Novel Therapeutic
Approaches in
Neuroblastoma
Duncan Ayers BPharm (Hons.)
MRPharmS MSc (Man.)
Centre for Integrated Genomic Medical
Research
Manchester Interdisciplinary Biocentre
The University of Manchester
Clinical Presentation of NB
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What is Neuroblastoma (NB)?
• Most common solid tumour
presenting in infants
• Usually present in children under 5
years old
• Derived from embryonic neural
crest cells
• Formation of self-regenerating
tumour stem cells
(From http://anrmeeting.org/2002.shtml)
Genetic Events in NB Progress
Normally originates from
the adrenal gland
Painless lump on
abdomen, neck or chest
Metastasis:
bone, spinal cord, occular
region, skin, vena cava
Catecholamine secretion:
tachycardia, raised BP,
sweating
(From
(adapted from Brodeur,
Brodeur, 2003)
http://www.indianpediatrics.net/mar2002/marwww.indianpediatrics.net/mar2002/mar-
308.htm)
Genetic Biomarkers for NB
Biochemical Markers for NB
• Gain at chromosome 17q
• Serum Lactate Dehydrogenase > 1500U/L
•Loss of heterozygosity at chromosome 1p36
•Serum neuronneuron-specific Enolase > 100ng/mL
•Loss of heterozygosity at chromosome
11q1411q14-22
•Serum Ferritin > 142ng/mL
•Near diploid or near tetraploid chromosomal
ploidy
(from Kushner, 2004)
•Urine Vanillyl Mandelic Acid / Homo Vanillic
Acid ratio < 1
(from Kushner, 2004)
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Molecular Biomarkers for NB
Other Biomarkers for NB
• MYCN oncogene amplification
• TrkA & TrkC:
TrkC: low or absent expression
• Age : increased mortality in children over the
age of 12 months
•TrkB:
TrkB: High expression
•Telomerase: Increased activity or high
expression
• Unfavourable Shimada histopathology on
examining NB biopsies
•CD44: Low or absent expression (CD44 is
involved in cell – cell adhesion propetries)
(from Kushner, 2004)
Pitfalls of Conventional
Chemotherapy
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NonNon-specific mode of action across most
tissue types
DoseDose-dependent cumulative adverse
effects (eg. Cisplatin)
(from Kushner, 2004)
Principles of Translational Medicine
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Molecular biology advances lead
to enhanced insight in tumour
aetiology and pathogenesis at
the molecular level
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Discovery of novel key
molecules & receptors which
can be exploited as novel drug
targets
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Such tumourtumour-specific drugs will
have lower adverse effects and
thus not be dose limited
- Dose limitations, thus reduced efficacy
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Resistance emergence to cytotoxic agents
- Multiple cytotoxic agents must be used, with
more distress to patient
List of Novel Therapies for NB
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MYCN oncogene inhibition
Anti – Telomerase strategies
Prevention of tumour angiogenesis
Immunotherrapeutic strategies
Retinoid therapy
Aptamers / RNAi
Induction of apoptosis
MYCN Inhibition Strategies
•http://users.ugent.be/~fspelema/neubla/images
http://users.ugent.be/~fspelema/neubla/images
•http://www.ncl.ac.uk/nicr/assets/photos
http://www.ncl.ac.uk/nicr/assets/photos
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MYCN Inhibition Strategies
MYCN Inhibition Strategies
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Targeting of MYCN gene expression
- gene silencing using RNAi
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Disruption of MYCNMYCN-MAX protein interactions
MYCN
(from Ponzielli et al, 2005)
MAX
NB developmental effects by
gene transcription &
expression
Anti-Telomerase Strategies
Anti-Telomerase Strategies
( adapted from Keith et al, 20002)
(Adapted from Binz et al, 2005)
Anti-Angiogenesis Strategies
Immunotherapeutic Strategies
(adapted from Ribatti et al, 2002)
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Increased
vascularization in NB
tumours, especially
when MYCN
amplification present
Vascular endothelial
growth factor (VEGF)
inhibition using
aptamers
a. Normal MYCN
expression
b. Increased MYCN
expression
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Exploitation of key
molecules in
inflammatory &
immune response
(eg. In antiantiangiogenesis)
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Monoclonal Antibody
therapy (eg. AntiAntidiasialoganglioside 2)
(adapted from: A. Halin et al, 2002; B. Dickerson et al,
2004; C. Borsi et al, 2003)
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Retinoid Therapy
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Aptamer Exploitation
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Effective in controlling
NB proliferation and
enhancing
differentiation
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Bind to retinoic acid
receptors and allow for
control of gene
expression in NB cells
(adapted from Reynolds
et al, 2003)
Aptamers are
synthetically produced
molecules consisting of
single stranded DNA or
RNA
Aptamer applications
include various analytical
and diagnostic
techniques, including
their implementation as
biosensors, or as
antisense sequences for
oncogenes
•www.univie.ac.at/.../
The Future of AntiAnti-NB Therapy...
Induction of Apoptosis (NB 4S Stage)
• Understanding the
mechanisms inducing
apoptosis in NB 4S stage is
essential for new anti – NB
therapies
• Identification and control of
InhibitorInhibitor-ofof-Apoptosis Protein
(IAP) family (eg.survivin, livin)
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Involvement of
pharmacogenetics approach to
drug design
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Creating antianti-cancer drugs
according to their gene
expression profile on target cells
thus avoiding collateral damage
to nonnon-target cells
i.e. Switch OFF only the
oncogenes whilst not
influencing other genes
Studying
abroad isn’
isn’t
boring .... !!
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