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Personalised Therapies for Cancer Patients: Future Vision or Immediate Necessity? Jonathan Knowles FiDiPro Professor, Finnish Institute of Molecular Medicine, Helsinki Vice Chairman, Chief Scientific Officer, Caris Life Sciences, Dallas Overview Personalised Therapy Past – The Efforts, Challenges & Accomplishments Present – The Opportunities Today Future – Making the Promise Possible Overview Personalised Therapy Past – The Efforts, Challenges & Accomplishments Present – The Opportunities Today Future – Making the Promise Possible Past and Future Challenges in Creating Personalised Therapies Today Diagnosis and treatment increasingly based on rapidly growing insights into molecular processes and variations in our genes The last 100 years Diagnosis and treatment based on increasing knowledge about biochemistry and cellular processes For more than 10,000 years Diagnosis and treatment based on what could be seen, smelled, tasted, palpated or intuited Large Number of Compounds Available What is the Right Combination for each Patient? • Total number of oncology drugs approved in US is around 3001 • Number of new cancer medicines and vaccines being tested in the US is 861 (either in clinical trials or awaiting approval by the FDA)2 • How can we best decide which is the best combination for efficacy? 1 Source: NCI, 2 Source: cancernetwork.com ‘09 Overview Personalised Therapy Past – The Efforts, Challenges & Accomplishments Present – The Opportunities Today Future – Making the Promise Possible Healthcare: Precise. Personalized. Using genetic, molecular, and diagnostic tests to create targeted treatment options correlated with success Changing the same-for-all approach to therapy • Good therapeutics follow good diagnostics1 • Response rates on drugs are unsatisfactory, varying widely from 20% to 75% depending on the drug and the disease.2 1 Lesko, et al, Clin Pharmacol Ther, 2007. 2 Schwiezer , Diagnostics 2009: Moving Towards Personalized Medicine 3 Roses. Nature, 2000 Advanced diagnostic methods We are on the verge of being able to identify inherited differences between individuals which can predict each patient's response to a medicine.3 Uses of Molecular Profiling: Target Now® Overview A combination of the most clinically relevant technologies Analysis IHC • Multiple profiles depending on tumor type with a total of over 30 different “protein targets” • Additional 22 IHC validated Microarray • Looking at the over- or underexpression of RNA in a whole genome microarray for both fresh frozen and FFPE tissues • Summarizing ~80 of the most significant or resistant targets FISH • Identifying gene copy number alterations in tumor tissue (EGFR, HER2, TOP2A, cMYC) Mutational Analysis • Identifying gene mutations in tumor tissue (e.g. KRAS, BRAF, EGFR, c-Kit, PIK3CA etc.) Delivers therapeutic guidance through molecular profiling Output Unique molecular “ blueprint” of patient tumor • Gene Expression • Quantitative Protein Expression • Mutational Analysis • Gene Copy Number Aberrations Literature-based prioritized ranking of drug targets in tumor and their associated therapies Information on therapies that might not otherwise have been considered based on the lineage of the tumor Where Does Molecular Profiling Fit in Clinical Practice? More aggressive 100% Esophagus Estimated deaths (% of new cases) 90% Pancreas Liver High mortality cancers where guidelines often fail quickly 80% 70% Ovary Lung Brain / Nervous system 60% Myeloma Stomach 50% Leukemia Non-responders in cancers with well established guidelines Colon Other non-responders 40% Other urinary Other respiratory Digestive 30% 20% Other genital 10% Kidney Uterus Oral cavity & pharynx Lymphoma Breast Bladder Skin Prostate Thyroid Rectum Less aggressive 0% - 50,000 Less common 100,000 150,000 Estimated new cases 200,000 250,000 More common Target Now ® Summary of Agents Clinical history and prior therapies Agents ranked. See next slide. Target Now® Details Agents Associated with Clinical Benefit Summaries of biomarker associations Overview Personalised Therapy Past – The Efforts, Challenges & Accomplishments Present – The Opportunities Today Future – Making the Promise Possible What does the future look like? Exosome Biology of Microvesicles Isolated Exosome/Microveslicle Microvesicle Levels are Increased in Cancer Plasma Samples Compared to Samples from Unaffected Individuals Microvesicle Levels P-value <0.0001 Pooled cancer patient samples: 17 prostate cancer patients, 18 colon cancer patients, 5 esophagus cancer patients, 3 pancreas cancer patients, 1 liver cancer patient, 1 rectal cancer patient sample (unpublished Caris data) Prostate Cancer: Published studies demonstrate potential of microvesicles to be used as tools for monitoring PCa patient response to Androgen Deprivation Therapy. n = 10 p<0.05 Mitchell et al., 2009 J. of Translational Medicine Microvesicles Populations in Plasma are: - A Major Vehicle for Cell-Cell Communication - Carry Cargo Based on Cell of Origin and Biological Purpose Tumor-derived microvesicles The Basis of the Carisome™ Platform A multiplex of capture and detection antibodies specific for different proteins are used, to capture, count and characterize microvesicles resulting in a test that is highly sensitive and specific Detector antibody emission Detector antibody emission Detector antibody emission Excitation wavelengths Y Y Y Y Y Quantity of cancer microvesicles In plasma Academic Collaborators Colon Cancer: Early diagnostic test to determine the need for colonoscopy N= 147 total 58 Normals 59 CRC 30 Confounders Cancer Markers Colon Cancer Cancer Specific Microvesicle Level Confounders Rheumatoid arthritis Normal Confounder CRC 3 Diabetes - Type II, Transitional cell carcinoma of the bladder 2 Rheumatoid arthritis, Marked degenerative arthritis Diabetes, Clear cell renal cell carcinoma. of the kidney Diabetes, Infiltrating ductal carcinoma of the breast Diabetes, Renal cell carcinoma 2 1 General and Colon Markers 1 Total Microvesicle Level 1 Chronic diverticulosis 9 Lung Cancer 10 20 20 Updated CRC data set (N=225) 100% 90% 80% Carisome CRC performance Sensitivity 70% 60% 50% 40% 30% 76 CRC (stage I-III) 80 Normals 69 Confounding diseases AUC 20% 0.952 10% 0% 0% 20% 40% 60% 1-Specificity 80% 100% Exosomes isolated from Colorectal Cancer plasma samples can be used to identify KRAS mutations from the tumor c. 13G>A CRC cell line cDNA from exosomes HCT116 DNA from cells Plasma-derived exosome cDNA from CRC patient FFPE DNA from CRC patient Observations 1. Mutations identified in cells from CRC cell lines were also detectable in the exosomes derived from those cell lines 2. KRAS mutations from the tumor of CRC patient samples could also be identified in plasma-derived exosomes from the same patients Summary: Carisome Platform Blood Based Minimally invasive serial monitoring patients Improved compliance (5ml blood rather than cancer tissue) Reduced sample collection costs Versatile Potential to identify early subject stratification (responders / non-responders) Allows multiple molecular analyses on a single subject sample (miRNA, mRNA, oncoproteins) Applicable across all cancer types Rapid assay time (12hours) Innovative Partnerships essential to help patients Personalized Therapies Require A MAJOR Mindset Change • Re-classification of diseases on a molecular level Academia • Focus on efficacy, not patient numbers • Major innovation in how we demonstrate clinical efficacy Pharma • Move on from companion diagnostics for each therapy to definition of the right combination from personalised diagnosis • Encourage novel partnerships and collaborations • Change in the way patient information is generated/used Hospitals/Physicians “The processes of disease are so complex that it is excessively difficult to search out the laws which control them, and, although we have seen a complete revolution in our ideas, what has been accomplished by the new school of medicine is only an earnest of what the future has in store .” Sir William Osler Teaching and Thinking, Two Functions of Medical School. McGill University 1895 Novel Partnerships are the key: