Personalised Therapies for Cancer Patients: Future Vision or Immediate Necessity?

1. 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

2. Overview • Personalised Therapy • Past – The Efforts, Challenges & Accomplishments • Present – The Opportunities Today • Future – Making the Promise Possible

3. Overview • Personalised Therapy • Past – The Efforts, Challenges & Accomplishments • Present – The Opportunities Today • Future – Making the Promise Possible

4. Today Diagnosis and treatment increasingly based on rapidly growing insights into molecular processes and variations in our genes Past and Future Challenges in Creating Personalised Therapies 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

5. Large Number of Compounds AvailableWhat 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

6. Overview • Personalised Therapy • Past – The Efforts, Challenges & Accomplishments • Present – The Opportunities Today • Future – Making the Promise Possible

7. Healthcare: Precise. Personalized.Using genetic, molecular, and diagnostic tests to create targeted treatment options correlated with success 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 • 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

8. Uses of Molecular Profiling: Target Now® Overview A combination of the most clinically relevant technologies Delivers therapeutic guidance through molecular profiling Analysis Output • IHC • Multiple profiles depending on tumor type with a total of over 30 different “protein targets” • Additional 22 IHC validated • 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 • Microarray • Looking at the over- or under- expression 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.)

9. Where Does Molecular Profiling Fit in Clinical Practice? More aggressive Esophagus Pancreas Liver High mortality cancers where guidelines often fail quickly Lung Ovary Brain / Nervous system Myeloma Stomach Estimated deaths (% of new cases) Non-responders in cancers with well established guidelines Leukemia Colon Other non-responders Other urinary Other respiratory Lymphoma Kidney Digestive Breast Bladder Oral cavity & pharynx Uterus Skin Other genital Prostate Thyroid Rectum Less aggressive Estimated new cases More common Less common

10. Target Now ® Summary of Agents Clinical history and prior therapies Agents ranked. See next slide.

11. Target Now® Details Agents Associated with Clinical Benefit Summaries of biomarker associations

12. Overview • Personalised Therapy • Past – The Efforts, Challenges & Accomplishments • Present – The Opportunities Today • Future – Making the Promise Possible

13. What does the future look like? Exosome

14. Biology of Microvesicles Isolated Exosome/Microveslicle

15. 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)

16. 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

17. 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

18. 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 Quantity of cancer microvesicles In plasma Excitation wavelengths Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

19. Academic Collaborators

20. Colon Cancer: Early diagnostic test to determine the need for colonoscopy N= 147 total 58 Normals 59 CRC 30 Confounders Colon Cancer Cancer Markers Cancer Specific Microvesicle Level Confounders General and Colon Markers Total Microvesicle Level 20

21. Updated CRC data set (N=225) Carisome CRC performance Sensitivity 76 CRC (stage I-III) 80 Normals 69 Confounding diseases 1-Specificity

22. 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 Mutations identified in cells from CRC cell lines were also detectable in the exosomes derived from those cell lines KRAS mutations from the tumor of CRC patient samples could also be identified in plasma-derived exosomes from the same patients

23. 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

24. Personalized Therapies Require A MAJOR Mindset Change • Re-classification of diseases on a molecular level • Focus on efficacy, not patient numbers • Major innovation in how we demonstrate clinical efficacy • 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 Academia Pharma Hospitals/Physicians

25. “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: