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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: