Predictive Biomarkers for Lung Cancer

1
Predictive Biomarkers for Lung Cancer
Current Status / Perspectives
Although curative resection of patients
with early-stage lung CA are performed, the
risk of relapse remains substantial
Indicates that there may be micro-invasion/metasta
sis have not been detected by general imaging
and/or pathological examinations
2
Predictive Biomarkers for Lung Cancer
Intended Goals

• Defining categories or tumor subsets that may
• improve the diagnostic classification of
  lung
• tumors

• Identifying specific genes, proteins, or
  accessory
• cells that could serve as targets for
  improved
• diagnosis and/or therapy

• Associating biomarkers with clinical outcomes

3
Predictive Biomarkers for Lung Cancer
Hurdles
There are no biomarkers universally recommended
to help in the clinical management of lung cancer
today.
4
Predictive Biomarkers for Lung Cancer
Challenges

• Single biomarker approach has not been proven
  to
• have strong predictive potential in lung
  cancer

• Use of molecular and nano-IVD technologies
  bring
• a key promise for identification of
  clinically
• meaningful biomarkers

• Clinical validation of candidate biomarkers
• remains a major challenge

5
Predictive Biomarkers for Lung Cancer
Challenges

• Use of biomarkers for early detection of
• lung cancer is promising but still
  methodologically
• challenging

• Clinical management of lung cancer will most
• probably first benefit from use of
  biomarkers

• Development of new therapeutic options for lung
  
• cancer will stimulate identification and
  clinical
• validation of new biomarkers

6
Predictive or diagnostic modelling
Use of one or more biomarkers to determine
prognosis or response to treatment beyond usual
clinical criteria

• Tissue based.
• Serum or urinary based
• Cellular based

7
Overview of Genomic Approach

• DNA / RNA microarray
• MicroRNA microarray
• Single nucleotide polymorphism (SNPs)
• Epigenetic (e.g. methylation) profiling

8
Metagene Analysis in NSCLA
Potti et al, NEJM, 2006
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Metagene Analysis in NSCLA
Application of the lung metagene model to refine
the assessment of risk and guide the use of
adjuvant chemotherapy in Stage 1A NSCLC
Potti et al, NEJM, 2006
10
Unique Micro RNA Profile in Lung Cancer Diagnosis
and Prognosis

• miRNAs are small non-coding RNAs which
• play key roles in regulating the translation
• and degradation of mRNAs

• Genetic and epigenetic alteration may
• affect miRNA expression, thereby
• leading to aberrant target gene(s)
• expression in cancers

• Yanaihara et al, Cancer Cell, 2006
• - miRNA profiles of 104 pairs of primary
• lung cancers and corresponding non-
• cancerous lung tissues were analyzed by
• miRNA microarrays
• - 43 miRNAs showed statistical differences

11
Unique Micro RNA Profile in Lung Cancer Diagnosis
and Prognosis

• Yanaihara et al, Cancer Cell, 2006
• - miRNA profiles of 104 pairs of primary
• lung cancers and corresponding non-
• cancerous lung tissues were analyzed by
• miRNA microarrays
• - 43 miRNAs showed statistical differences

• A univariate Cox proportional hazard
• regression model with a global permutation
• test indicated that expression of the miRNAs
• has-mir-155 and has-let-7a-2 was related to
• adenocarcinoma patient outcome

• Lung adenocarcinoma patients with
• either high has-mir-155 or reduced
• has-let-7a-2 expression had poor survival

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Overview of Proteomic Approach
13
Spectra from human normal lung and NSCLC tissues
NL
Relative Intensity
LC





3000
5500
8000
10500
13000
(Mass/Charge)
14
Cluster analysis between Tumor and Normal lung
(82 signals)
15
Kaplan-Meier survival curves based on 15 MS peaks
1.0
Good Prognosis Group
Poor Prognosis Group
0.8
0.6
Survival
0.4
P lt 0.0001
0.2
50
0
Time in Months
0
10
20
30
40
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Grand Serology Pedigreed database
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Clinical Correlations in NSCLC (interim data)
Clinical Correlations in Esophageal Cancer
(interim data)
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Cellular Biomarkers

• Circulating cancer cells (EpCAM cells)
• Endothelial progenitor cells (CD133VEGFR2
  cells)
• Hemangiocytes (CXCR4VEGFR1 myelomonocytic
• precursor cells pro-angiogenic
  pre-metastatic niche)
• Stromal cells (pericytes, myofibroblasts)

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Inflammation Tumor, Ischemia Regenerating
Tissue Hypoxia Wound Healing
Neo-angiogenic Niche
Bone marrow
Bone marrow
Pro
-
angiogeic
Pro
-
angiogeic
Endothelial
Endothelial
hematopoietic
hematopoietic
progenitors
progenitors
stem/progenitor cells
stem/progenitor cells
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Hypothesis
NSCLC is associated with an elevated
hemangiogenic profile, therefore, surgical
removal of primary tumor may normalize this
dysregulation in hemangiogenesis
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Assessment of Hemangiogenic Biomarkers in NSCLC
Schema
EPCs
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HUVEC-Based Functional Angiogenic Scale
5
4
3
2
1
0
0 Well separated HUVECs 1 Cells begin
to migrate and align 2 Visible capillary
tubes no sprouting 3 Sprouting of new
capillary tubes 4 Polygonal structures
begin to form 5 Presence of complex
mesh-like structures
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Functional Angiogenic Scale
24
Circulating CD133VEGFR2 Endothelial Progenitor
Cells
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Plasma SDF-1 Levels
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Predictive Modelling

• Permit risk stratification.
• Customize treatment
• Less extensive surgery
• Rational drug selection
• Monitoring response to therapy.

27
Circulating Hematopoietic Progenitor Cells
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Intraplatelet VEGF-A Levels
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Cancer-Testis Genes are expressed and are markers
of poor outcome in pulmonary adenocarcinoma
Ali O. Gure,CCR 2005