Precision Medicine: Personalized Treatment

Precision Medicine

• Precision medicine is an evolving field utilizing diagnostic tests to identify specific biological markers.
• Often genetic, these markers help determine the most effective medical treatments and procedures for each patient.
• This personalized approach can detect disease onset early, prevent progression, improve healthcare system efficiency and enhances quality, accessibility, and affordability.
• The goal is to target the right treatments to the right patients at the right time.

Three Eras of Medicine

• Intuitive Medicine (1950s-1980s) involved the prescription of general therapies based on the identification of general symptoms.
• Evidence-Based Medicine (1980s-2000s) was marked by randomized controlled clinical trials.

The Shift to Precision Medicine

• Precision medicine (2010s-Present) emphasizes precise diagnoses to provide precise understanding and therapy.
• Personalized medicine focuses on identifying molecular markers to signal disease risk before symptoms appear.
• This facilitates early intervention and prevention.
• People with certain BRCA1 or BRCA2 gene variations have an increased risk (up to 85%) of developing breast cancer.
• PCSK9 inhibitors reduce cholesterol levels and the chances of CAD by targeting mutations in the LDL receptors gene PCSK9.

Targeted Therapies

• It involves developing molecular diagnostics.
• Aids in breast cancer treatment through the use of mAbs like Herceptin.
• Includes treatments targeting genetic variants, such as BRAF in melanoma and ALK and EGFR in non-small cell lung cancer.
• Molecular diagnostics help determine prognosis and treatment.

Discovery of EGFR Mutations

• In the early 2000s, Non-Small Cell Lung Cancer (NSCLC) research revealed distinct molecular profiles in a heterogeneous group.
• Epidermal Growth Factor Receptor (EGFR) mutations were found to be common in some NSCLC subsets.
• Patients with EGFR mutations responded positively to EGFR tyrosine kinase inhibitors (TKIs).
• Genetic testing is essential for identifying EGFR mutations, allowing for tailored treatment.

Identification of ALK Rearrangements

• Groundbreaking discovery of ALK fusion genes occurred in 2007.
• Around 2007, researchers found ALK gene rearrangements in a small subset of NSCLC patients.
• The fusion of ALK with other genes was identified as an oncogenic driver in lung cancer.
• Crizotinib was developed as a targeted therapy to inhibit abnormal ALK signalling.
• Clinical trials showed crizotinib's efficacy in ALK-positive NSCLC patients.
• Alectinib, ceritinib, and brigatinib were developed as ALK inhibitors.
• Targeting EGFR and ALK mutations with specific inhibitors significantly extended survival rates for some patients.

Reducing Adverse Drug Reactions

• Pharmacogenomics: Deciding on medicines based on a person's molecular makeup.
• Adverse drug reactions (ADR) are caused by CYP450 mutations that affect drug metabolism.

Warfarin and Pharmacogenomics

• Genetic variations in drug-metabolizing enzymes complicate warfarin use.
• Variation in (CYP2C9) and an enzyme that activates vitamin K (VKORC1) complicate the safe use of warfarin.
• Testing can help ensure the safe use of medicines in areas like cardiology, haematology, infectious diseases, cancer, and dermatology.
• CYP2C9 (Cytochrome P450 2C9) is involved in the metabolism of various drugs, including warfarin leading to potential side effects.
• VKORC1 (Vitamin K Epoxide Reductase Complex 1) plays a vital role in the vitamin K cycle impacting the sensitivity of individuals to warfarin.

Deciding on Course of Treatment and Drug Repurposing

• Molecular testing helps identify appropriate therapies for specific patient populations.
• Alterations in underlying genomes and biomarkers help fine tune drugs.
• Immune checkpoint inhibitors like pembrolizumab got expanded approvals.
• Initially was approved in 2014 for melanoma, but was later approved for non-small cell lung cancer in 2015.
• Drug repurposing finds new uses for existing drugs, relying on understanding molecular pathways.

Human Genome Project (HGP)

• The project aimed to understand the position and function of every single human gene, and it involved international collaboration.
• The human genome consists of roughly 30,000 genes.
• In 2000, Bill Clinton called the HGP "the most important, most wondrous map ever produced by humankind."
• Scientists aimed to map the human genome to locate genes and sequence nucleotide bases within them to allow scientists can read the complete instructions that our cells follow to build a human being.
• The project involved twenty institutes from six different countries, and it took 13 years.
• The sequencing technology could only process a few hundred base pairs of DNA at a time so the DNA was cut into small pieces.
• Sections of 200,000 base pairs each were inserted into bacterial DNA, as living libraries of DNA clones.
• Institutes collaborated in cultures resulting data was pieced together to form the whole genome sequence
• Shotgun Sequencing randomly breaking the genome into smaller fragments.
• Automated DNA sequencers determined the order of nucleotide bases in each fragment
• Fragments were inserted into bacterial artificial chromosomes (BACs) to create libraries of cloned DNA fragments.
• Access: Provide free and open access to the data deposited in easily available online public databases.
• Work continues to refine the "reference" human genome sequence.
• SNPs (single nucleotide polymorphisms): Genetic variation differences in single bases.
• HapMap project: 3 year → chart the patterns of genetic variation common in the world's population- Results 2005 simplify studies to understand how genetic variation contributes to health and disease.
• 1000 genome project*: Launched in January 2008 to to identify medically important variations to map on the genome.
• The HGP completed in April 2003 and published in 2004 and took 13 years, costing billions of dollars.
• In contrast, Watson's genome was sequenced in 2007 in 4 months for $1 million.
• Sequencing costs have since decreased as Helicos sequenced in 1 month for $48,000 in 2009 and current sequencing in 1 or 2 weeks costs 6,000 €.

Implications of Genomic Discoveries

• Tailoring treatments to individual genetic makeup improves treatment efficacy and reduces adverse effects.
• Increased access to genomic information raises privacy and security concerns.
• Possibility of discrimination necessitates legislation and ethical guidelines.
• Availability of affordable genetic testing raises questions of data interpretation and medical interventions.

Positive Impacts of Genomics

• There is need for improved genomic literacy to enable informed decisions.
• Genomic discoveries foster in new therapies, diagnostics, and technologies for economic growth.
• Genomic research expands understanding of biological processes and scientific innovations.
• Personalizing medicine through genomics involves tailoring medical treatments and interventions to individual characteristics

Personalized Medicine and Genomics

• Genetic tests identify variations linked to diseases for accurate diagnoses and predictive measures.
• Assessment of an individual’s risk of developing certain diseases in the future, allowing for proactive measures or preventive strategies.
• Pharmacogenomics: Drug response: understanding an individual’s genetic makeup can predict how they will respond to certain medications
• Genonomic info used in cancer treatment to help create targeted therapies involved in cancer cell growth, leading to more effective and less toxic treatments.
• Gene therapy can aims to correct or replace the faulty gene
• Lifestyle recommendations can be personalized based on individual genetics.

Data and Rare Diseases

• Genomic sequencing has greatly improved the ability to diagnose rare genetic disorders
• EHRs integrating genomic data helps healthcare providers with decision-making.

Example of Precision Medicine in Action

• A child admitted to hospital with severe eczema and immune system issues was sequenced and found to have a base change.
• He was diagnosed with IPEX syndrome.
• IPEX is rare.
• Affected children can die without a bone marrow transplant, which involves replacing the immune system.