What factors can pharmacogenetics influence?

• Drug metabolism

• Drug transport

• Receptor binding

• Drug efficacy

• Toxicity risk

What is the difference between pharmacogenetics and pharmacogenomics?

Pharmacogenetics:

• Focuses on single-gene effects on drug response

Pharmacogenomics:

• Studies genome-wide influences on treatment response

Why is pharmacogenetics clinically important?

It helps clinicians:

• Choose optimal therapy

• Select correct dose

• Avoid toxicity

• Predict non-response

before treatment starts.

How does pharmacogenetics improve drug development?

• Identify responsive patient groups

• Improve clinical trial design

• Reduce drug failure rates

• Discover biomarkers

What is DNA sequencing?

DNA sequencing determines the precise nucleotide order within DNA

What is next-generation sequencing (NGS)?

NGS is a high-throughput sequencing technology allowing:

• Rapid sequencing

• Simultaneous analysis of many genes

• Large-scale genomic profiling

What is a biomarker?

A measurable biological characteristic indicating disease state or treatment response

What are diagnostic biomarkers?

Biomarkers used to:

• Detect disease

• Confirm diagnosis

What are prognostic biomarkers?

Biomarkers predicting:

• Disease progression

• Survival

• Clinical outcome

regardless of treatment.

What are predictive biomarkers?

Biomarkers predicting likelihood of response to a specific therapy

What is a mutation?

A change in DNA sequence

What can cause mutations?

• radiation

• Cigarette smoke

• Alcohol

• Chemicals

What is a point mutation?

A single nucleotide change in DNA

What is a missense mutation?

Changes one amino acid into another.

What is a nonsense mutation?

Introduces a premature stop codon
causing truncated protein production.

What is a frameshift mutation?

Alters the DNA reading frame
through insertion or deletion

What are germline mutations?

• Are inherited

• Exist in reproductive cells

• Are present from conception

• Can be passed to offspring

What are somatic mutations?

Somatic mutations:

• Occur during life

• Affect non-reproductive cells

• Are not inherited

What is cancer?

Cancer is a disease characterised by:

• Uncontrolled proliferation

• Loss of growth regulation

What is oncogenesis?

The process by which normal cells transform into cancer cells

What molecular processes commonly become disrupted in cancer?

• Cell cycle control

• DNA repair

• Apoptosis

• Growth signalling

What are proto-oncogenes?

normal genes regulating:

• Cell growth

• Differentiation

• Survival

Mutation converts them into oncogenes.

What are oncogenes?

Oncogenes are mutated or overactive genes promoting:

• Excess proliferation

• Survival signalling

• Tumour growth

What are tumour suppressor genes?

Tumour suppressor genes normally:

• Inhibit proliferation

• Repair DNA

• Trigger apoptosis

Loss of function promotes cancer.

What are the major hallmarks of cancer?

• Sustained proliferative signalling

• Evading growth suppressors

• Resisting cell death

• Replicative immortality

• Angiogenesis

• Invasion and metastasis

What is sustained proliferative signalling?

Cancer cells continuously activate:

• Growth pathways

• Cell cycle signalling

allowing uncontrolled division

What is angiogenesis?

The formation of new blood vessels.

Tumours induce angiogenesis to:

• Obtain oxygen

• Obtain nutrients

• Support tumour growth

What is metastasis?

The spread of cancer cells to distant tissues

What is apoptosis?

It’s programmed cell death. It removes:

• Damaged cells

• Mutated cells

• Dangerous cells

Why is resistance to apoptosis important in cancer?

Cancer cells survive despite:

• DNA damage

• Mutations

• Cellular stress

allowing tumour progression

What is genomic instability?

• Increased mutation frequency

• Chromosomal abnormalities

• DNA repair defects

which accelerate tumour evolution.

What is Knudson’s two-hit hypothesis?

Tumour suppressor genes generally require:

• Two inactivating mutations (“hits”)

before malignant transformation occurs.

What is BRCA1?

A tumour suppressor gene involved in DNA double-strand break repair

what DNA repair mechanism involves BRCA1?

Homologous recombination repair

Why is BRCA1 important for genomic stability?

BRCA1 repairs DNA damage and prevents:

• Mutation accumulation

• Chromosomal instability

• Cancer development

What cancers are strongly associated with BRCA1 mutations?

• Breast cancer

• Ovarian cancer

Why are inherited BRCA1 mutations dangerous?

Patients inherit:

• One defective allele

Cancer develops after:

• Loss of the second functional allele

What is PARP?

a DNA repair enzyme involved in the repair of single-strand DNA breaks

What is synthetic lethality?

Two defects together cause cell death
but either defect alone is survivable

Why are BRCA1-deficient cells sensitive to PARP inhibitors?

• BRCA1-deficient cells already lack homologous recombination repair

• PARP inhibition blocks backup repair pathways

Result:

• Catastrophic DNA damage

• Cell death

What drug is given as an example of a PARP inhibitor?

Olaparib

How does olaparib work?

• Inhibits PARP enzymes

• Prevents DNA repair

• Exploits synthetic lethality

• Selectively kills BRCA-mutant tumour cells

What is EGFR?

Epidermal Growth Factor Receptor

A tyrosine kinase receptor involved in signalling pathways that regulate cellular processes including proliferation

Which signalling pathways are activated by EGFR?

• MAPK

• PI3K-AKT

• JAK-STAT

What happens when EGFR is mutated?

Mutated EGFR may become:

• Constitutively active

leading to:

• Continuous proliferation signalling

What are EGFR tyrosine kinase inhibitors?

• Gefitinib

• Erlotinib

How do EGFR inhibitors work?

• Bind the tyrosine kinase domain

• Prevent phosphorylation

• Block downstream signalling pathways

What is Cetuximab?

A monoclonal antibody targeting EGFR

How does cetuximab work?

• Binds extracellular EGFR

• Prevents receptor activation

• Reduces proliferative signalling

What is K-Ras?

A downstream signalling protein within the EGFR pathway.

Why do K-Ras mutations cause resistance to cetuximab?

Mutated K-Ras remains:

• Constitutively active

Therefore:

• Signalling continues even if EGFR is inhibited.

What are CDK4 and CDK6?

Cyclin-dependent kinases regulating G1 → S phase transition within the cell cycle.

Why are CDK4/6 important therapeutic targets in oncology?

CDK4/6 are key regulators of the cell cycle, inhibiting them can interfere with cancer cell proliferation

What happens when CDK4/6 become overactive?

• Excess proliferation

• Cell cycle dysregulation

• Tumour growth

What is Palbociclib?

A selective CDK4/6 inhibitor used in breast cancer

How does palbociclib work?

• Inhibits CDK4/6

• Prevents Rb phosphorylation

• Causes G1 cell cycle arrest

Why are aromatase inhibitors important in breast cancer?

• Reduce oestrogen production

• Reduce stimulation of hormone-sensitive tumours

What challenges face precision medicine?

• High cost

• Drug resistance

• Complex genomic interpretation

• Ethical concerns

• Unequal access