Precision Medicine and Oncology Lecture Notes PDF

School of Pharmacy PRECISION MEDICINE AND ONCOLOGY Prof Darius Widera School of Pharmacy, Pharmacology Division 1 Copyright University of Reading LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIM...

School of Pharmacy PRECISION MEDICINE AND ONCOLOGY Prof Darius Widera School of Pharmacy, Pharmacology Division 1 Copyright University of Reading LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT LEARNING OBJECTIVES After this lecture and further reading, students can: Define and discuss the concept of precision medicine. Know pathophysiological processes associated with hallmarks of cancer Understand how precision medicine can be applied to the field of oncology. Explain, with examples, how precision medicine is used in clinical practice to stratify cancer patients for therapy. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS Definition Pharmacogenetics can be defined as the application of genetic analysis to predict drug response, efficacy and toxicity 3 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS Definition Pharmacogenetics can be defined as the application of genetic analysis to predict drug response, efficacy and toxicity Use of Pharmacogenetics 4 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS Definition Pharmacogenetics can be defined as the application of genetic analysis to predict drug response, efficacy and toxicity Use of Pharmacogenetics Drug discovery and development: identifying potential responders and non-responders to a drug at an early stage, using genetic variants that are markers of drug efficacy 5 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS Definition Pharmacogenetics can be defined as the application of genetic analysis to predict drug response, efficacy and toxicity Use of Pharmacogenetics Drug discovery and development: identifying potential responders and non-responders to a drug at an early stage, using genetic variants that are markers of drug efficacy Prescribing: Genetic test could function as an efficient factor in determining the best choice of drug for a given patient and condition based on their individual genotype 6 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENETIC TESTING IS AFFORDABLE 7 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT 100,000 GENOMES LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT 100,000 genomes 100,000 GENOMES LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENETIC TESTING WIDELY AVAILABLE 10 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENETIC TESTING WIDELY AVAILABLE 11 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENETIC TESTING WIDELY AVAILABLE 12 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS AND PERSONALISED MEDICINE 13 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS AND PERSONALISED MEDICINE 38% of patients with depression do not respond to the first drug they are prescribed 14 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS AND PERSONALISED MEDICINE 38% of patients with depression do not respond to the first drug they are prescribed 40% of patients with asthma do not respond to the most commonly prescribed drugs 15 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS AND PERSONALISED MEDICINE 38% of patients with depression do not respond to the first drug they are prescribed 40% of patients with asthma do not respond to the most commonly prescribed drugs Type 2 diabetes (43%), arthritis (50%), and Alzheimer's disease patients tend to (70%) not respond to the most commonly prescribed drug 16 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS AND PERSONALISED MEDICINE 38% of patients with depression do not respond to the first drug they are prescribed 40% of patients with asthma do not respond to the most commonly prescribed drugs Type 2 diabetes (43%), arthritis (50%), and Alzheimer's disease patients tend to (70%) not respond to the most commonly prescribed drug 17 Each cancerLIMITLESS is different POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PHARMACOGENETICS AND PERSONALISED MEDICINE 18 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED MEDICINE LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED MEDICINE Pharmacogenomics/pharmacogenetics use patient-specific genetic information to predict their response to particular drugs LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED MEDICINE Pharmacogenomics/pharmacogenetics use patient-specific genetic information to predict their response to particular drugs This allows individualisation of health care LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED MEDICINE Pharmacogenomics/pharmacogenetics use patient-specific genetic information to predict their response to particular drugs This allows individualisation of health care Use of genetic and biomarker information to predict an individual's risk of disease or to select the most effective and safest treatment LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED MEDICINE Pharmacogenomics/pharmacogenetics use patient-specific genetic information to predict their response to particular drugs This allows individualisation of health care Use of genetic and biomarker information to predict an individual's risk of disease or to select the most effective and safest treatment “the right drug, for the right patient, at the right dose” LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED OR PRECISION? Personalised medicine LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED OR PRECISION? Precision medicine Personalised medicine LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED OR PRECISION? LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED OR PRECISION? Precision medicine Personalised medicine LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED OR PRECISION? Stratified medicine Precision medicine Personalised medicine LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PERSONALISED OR PRECISION? LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TRADITIONAL/STRATIFIED/PRECISION MEDICINE LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  31 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. 32 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. Gene mutations can occur at any time during the life of a cell. 33 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. Gene mutations can occur at any time during the life of a cell. Can be caused by: 34 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. Gene mutations can occur at any time during the life of a cell. Can be caused by: Substances or factors that can cause DNA to mutate 35 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. Gene mutations can occur at any time during the life of a cell. Can be caused by: Substances or factors that can cause DNA to mutate e.g. - Viruses 36 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. Gene mutations can occur at any time during the life of a cell. Can be caused by: Substances or factors that can cause DNA to mutate e.g. - Viruses - Cigarette smoke 37 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. Gene mutations can occur at any time during the life of a cell. Can be caused by: Substances or factors that can cause DNA to mutate e.g. - Viruses - Cigarette smoke - Alcohol 38 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. Gene mutations can occur at any time during the life of a cell. Can be caused by: Substances or factors that can cause DNA to mutate e.g. - Viruses - Cigarette smoke - Alcohol - Radiation 39 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. Gene mutations can occur at any time during the life of a cell. Can be caused by: Substances or factors that can cause DNA to mutate e.g. - Viruses - Cigarette smoke - Alcohol - Radiation - Chemicals 40 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS A gene mutation results when the specific sequence of a gene changes. Gene mutations can occur at any time during the life of a cell. Can be caused by: Substances or factors that can cause DNA to mutate e.g. - Viruses - Cigarette smoke - Alcohol - Radiation - Chemicals - UV 41 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS All mutations are heritable in that they will be copied during DNA replication. 42 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS All mutations are heritable in that they will be copied during DNA replication. Not all mutations will be passed on to future generations, however. 43 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENE MUTATIONS All mutations are heritable in that they will be copied during DNA replication. Not all mutations will be passed on to future generations, however. Only changes that affect the genetic information contained in the reproductive cells of an organism, called germ cell mutations, will be passed on to offspring. 44 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT HOW DOES THIS RELATE TO ONCOLOGY? LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT HOW DOES THIS RELATE TO ONCOLOGY? Mutations in genes linked to cell survival and cell proliferation play a central role in oncogenesis LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT HOW DOES THIS RELATE TO ONCOLOGY? Mutations in genes linked to cell survival and cell proliferation play a central role in oncogenesis Provides a key link between mutagens and cancer LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT HOW DOES THIS RELATE TO ONCOLOGY? Mutations in genes linked to cell survival and cell proliferation play a central role in oncogenesis Provides a key link between mutagens and cancer Identifying these DNA changes can be crucial for diagnosis and in choice of treatment LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TWO KEY ASPECTS LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TWO KEY ASPECTS Germline risk – Variants present in an individual's genome since conception that increase risk of developing cancer LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TWO KEY ASPECTS Germline risk – Variants present in an individual's genome since conception that increase risk of developing cancer Somatic mutations found in tumours – These are mutations that occur during a patient's lifetime that directly lead to oncogenesis LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TWO KEY ASPECTS Germline risk – Variants present in an individual's genome since conception that increase risk of developing cancer Somatic mutations found in tumours – These are mutations that occur during a patient's lifetime that directly lead to oncogenesis Both have consequences for treatment LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DNA SEQUENCING LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DNA SEQUENCING LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DNA SEQUENCING LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DNA SEQUENCING LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DNA SEQUENCING LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DNA SEQUENCING LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PRECISION MEDICINE - EXAMPLE A skin biopsy taken from the patient in this case report was dissociated and sequenced at the single-cell level with the 10X Genomics platform. Unbiased clustering and differential gene-expression pathway analysis revealed an overactive JAK–STAT pathway in this patient’s T cells. On the basis of this finding, the patient was successfully treated with the JAK inhibitor tofacitinib. Nature Medicine (Nat Med) ISSN 1546-170X (online) ISSN 1078-8956 (print) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT HOW DOES THIS RELATE TO ONCOLOGY? LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT HOW DOES THIS RELATE TO ONCOLOGY? LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT THE HALLMARKS OF CANCER HALLMARKS OF CANCER Robert Weinberg LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT The hallmarks of cancer THE HALLMARKS OF CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT The hallmarks of cancer THE HALLMARKS OF CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT The hallmarks of cancer THE HALLMARKS OF CANCER SUSTAINED PROLIFERATION! LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT The hallmarks of cancer THE HALLMARKS OF CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT The hallmarks of cancer THE HALLMARKS OF CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT The hallmarks of cancer THE HALLMARKS OF CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT The hallmarks of cancer THE HALLMARKS OF CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT The hallmarks of cancer THE HALLMARKS OF CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT The hallmarks of cancer THE HALLMARKS OF CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER “It takes (at least) two to tango". Alfred G. Knudson The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA. It was first proposed by Carl O. Nordling in 1953, published later by Alfred G. Knudson in 1971. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DE-REGULATION OF BASIC CELL FATE REGULATION CONTRIBUTES TO CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER AND PRECISION MEDICINE Source: Bayer LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER AND PRECISION MEDICINE Source: Bayer LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER AND PRECISION MEDICINE LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Case study 1: BRCA1 Case study #1: BRCA1 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT BRCA1 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT BRCA1 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT BRCA1 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT BRCA1 AND RISK OF DEVELOPING BREAST CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DETECTION Nature Medicine 17, 283–284 (2011) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CASE STUDY 1: BRCA1 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  BRCA1 GENE AND FUNCTION BRCA1: human tumour suppressor gene (also known as a caretaker gene and is responsible for repairing DNA (double strand breaks). Nature Medicine 17, 283–284 (2011) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  BRCA1 GENE AND FUNCTION BRCA1: human tumour suppressor gene (also known as a caretaker gene and is responsible for repairing DNA (double strand breaks). Nature Medicine 17, 283–284 (2011) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Targeting BRCA1 TARGETING BRCA1 PARP enzyme is essential for initiating various forms of DNA repair. Inhibiting its enzyme activity with small molecules thus achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PARP LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PARP LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT OLAPARIB Olaparib is a PARP inhibitor LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT OLAPARIB Olaparib: PARP inhibitor LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Case study 2: EGFR Case study #2: EGFR LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT EGF RECEPTOR LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT EGF RECEPTOR MUTATIONS Nature Reviews Clinical Oncology 10, 235 244 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GEFITINIB Gefitinib: EGFR inhibitor with tyrosine kinase as a target LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT ERLOTINIB Erlotinib: EGFR inhibitor with tyrosine kinase as a target LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT MUTATIONS Tyrosine kinase domain if often affected by mutations LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  ALTERNATE PATHWAYS Mutations in K-Ras define response to cetuximab LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  ALTERNATE PATHWAYS – K-RAS MUTATIONS Mutations in K-Ras define response to cetuximab LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  ALTERNATE PATHWAYS – K-RAS MUTATIONS Mutations in K-Ras define response to cetuximab LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TARGETING EGFR - CETUXIMAB LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TARGETING EGFR - CETUXIMAB Cetuximab is a recombinant monoclonal antibody that binds to and inhibits the activity of the EGF receptor This reduces cell proliferation; however this is only the case if the tumour/tumours have wild type K-ras A genetic test for K-ras mutations is therefore required prior to prescribing cetuximab LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Case study 3: CDK 4/6 Case study #3: CDK 4/6 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  CDK 4/6 K 4/6 (Cell Cycle Dependent Kinase 4/6): Key regulator of the cell cyc LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PALBOCICLIB Palbococlib is a selective inhibitor of the cyclin- dependent kinases CDK4 and CDK6. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PALBOCICLIB LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PALBOCICLIB LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PALBOCICLIB Aromatase (oestrogen synthase) inhibitor LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PALBOCICLIB LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PALBOCICLIB LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT PALBOCICLIB LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 130 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT MRNA VACCINES 131 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT MRNA VACCINES 132 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT MRNA VACCINES 133 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 134 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 135 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 136 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 137 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 138 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 139 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 1. Patient tumor biopsies and healthy tissue (are subjected to next-generation sequencing. 2. By comparing the sequences obtained from tumor and normal DNA, tumour-specific differences in protein-coding genes are identified. A computational pipeline is used to examine the mutant peptide regions for binding to the patient’s HLA. 3. These data can facilitate selection of multiple mutations to design unique neoepitope vaccines manufactured under GMP conditions. 4. 140 AdministrationLIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 141 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANCER VACCINES 142 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT FUTURE CANCER TREATMENT 143 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT FUTURE CANCER TREATMENT 144 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT ECONOMIES OF SCALE LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CONCLUSIONS Precision medicine is already playing a major role in stratifying cancer patients to identify the right treatment for the right individual Increasing use of genetic analysis to screen patients and tumours BRCA1 and EGFR mutations current clinically relevant examples Use is likely to increase in oncology over time, and will increase in other disorders LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT THANK YOU FOR YOUR ATTENTION! LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT