✅ M3 - Precision Medicine

Question 1

What are the different definitions and uses of medicine?

Answer 1

1. Personalised medicine: an approach to both preventative care and drug therapy that is based on the individual’s genetic & other relevant information
   -> downside: purely for that person (not that specific)
2. Precision medicine: tailoring of medical treatment to the individual characteristics of each patient, usually involving patients being classified into subpopulations
   -> patient is not a completely distinct individual
3. P4 medicine: predictive, preventative, personalised, and participatory medicine
   -> patient also involved in the decision (not from doctors only)

Question 2

What is the difference in approaches between traditional and precision medicine?

Answer 2

1. Traditional approach: “one size fits all” drug prescribed for “typical” patient (e.g. pre-made suit) => BUT not successful for everyone, genetically and environmentally different
2. Move to Precision medicine: “specific drugs with personalised quantity and treatment frequency” (e.g. bespoke suit) => BUT very expensive

Question 3

What is the history/origin of precision medicine?

Answer 3

The idea is not new

1902: family line inheritance of alkaptunoria (rare disease) -> needs personalised treatment

1956: discovered genetic basis of selective toxicity of primaquine, an anti-malarial drug

1977: discovered role of cytochrome p450 metabolising enzyme variations in overdose toxicity (some variations tolerate/react better to drugs)

2003: finish of human genome project

Question 4

What is biomarker & how is it related to the development of precision medicine through human genome project?

Answer 4

Biomarker: a naturally occurring molecule, gene, or characteristic by which a particular pathological or physiological process, disease, etc. can be identified.
=> We advance by using biomarker

Pharmacogenomics (PGx): a field of study that looks at how a person’s genes affect their response to drugs.
- At start: only know 4 drugs with (PGx) info.
- Now: 261 drugs with PGx info, 363 drug - biomarker pairs

Question 5

What are the changes we are looking for to create precision medicine?

Answer 5

• Generally anything in the body (e.g. function, expression, interaction, physiological measurement, etc.) that informs a change between pre-diagnosis and post-diagnosis.
• We can obtain information from tests, such as:
  1. Genomics (genetic material)
  2. Transcriptomics (active gene)
  3. Proteomic (protein)
  4. Lipidomics (fat-related molecules)
  5. Metabolomics (small molecules in body)
  6. Epigenomics (gene control)

Question 6

How do biomarkers informs disease & its progression?

6 key-steps of disease progression (an overview)

Answer 6

1. Presence of a disease (presence of biomarker which commonly appears in patients)
2. Risk of developing a disease (biomarker presence/absence risk factor of disease onset)
3. Prognosis (risk of recurrence & inheritance)
4. Predictive (patients’ future responses to treatment)
5. PGx (find out reaction to drugs)
6. Monitoring treatment response (amount of biomarker)

Question 7

Examples of how biomarker informs disease & its progression”? [1]

Answer 7

1. Presence of a disease: diagnosis of prostate cancer using PSA (prostate-specific antigen)
   - PSA can be high for multiple reasons -> false positives
   - Low specificity (not certain)
   - Requires further tests to confirm diagnosis (e.g. biopsy) -> stress, costs, and risks of infection
2. Risk of developing a disease: predicting likelihood of breast and ovarian cancers (mutation of BRCA1 or BRCA2 gene)
   - Using BRAC analysis
   - positive for mutation -> 85% lifetime chance of breast cancer, 60% for ovarian cancer
   - negative for mutation -> 13% lifetime chance of breast cancer, 0.7% for ovarian cancer

Question 8

Examples of how biomarker informs disease & its progression”? [2]

Answer 8

3. Prognosis (disease progression): help determine risk of recurrence and aid in treatment decision.
   - Utilise a number of biomarkers
   - E.g. 70-gene risk of recurrence signature
4. Predictive (patients’ future responses to treatment): targeting therapy based on molecular diagnosis & drug-biomarker pairing
   - 25-30% patients with breast cancer are HER2 positive
   - over-expression of HER2 cell-surface receptor -> lead to abnormal cell growth
   - Drug developed + chemotherapy => 52% reduction in re-occurrence of tumour (than just chemo alone)
   - Requires high selectivity & specificity of cause
   - Issue with sensitivity in the type of test used (to measure expression of HER2)

Question 9

Examples of how biomarker informs disease & its progression”? [3]

Answer 9

5. PGx (find out reaction to drugs): improve dosing, efficacy & reducing side/adverse effects:
   - Liver metabolising enzyme mutations (drug-breakdown enzyme) -> specific to drugs
   - Lots of mutations (thousands)
   - Types:
   + slow metabolisers -> overdose toxicity
   + normal metabolisers
   + fast metabolisers
   + ultra fast metabolisers: drug does not work
   => e.g. prevent-blood-clot drugs for stent patients
6. Monitoring treatment response:
   - identify expression of Ki67 in tumour cell growth
   - if treatment is working -> reduction in Ki67 as indication
   - but more invasive (requires biopsy to analyse)

Question 10

What are the 3 benefits of biomarkers and precision medicine?

Answer 10

1. Some allow changing lifestyle -> reduce disease risk onset
2. Some allow early decision-making (BRCA 1&2)
3. Some aid drug development
   - reduces cost, attrition rate and time of development
   - stratifying patients for clinical trials -> change how clinical trials are carried out
   - easier to pick up effect in same mutation group
   - improves chance of positive outcomes rather than negative

Question 11

Other applications of precision medicine?
(NOT just genes and drugs)

Answer 11

• Tinnitus masker: white noise player for hearing disruption
• Software-based quantitative EEG analysis: looking at brain wave for diagnosis
• Artificial pancreas device system: personalised diabetic treatments
• Custom made splints: repair poorly developed organ/body parts

Question 12

What are some controversies over precision medicine?

Answer 12

1. Ethics:
   - Concerns over genome data protection and privacy
   - Concerns over false diagnosis
2. Gene mutations/variations:
   - Too many mutations
   - May not correctly identified main gene that causes specific disease
3. Genomic statistic:
   - How do we cope with handling large amount of data?
   - Implications for AI
4. Does it work?
   - Works for some, but not all
   - Expensive but uncertain (wasted effort)

Question 13

What is meant by ‘direct to consumer’ tests?

Answer 13

1. Usually require a biological specimen (eg. saliva) which is then sent to company for analysis
2. The specimen tested can reveal:
   - Microbiome
   - Toxins in body
   - Ancestry (DNA)
   - Prediction of disease risk
3. Example: 23 & Me -> very popular for people to test their genetic material & find out about themselves

Question 14

What is the history (timeline) of 23 & me?

Answer 14

2007: launched, first company to offer autosomal DNA ancestry testing

2013: stopped personal genome service in US but still offer ancestry service (ethical implication)

2014: launched in Canada and UK (different regulations)

2015-2018: FDA approved numerous “disease-carrier” tests (no longer testing for full genome)

2018: partnerships with different pharmaceutical companies
- GSK: allowed sharing of personal data
- Using genome information to find patients carrying disease to develop new drugs in clinical trial (2020) -> ethical? (data leak risk)

2021: Merged with Richard Brandson’s VG Acquisition Corp.

Question 15

What are we trying to detect by using this service?

Answer 15

1. Trying to detect a target or multiple targets that tell us about the disease
2. Help with prediction, cause, diagnosis, progression, regression, or outcome of treatment of disease
3. Where do we detect these biomarkers?
   - Any part of the body where we can look at protein, DNA, cell, for examples:
   - Tissue (normal or diseased)
   - Blood (most common for testing disease)
   - Saliva (ancestry test)
   - Sweat
   - Hair (test for toxins)

Question 16

What are the common technologies employed?

(don’t have to learn by heart)

Answer 16

1. To identify DNA/genetic biomarkers from patients:
   - DNA sequencing
   - PCR: good to analyse specific genes you want to look at
   - Microarrays: detect and characterise genetic variations, e.g. single nucleotide polymorphisms (SNPs), copy number variations (CNVs), across the genome.
2. To identify protein biomarkers from patients:
   - The enzyme-linked immunosorbent assay (ELISA): measure the presence and concentration of specific proteins
   - Gel electrophoresis: separate different components of proteins
   - Surface plasmon resonance (SPR)
   - Mass-sensing BioCD protein array
   - Surface enhanced Raman spectroscopy (SERS)
   - colorimetric assay; electrochemical assay; fluorescence methods

Question 17

How to test both genetic and protein biomarker at the same time? What are the advantages?

Answer 17

1. Identification technology of >1 biomarker at a time is far more beneficial for patient and health service.
2. Advantages:
   - Reduces costs of performing multiple single tests
   - Reduces variability in test performance and accuracy (PCR is not good for testing alot of samples)
   Provides all results at one time
3. What are these types of tests:
   - Bundled tests: multiple independent tests from same sample
   - Multiplexing: measured from same analyte at same time and quantified at same time

Question 18

Explain the rise/development of companion diagnostics (CDx)? Give some examples of where this technology is used.

Answer 18

1. Purpose: having a companion diagnosis of specific drug-gene biomarker pair alongside the disease diagnosis (effective treatment based on precision medicine approach)
2. CDx FDA approved and helped accelerate product to market (process validated and approved)
3. Example: Zelboraf – CDx Cobas™ Platform (Roche)
   - Detect BRAF V600E mutation (growth factor of cancer) via real-time PCR

Question 19

What may be the alternative to CDx?

Answer 19

1. Gefitinib: tyrosine kinase (EGFR-TK) inhibitor
   - Usage: in non-small cell lung cancer (NSCLC) with EGFR-TK mutations that activate the growth factor
   - Purpose: promise of improved clinical outcome by stratifying population
2. Why is this a concern?
   - 10 tests used to detect mutation in protein
   - NOT validated as equivalent to CDx because of limited clinical outcome
3. Conclusion: Different tests need to be compared and linked to patient outcomes -> Test the difference in measurements

Question 20

What is the Amplichip CYP450 Tests (ROCHE)?

Answer 20

1. Usage: determines metabolic capacity of person
2. How? Analysis of CYP2D6 and CYP2C19 => Multiple SNPs and other variations
3. Microarray-based test using purified DNA from blood

=> FDA approved

Question 21

What is the application of 3D printing in developing precision medicine?
Evaluate its pros & cons?

Answer 21

1. 3D printing of pills
   - Allows polypills to be formed
   - Change dose according to patient specific age, weight, organ function
   - Change in dissolution rate of tablets (eg. Spritam for epilepsy)
2. 3D printing of organs and tissues, example: Fripp Design, Sheffield
3. Pros of 3D printing:
   - Highly adaptable
   - On-demand
   - Fast prototyping
   - Cost effective
   - Allows complex and intricate design
   - Scalability
4. Cons of 3D printing:
   - Sustainability: plastics used; energy used
   - Inconsistency
   - Cyber Risk
   - Copyright
   - Low throughput?

Question 22

Explain what is meant by OncoType DX

Answer 22

1. A genomic test that helps identify the underlying tumour biology for breast cancer
   - Usage: test patients positive for ER (oestrogen receptor) and negative for HER2
   - Biopsy taken by pathologist and sent to Genomic Health Lab
2. Genome components:
   - 16 genes associated with breast cancer
   - 5 housekeeping genes (associate with maintaining primary cellular function)
3. How it works:
   - Detects these genes and uses a formula to calculate the Reoccurrence score
   - Score 1-100 determines whether chemotherapy is required
   - Check likely reoccurrence of tumour within the next 10 years

Question 23

Explain what is PGX Predict Clozapine used for? (another example of precision medicine based on CDx)

Answer 23

1. Clozapine is an antipsychotic drug (for schizophrenia)
   - Can cause agranulocytosis (decrease in the number of a white blood cell type in blood)
   - Needs weekly blood monitoring
2. Genome components:
   - Associated with variants in HLA complex (part of the immune system)
3. How it works: identifies 10 genes to give:
   - Drug metabolism profile
   - Blood clotting factors
   - Metabolic genes
   - Blood clotting genes
   - P-glycoprotein
   - HLA variants
4. Effectiveness: FDA approved
   - 21% sensitivity
   - 98% specificity
   => Lack of clinical take up so taken off market

Question 24

Explain what is FDA Phyziotype (Genomas) used for?

Answer 24

1. Used to detect antipsychotic drug-induced metabolic changes
   - Weight gain
   - Hyperlipidemia
   - Diabetic risks
2. Identifies SNPs in genes associated with:
   - Antipsychotic pharmacology
   - Appetite control
   - Energy regulation
   - Endocrinology
   - Cholesterol homeostasis
3. How it works: Signature used with biomathematical algorithm to determine risk profile

=> See the risk effects of antipsychotic drugs on body metabolism (that may lead to the onset of metabolic complications)

Question 25

Explain what GeneSight Psychotropic Test is used for? (Yet another example)

Answer 25

1. DNA test looking for specific mutations in genes associated with:
   - Efficacy of antidepressants
   - Antidepressants’ metabolism
2. Effectiveness: Allows for better dosing and drug selection for patients

Question 26

Explain what are meant by Telemedicine and Biosensors? Give an example of how these could be used?

Answer 26

1. What it is:
   - Telemedicine: provision of healthcare services
2. Example context of usage: Parkinson’s disease (PD) - measure tremor and freezing of gait most commonly.
3. Two examples of existing devices to support patients with PD:
   - SENSE-PARK system: used for gait, hypokinesia, dyskinesia, sleeping, etc.
   - Parkinson’s Kinetigraph: a wrist worn logger

Question 27

What is the issue with precision medicine via targeting gene?

Answer 27

1. Gene mutation
   - Identify cancer causing gene
   - Have all mutations been identified?
   - A second mutation may render targeted therapy ineffective
   - Driver mutations & passenger mutations -> driver mutation targeted by therapy or not?
2. Gene variations
   - Work carried out by groups at The Karolinska Institute (Sweden)
   - Shown > 60000 variations in cytochrome P450 metabolising enzymes -> 90% rare; 50% new findings (2015)
   - Each person carries >1000 gene variations that determine response to drug -> Currently tests only cover a fraction of the relevant genetic variations

=> Therefore pharmacogenomics for drug dosing fairly ineffectual