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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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Mutations can activate oncogenes or silencetumour suppressor genes

oncogenes

(bad)

tumour suppressor genes

(good)


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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

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