The global effort to understand the molecular drivers of cancer is now coming to fruition with the identification of specific genomic events that affect signalling through key oncogenic pathways.
Targeting these pathways is beginning to profoundly change the management of patients with cancer. A key feature of oncogenic signalling is a requirement for cells to grow and proliferate, processes that are intimately linked to protein synthesis and the provision of metabolic substrates for replication of cellular components. Specifically, increases in ribosomal assembly, mRNA translation and glycolysis are key downstream events in many of the most important pathways involved in malignant transformation. However, it is increasingly recognised that tumour heterogeneity both between lesions and within lesions in individual patients and the development of resistance represent fundamental challenges to the attainment of durable responses to targeted therapies. Unravelling the links between oncogenic signalling and their effect on cell biology will be critical to designing new therapeutic approaches and improving patient outcomes.
Targeting key oncogenic events
Our program has been at the forefront of developing therapies that target key oncogenic events in tumourigenesis, including novel approaches identified via our fundamental discoveries in the role of ribosome biogenesis in cancer. Furthermore, we specialise in the use of molecular imaging to characterise tumour heterogeneity in humans. Our aim is to use a diverse range of platforms, including expertise in fundamental cancer cell biology and signalling, preclinical models of human cancer and clinical studies, to better understand the key proteins, signalling pathways and cellular processes required for oncogenic transformation, and how best to target these events to advance the development of novel anti-cancer therapeutics. A major outcome will be defining the effectiveness of antagonising these key processes as first-line therapies and determining whether such antagonism overcomes resistance to targeted treatments.
We specifically hypothesise that:
- Cancer cells transformed by a variety of oncogenes become addicted to deranged ribosome biogenesis and metabolic processes downstream of oncogenic signalling pathways, such as MYC, BRAF, RAS, CDK4 and PI3K/AKT/mTOR, and thus targeting these processes alone or in combination will provide novel therapeutic avenues to treat oncogene-addicted cancer.
- Intrinsic and acquired tumour heterogeneity are critical in the biology of a wide range of tumours and essential in understanding resistance to therapies targeting oncogenes.
- Even when initially sensitive, cancer cells will become resistant to therapies that target oncogenes through genomic and metabolic adaptation, and thus novel strategies to overcome these mechanisms of resistance are required. Our integrated skills in PET imaging, genomic profiling, cell biology and translational platforms will allow us to definitively address these central concepts in cancer biology.
Key collaborative papers
Devlin JR, Hannan KM, Hein N, Cullinane C, Kusnadi E, Ng PY, George AJ, Shortt J, Bywater MJ, Poortinga G, Sanij E, Kang J, Drygin D, O'Brien S, Johnstone RW, McArthur GA, Hannan RD, Pearson RB (2016). Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discov. 6(1):59-70.
Parmenter TJ, Kleinschmidt M, Kinross KM, Bond ST, Li J, Kaadige MR, Rao A, Sheppard KE, Hugo W, Pupo GM, Pearson RB, McGee SL, Long GV, Scolyer RA, Rizos H, Lo RS, Cullinane C, Ayer DE, Ribas A, Johnstone RW, Hicks RJ, McArthur GA (2014). Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. 4(4):423-33.
Wall M, Poortinga G, Stanley KL, Lindemann RK, Bots M, Chan CJ, Bywater MJ, Kinross KM, Astle MV, Waldeck K, Hannan KM, Shortt J, Smyth MJ, Lowe SW, Hannan RD, Pearson RB, Johnstone RW, McArthur GA (2013). The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discov. 3(1):82-95.
Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, Wall M, Cluse L, Drygin D, Anderes K, Huser N, Proffitt C, Bliesath J, Haddach M, Schwaebe MK, Ryckman DM, Rice WG, Schmitt C, Lowe SW, Johnstone RW, Pearson RB, McArthur GA, Hannan RD (2012). Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell. 22(1):51-65.
Kinross KM, Montgomery KG, Kleinschmidt M, Waring P, Ivetac I, Tikoo A, Saad M, Hare L, Roh V, Mantamadiotis T, Sheppard KE, Ryland GL, Campbell IG, Gorringe KL, Christensen JG, Cullinane C, Hicks RJ, Pearson RB, Johnstone RW, McArthur GA, Phillips WA (2012). An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J Clin Invest. 122(2):553-7.