Transcript Alleati per un’antropologia positiva Scienza e Vita in

RUOLO DELLA TERAPIA ANTIANGIOGENICA
NEL CARCINOMA MAMMARIO
Indicatori biologici
di risposta
Paolo Marchetti
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Inhibition of Angiogenesis for Anti-Cancer Purposes
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• Angiogenesis is a key process to tumor growth, and a limited
process in healthy adults
• Resistance to anti-angiogenesis drugs is also unlikely to occur,
or at least at a much lower rate than seen with traditional
cytotoxic chemotherapeutics, particularly if the genetically
stable endothelial cells are targeted
• While physiologic angiogenesis is a tightly orchestrated
process that is regulated by a balance of pro- and antiangiogenic factors, tumor angiogenesis is erratic and irregular,
with leaky vessels that are poorly formed
Kristina M. Cook and William D. Figg, CA Cancer J Clin. 2010
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Types of Biomarkers forAntiangiogenic Therapy in Cancer
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• Predictive
• Prognostic
• Pharmacologic
• Response/Resistance
• Safety
• Surrogate
Evidence of Need for Biomarkers:
Variability of Response
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• Same symptoms
• Same findings
• Same disease
• Same drug......
Eric Van Cutsem & Donald McDonald, Prime Oncology 2010
Evidence of Need for Biomarkers:
Variability of Response
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– Same symptoms
– Same findings
– Same disease
• Same drug......
Eric Van Cutsem & Donald McDonald, Prime Oncology 2010
• ...Different effects
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Variability of disease
Drug metabolism
Drug-drug interactions
Noncompliance
Angiogenesis Inhibition
Response Biomarkers
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• The complex molecular pathways that govern
tumor angiogenesis are logical targets for
pharmacological manipulation given the
important role they play in the growth and
development of cancers
• A lack of validated biomarkers and patient
screening restricts our ability to tailor specific
drugs to patient cohorts, and might be seen as
one of the largest barriers to success in
angiogenesis inhibition
Kristina M. Cook and William D. Figg, CA Cancer J Clin. 2010
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Eric Van Cutsem & Donald McDonald, Prime Oncology 2010
Antiangiogenic Biomarkers Are Centered
on VEGF Pathway
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Pathways and mechanisms that can lead
to increased angiogenesis
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Maria Alsina and Coll, 2010
Pathways and mechanisms that can lead
to increased angiogenesis
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Biomarkers:
For the Tumor or for the Agent?
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Biomarkers:
For the Tumor or for the Agent?
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• How and where to look for biomarkers
– Tumor imaging
– Tumor histopathology
– Tumor DNA/RNA/protein expression
– Tumor mutations
– Host polymorphisms
– Blood chemistry, tumor cells, immune cells
– Urine
Eric Van Cutsem & Donald McDonald, Prime Oncology 2010
Key Anti-VEGF Biomarkers
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VEGF
CECs
E-selectin
VEGFR-2
Polymorphisms
CD31
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VCAM-1
MVD
PlGF
bFGF
ICAM
EGF
bFGF, basic fibroblast growth factors; CEC, circulating endothelial cell; EGF, epidermal growth
factor; MVD, microvesseldensity; PlCF, placental growth factor; NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor
Biomarker Complexity:
Primary Tumor vs Metastases
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A Look Forward: What Type of Biomarkers Will
Be Most Useful in Antiangiogenic Therapy?
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• SNPs
• Imaging
• Circulating tumor cells
• Clinical Biomarkers
SNPs in the VEGF Pathway
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Genetic and Proteomic Biomarkers
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A Look Forward: What Type of Biomarkers Will
Be Most Useful in Antiangiogenic Therapy?
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• SNPs
• Imaging (dynamic contrast-enhanced (DCE)-MRI, DCE
perfusion CT, PET):
– Especially useful for the development of new
agents
– Goal: Integrate imaging with molecular markers
– Drawbacks: Must treat patient first; therefore, not
completely predictive
• Circulating tumor cells
• Clinical Biomarkers
A Look Forward: What Type of Biomarkers Will
Be Most Useful in Antiangiogenic Therapy?
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• SNPs
• Imaging
• Circulating tumor cells
•Surrogate marker
•Reflective of vascular biology
•Early data as predictive marker
• Clinical Biomarkers
A Look Forward: What Type of Biomarkers Will
Be Most Useful in Antiangiogenic Therapy?
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• SNPs
• Imaging
•Circulating tumor cells
•Clinical Biomarkers
•Hypertension
Angiogenesis Biomarkers
Key Messages
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• Making progress
• Starting to understand tumor biology
• Clinical need for markers due to increase in
treatment options
• Entering a new era of predictive markers for
antiangiogenic therapy
• Increasing awareness that collaboration is
necessary for marker development
• Integration of marker types key for future
Eric Van Cutsem & Donald McDonald, Prime Oncology 2010
Conclusions
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• The possible role of biomarkers in better selecting patients
who would derive the greatest benefit from the
antiangiogenic therapy has not been taken into account in
approving antiangiogenic drugs for cancer management.
• These biomarkers might be useful for monitoring
angiogenesis, assessing drug activity and distinguishing
between effective and noneffective drugs that predict
clinical outcome and response to therapy, defining the
optimum biological dose, facilitating development of
combination therapies, and rapidly identifying resistance to
treatment.
Maria Alsina and Coll, 2010
Conclusions
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• However, no validated biomarkers of
angiogenic or antiangiogenic activity are
available for routine clinical use
• Advances in this field will facilitate the
integration of biomarkers with functional and
clinical data in the selection of treatment
• It is hoped these prognostic and predictive
factors will be integrated, at some time point,
in the treatment algorithms
Maria Alsina and Coll, 2010
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