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Dr Keith Giles Laboratory for Cancer Medicine, Presentation Transcript
Dr Keith Giles Laboratory for Cancer Medicine, Western Australian Institute for Medical Research, School of Medicine and Pharmacology, University of Western Australia [email_address] Genetics of brain tumours
Overview 1. Glioblastoma - the most common & lethal form of adult primary 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
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
organism organ cell Molecular biology molecules: DNA, RNA, proteins
What cells make up a tumour?
DNA (genes) RNA Protein Structure & function of cells Disease How genes cause disease
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
Genetic basis of cancer Mutations can activate oncogenes or silence tumour suppressor genes oncogenes (bad) tumour suppressor genes (good)
Genetic basis of cancer There is increased or decreased expression of specific genes in cancer Normal cell Cancer cell Gene A Gene B Gene A Gene B
Genetic basis of cancer These changes (mutations) can be studied in the laboratory using sophisticated genetic analysis methods
The hallmarks of cancer
How does glioblastoma arise?
Two main pathways by which glioblastomas develop (primary vs secondary)
Primary and secondary glioblastomas can arise via different mutations
3. Mutations between primary or secondary glioblastomas can differ
Molecular development of glioblastoma
Increased EGFR expression and signaling in glioblastoma normal cell growth glioblastoma cell growth
How can understanding the genetics of cancer cells (glioblastoma) help us to develop new treatments for the disease?
Understand what has “gone wrong” in glioblastoma cells Design a drug to correct what has “ gone wrong”
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
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.
More work is needed but progress is being made… “ I’ve been treating glioblastoma for about 22 years. I’ve taken care of more than 20,000 patients. The kinds of things we’ve seen in the clinic in the last four years blows away anything I saw in the previous 18 years of my 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.
Acknowledgements Rebecca Webster, Priscilla Zhang, Karina Price, Michael Epis, Andrew Barker, Felicity Kalinowski The Leedman Lab Western Australian Institute for Medical Research Terry Johns (Monash), Kerrie McDonald (Lowy), Greg Goodall (Hanson), John Mattick (UQ) Cancer Council WA & Pearl Bethel Allan Research Grant Endowment National Health and Medical Research Council
miRNAs may act as tumour suppressors or oncogenes
miRNAs bind to specific target mRNAs, regulate 1/3 of all genes
One miRNA can have 100’s of mRNA targets
microRNAs block expression of target genes
Glioblastomas arise from glial cells
Glioblastomas are a group of low-grade and high-grade brain tumours that 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