a biologi molekular gbm
TRANSCRIPT
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Overview
1. Glioblastoma - the most common & lethal form of adultprimary brain tumour
2. What we know about the molecular biology of glioblastoma
3. Targeted therapy of glioblastoma
4. New advances in understanding glioblastoma genetics
5. Research into microRNAs and glioblastoma
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Glioblastoma
Most common & lethal primary brain tumour in adults
Highly resistant to therapy (surgery, radiation therapy &
chemotherapy)
Disease recurrence is common following surgery
Life expectancy of glioblastoma multiforme patients (GBM;
Grade IV) is ~14 months
Urgent need for new treatment options
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What cells make up a tumour?
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Genetic basis of cancer
Cancers originate as the result of hereditary or accumulated
changes (mutations) in genes that control critical processes in
cells
DNA
sequence G A C T A A T C G G Normal gene
G A C T A G T C G G Single base change
G A C T A A C C A T C G G Insertion
G A C T C G G Deletion
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Genetic basis of cancer
Mutations can activate oncogenes or silencetumour suppressor genes
oncogenes
(bad)
tumour suppressor genes
(good)
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Genetic basis of cancer
There is increased or decreased expression of specific genes incancer
Normal cell Cancer cell
Gene A
Gene B
Gene A
Gene B
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The hallmarks of cancer
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How does glioblastoma arise?
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1. Two main pathways by which glioblastomas
develop (primary vs secondary)
2. Primary and secondary glioblastomas can arise viadifferent mutations
3. Mutations between primary or secondary
glioblastomas can differ
Molecular development of glioblastoma
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Increased EGFR expression and
signaling in glioblastoma
normal
cell
growth
glioblastoma
cell
growth
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How can understanding the genetics of cancer
cells (glioblastoma)
help us to develop new treatments for the
disease?
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Targeted cancer therapy
Find & understand mutation/alteration that drives
cancer cell growth (choosing the right target)
Design & develop drug that specifically targets
this mutation/alteration
Normal cells lack the mutation & should be
relatively unaffected; side effects should be minimised
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Gleevec & chronic myelogenous
leukaemia (CML)
(TIME magazine,
May 2001)
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(Tyrosine
kinase
Inhibitor)
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Is there a gleevec forglioblastoma?
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Not yet
There may never be
one drug that works on
all glioblastomas
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Why?
Heterogeneity(no single mutation causes all
glioblastomas)
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Redundancy
(a glioblastoma is not dependent on onemutation; other mutations can
compensate)
growth
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Resistance(by targeting one mutation, new
mutations can arise that allow
glioblastoma cells to escape this targeting)
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Case study of a targetedglioblastoma drug
Erlotinib (Tarceva)
(A small molecule tyrosine kinase inhibitor of
the epidermal growth factor receptor [EGFR])
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Epidermal growth factor receptor
(EGFR) as a therapeutic target in glioblastoma
ERK1/2PI3K/Akt
Tyrosine kinaseinhibitor (erlotinib)
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The rationale for using erlotinib to treat
glioblastoma
About half of glioblastomas have high expression of EGFR
Blocking EGFR should block glioblastoma growth &
invasion
Promising results in other cancer with high expression of
EGFR (eg. lung)
Small molecule tyrosine kinase inhibitor (TKI) - crosses
blood-brain barrier
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Erlotinib and glioblastoma
Unfortunately, few patients (~10-20%) respond to erlotinib
and survival benefit is small
Need to identify what determines whether a patient will
respond/not respond to erlotinib
Combine erlotinib with other treatments (chemotherapy,
other targeted agents, radiation therapy) to improveresponses and increase patient survival
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Mutations downstream of EGFR render glioblastoma cells
resistant to erlotinib
ERK1/2PI3K/Akt
Tyrosine kinaseinhibitor (erlotinib)
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New advances inunderstanding of glioblastoma
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Brain tumour stem cells
Cancer stem cell hypothesis: tumours are dependent on a small population
of cancer stem cells that are distinct from the more abundant tumour cells.
Cancer stem cells are highly resistant to conventional cancer therapies
Express specific cell surface markers (eg. CD133).
Molecular characterisation has identified possible drug targets for brain
tumour stem cells.
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Targeting brain tumour stem cells
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The Cancer Genome Project
Human Genome Project: database of a complete genome of a normal
human
Cancer Genome Project: established in 2006; to characterise >10,000
tumours at a molecular level from at least 20 tumour types (incl.
glioblastoma) by 2015.
Will identify many more mutations responsible for glioblastomas - new
treatment targets?
Made possible by rapid development of high throughput techniques -
researchers can screen millions of DNA bases quickly and cheaply. This has
only been feasible in the last few years.
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The Cancer Genome Project
Some achievements to date in understanding glioblastoma:
(1) Discovery that patients with an unmethylated version of
MGMT gene respond better to temozolomide. Patient selection?
(2) Discovery that a subset of glioblastoma patients that live an
average of three years have different gene mutations to regular
glioblastoma patients. What do these do?
(3) Identification of at least four glioblastoma subtypes, based on
their DNA signatures. Survival, response to aggressive
chemotherapy & radiotherapy differed according to subtype.
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Culture of glioblastoma cell lines in the laboratory
glioblastoma cell line
glioblastoma tumour
Study gene mutations/alterations
Study new treatments
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Summary
Glioblastomas are different & often arise via different mutations.
This might explain why they can respond differently to treatment.
First generation of targeted agents have yielded disappointing
results, but research can explain why this has been the case and
improvements made to future drug design.
Understanding all of the important mutations in glioblastoma (eg.
via large scale research efforts such as the Cancer Genome Project)
should allow the development of new drugs that are effective in
patients with the correct mutation.
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More work is needed
but progress is being made
Ive been treating glioblastoma for about 22 years. Ive
taken care of more than 20,000 patients. The kinds of
things weve seen in the clinic in the last four years
blows away anything I saw in the previous 18 years ofmy career.
Howard Fine, MD - Chief, Neuro-oncology, Centre for Cancer
Research, National National Cancer Institute, commenting in
Jan 2010 on a report estimating that the percentage of
glioblastoma patients who survive two years from diagnosis has
more than tripled in the last five years as a result of new
treatment regimens.
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Glioblastomas arise from glial cells
Glioblastomas are a group of low-grade and high-grade brain tumoursthat originate from glia (Greek for glue)
Normally, glial cells (eg. astrocytes) provide support to neurons (nerve
cells): nutrients, mechanical support, development, immune function
Genetic alterations occur in glial cells glioblastoma