Walter and Eliza Hall Institute, Victoria
After visiting Phillip Island last year, the Lorne Cancer Conference returned to its spiritual, and now refurbished, home at Lorne. Grey skies kept the lure of the surf at bay and everyone inside the seminar room for three days of presentations, covering an exciting program with a focus on oncogenesis and targeted drug therapies.
The first day featured sessions on apoptosis, tumour suppressors and molecular therapeutics. Highlights included Doug Green’s surprising story of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and its role in protecting cells from caspase independent death. Numerous reports have now shown that cells with inactivated caspase cascades can still die in response to mitochondrial apoptotic signalling. A genetic screen was used to identify GAPDH as the major gene that promoted mitochondrial recovery and cell survival in cells lacking a functional caspase-dependent death mechanism. GAPDH is often over-expressed in cancer, but previously it was assumed to be important only for glycolytic metabolism and was not associated with cell survival. Saul Rosenberg (Abbot Laboratories) presented the development of a new drug, ABT-737, that inhibits members of the anti-apoptotic Bcl-2 family. Along with Jerry Adams (Walter and Eliza Hall Institute), who presented in a later session, Rosenberg described how ABT-737 antagonised Bcl-2 proteins to render tumours more sensitive to chemotherapeutic agents, while exhibiting very low toxicity in normal and cancerous cells. Interestingly, B-cell lymphomas and other tumours associated with translocations involving Bcl-2, underwent apoptosis when treated with the compound alone.
Friday delivered an action-packed program, beginning with a session on cancer epigenetics sponsored by The Cancer Council Australia. One of the major themes of the conference was the genetic regulation of senescence and ageing. David Sinclair (Deptartment of Pathology, Harvard University) gave the first presentation in this session, showing his recent work on SIRT-1, the mammalian homologue of a family of histone deacetylases (HDACs) called sirtuins. Sirtuins are known to prolong the lifespan of simple organisms such as yeast and Drosophila. He presented data showing that mammalian sirtuins, like those in simpler organisms, delay aging by associating and stabilising highly repetitive DNA, but that this association decreases with age – stressing the links between epigenetic silencing by this family of HDACs, genomic instability, and ageing. Robyn Ward (St Vincent’s Hospital, Sydney) presented her findings on the role of epigenetic mutations in hereditary non-polyposis colorectal cancer (HNPCC). HNPCC is a cancer predisposition caused by heterozygous germline mutations of the DNA mismatch repair genes MLH1 or MSH2. Individuals were identified that do not carry mutations in these genes, but instead carried soma-wide monoallelic silencing of MLH1. The clinical outcomes of these individuals demonstrated the monoallelic silencing epimutation is functionally equivalent to heterozygous mutation, but examination of family members demonstrated that the inheritance of the epimutation is weak and may result in complex family histories. Victoria Richon (Merck Research Laboratories, Boston) and Ralf Lindemann (Peter MacCallum Cancer Centre) delivered reports respectively on the progress of clinical trials with HDAC inhibitors and the mechanism by which they engage apoptotic pathways.
Other sessions on Friday focused on the genetic basis of cancer and apoptosis. Gerard Evans (University of California San Francisco) described the use of an oestrogen-receptor regulated p53 protein to investigate the role of p53 in tumour suppression and found evidence that p53’s DNA damage response is separate from its role as a tumour suppressor. Perhaps even more intriguingly, Carlo Croce (Ohio State University) presented work showing the role of microRNA in the development of leukaemia, with microRNA expression being used to predict disease progression in chronic lymphocytic leukaemia. A surprise guest, Anne-Maree Pearse (Tasmanian Department Primary Industry), told the colourful story of the facial tumour disease in Tasmanian devils and described the cytogenetic evidence that suggests it is transmitted as an infectious allograft when the temperamental animals bite each other.
The first plenary session was sponsored by The Cancer Council Australia and was delivered by Charles Sherr (St Jude Children’s Research Hospital, Tennessee), who presented on the ARF tumour suppressor and its role in childhood leukaemia. The BCR-ABL fusion protein is an important initiating event in both acute lymphoid leukaemia (ALL) and chronic myelogenous leukaemia, but only ALL is commonly associated with ARF deletions. Sherr presented a model where BCR-ABL was expressed in pre-B cells from wild type and ARF null mice, showing that the ARF deletion was required for these BCR-ABL expressing cells to induce leukaemia in mice. Additionally, these cells were resistant to treatment with high doses of kinase inhibitors, suggesting that loss of ARF deletions may be important in resistance to Imatinib. ARF does not necessarily need to be deleted in cancer, but can be inactivated by epigenetic silencing or by over expression of specific repressor proteins. Sherr presented evidence that dominant mutations in the ARF binding partner nucleophosmin can trap ARF in the cytoplasm and lead to partial suppression of its tumour suppressor function.
The final day featured sessions on oncogenes, molecular therapeutics and ageing. George Demetri (Dana–Farber Cancer Institute, Boston) delivered an inspiring account of his successful treatment of Gastrointestinal Stromal Tumours (GIST) with Imatinib. Demetri highlighted the importance of PET for functional analysis of cancer treatment and detailed the progress being made in treating Imatinib resistance. In another session on the topic of ageing and cancer, Cynthia Kenyon (University of California San Francisco) described a model for studying the effects of ageing on tumour progression using long lived C. elegans mutants, which spontaneously form germ line tumours.
The Ashley Dunn oration was delivered by Elizabeth Blackburn (University of California San Francisco), who was the first to characterise the telomerase enzyme. Results from her laboratory have shown that downregulating telomerase by RNA interference rapidly induced growth arrest in cancer cells, without requiring uncapping or substantial shortening of the telomeres. In addition, microarray analysis showed that the knockdown of telomerase changed the expression of many genes – including downregulation of genes implicated in metastasis and angiogenesis. Curiously, expression of a dominant-negative mutant telomerase template RNA produced a very different outcome, uncapping telomeres and rapidly inducing apoptosis in cancerous and pre-cancerous human cells. Her work promotes telomerase as a potential target for anti-cancer therapies.
Many thanks and congratulations must be extended to the organisers for assembling such an excellent array of speakers and to the speakers themselves for the high quality of their research and presentation. Thanks must also go to The Cancer Council Australia, the principal sponsor of the Lorne Cancer Conference and for generously sponsoring the first plenary session and the cancer epigenetics session.