1. Ancha Baranova George Mason University, Fairfax, VA
Genome, transcriptome and proteome features of malignant cells as a source of combinatorial biomarkers for clinical translation
Ancha Baranova
George Mason University, Fairfax, VA

2. Key word to understanding of cancer phenomenon
PROGRESSION
From bad
to worse
then to full catastrophe

3. LUNG CARCINOMA PROGRESSION
e.g. carcinogen
from the smoke
e.g. Smoke

4. How long it usually takes: DECADES
It takes ≈17 years for a large benign tumor to evolve into an advanced cancer
but <2 years for cells within that cancer to acquire the ability to metastasize
Sequencing studies show that virtually all of the mutations necessary for metastasis are already present in all of the cells of the antecedent carcinoma.
/pnas ; Jones et al., 2008
17 years

5. TRUTH: Majority of human tumors sit in our bodies undiagnosed for decades
Major implication for translational research: 1) need for early biomarkers; 2) need for evaluation of how far away the tumor was from sprouting metastasis  basis for post-surgical treatment and care

6. Problem: in biomarker research all low-hanging fruits already collected
PSA, CEA, AFP….

7. Single biomarkers have problems with differentiating “grey area” diseases, i.e. inflammatory conditions
Solution:
Biomarker panels
PSA LeveL
Controls
Prostate
cancer
Other
cancers
Benign
genitourinary
diseases
BPH
Barak et al., 1989

8. Now: from where these biomarker for biomarker panels are usually coming ?
A fishing
expedition:
Differences
often reflect
Inflammation,
fibrosis
and other
common properties
Image courtesy of Purdue University, Dr. W. Andy Tao

9. Two-pronged approach proposed:
TUMOR vs. a MIX of various normal cells
Perform transcriptome (in silico) and proteome (using antigen screening) subtractions
DISTANCE ANALYSIS:
Use entire pattern of gene expression to evaluate of how far away the excised tumor was from sprouting metastasis
Most TARGETED
approach:
Most GENERAL
approach:

10. Two-pronged approach proposed:
Based on previous works of collaborative consortium:
TUMOR vs. a MIX of various normal cells
Perform transcriptome (in silico) and proteome (using antigen screening) subtractions
Most TARGETED
approach:
Will uncover tumor biomarkers that cannot be masked by antigen production in normal tissue

11. Most Targeted Approach: Consortium
Blokhin Russian Oncological Scientific Center, Moscow (sample collection and processing)
Caerus Discovery LLC, Manassas, VA
(capture of protein biomarker as differentially expressed antigens)
Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk
(development of tumor protein biomarkers as targets for antibody-guided drug delivery)
Biomedical Center, StPeterburg
(differential display of tumor RNAs)
Research Center for Medical Genetics RAMS
(non-coding Tumor RNAs)
George Mason University, Fairfax, USA
(biomarker validation, bioinformatics support and general coordination)
Most TARGETED
approach:

12. Two-pronged approach proposed:
DISTANCE ANALYSIS:
Use entire pattern of gene expression to evaluate of how far away the excised tumor was from sprouting metastasis
Most GENERAL
approach:

13. Simple words explanation forusing entire transcriptome as biomarker
Who is that? -- Instant answer (same person, Darwin)
Biomarker approach:
X: Distance from the end of nose
to the upper lip
Y: Diameter of the eye orbit
Z: Number of hairs in the beard

14. Two-pronged approach proposed:
Blokhin Russian Oncological Scientific Center, Moscow (sample collection and processing)
Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk
(next gene sequencing and microarray)
Vavilov Institute of General Genetics
Research Center for Medical Genetics RAMS
(distance analysis of samples based on summed evaluation of non-coding RNAs)
University of Arkansas for Medical Sciences (Little Rock, AK)
(distance analysis of whole genome patterns)
George Mason University, Fairfax, USA
(development of attractor descriptors, bioinformatics support and general coordination)
DISTANCE ANALYSIS:
Use entire pattern of gene expression to evaluate of how far away the excised tumor was from sprouting metastasis
Most GENERAL
approach:

15. VISION for the FUTURE
New generation of tumor markers specific to the malignancy but not to the any normal cell type will allow:
True early diagnostics of dormant tumors
2) More specific antibody-guided delivery of therapeutic agents to the tumors

16. VISION for the FUTURE Comparison of prognoses for
This tumor and That tumor

17. Same strategy can be realized using NextGen Seq
Very possible;
low sequence coverage of transcripts will be enough;
cost-efficient cut-off needs to be determined

18. VISION for the FUTURE REFERENCE LAB
Profiles 100s normal samples for prostate;
Establishes its own, equipment-specific
NORMAL SPACE
For every single tumor sample,
the distance from normal tissue space is measured

19. How bad is my tumor? Answer: exact distance from “Ideal” norm
Your tumor