IMMUNOBIOLOGY OF CANCER
Osteosarcoma is a highly malignant tumour of bone and the third most common cancer in the adolescent population. Patients are commonly treated with aggressive surgery and intensive adjuvant chemotherapy that can result in life-long morbidity. The five-year survival for those with metastatic or recurrent disease is less than 25% and has remained unchanged for the last 30 years. The propensity of these tumours to metastasise and limited second-line treatment options requires urgent identification of new treatment strategies.
Tumour-induced immune suppression is a major obstacle in the treatment of many solid tumours. Osteosarcomas are characterised by high levels of chromosomal instability, with few therapeutically targetable mutations. This high level of genomic complexity may be the Achilles’ heel that allows the immune system to clear malignant cells once immune tolerance pathways are disabled.
The focus of our research is to understand how these tumours evade detection by the immune system and ways in which this could be therapeutically targeted. Areas of interest include utilising genomic technologies to investigate molecular sculpting of the tumour by the immune system, the role of inflammatory cytokines, immune checkpoint blockade and chemotherapy induced modification of immune response.
Utilising preclinical models developed in the laboratory we aim to identify treatment strategies, which can be tested rapidly in the clinic. Our overall aim is to target minimal residual disease, where we think immune modulatory strategies will have the greatest effect and identify new treatment options that can increase the survival rate and quality of life for people diagnosed with osteosarcoma.
Kansara M, Teng M, Smyth MJ, Thomas DM. (2014) Translational biology of osteosarcoma Nature Reviews Cancer, 14,722-735
Kansara M & Thomas DM (2014) RB1-mediated cell-autonomous and host-dependent oncosuppressor mechanisms in radiation-induced osteosarcoma. Oncoimmunology Jan 1, 2014,3(1):e27569.
Kansara M, Leong HS, Lin DM, Popkiss S, Pang, P, Garsed DW, Walkley CR, Cullinane C, Ellul J, Haynes NM, Hicks R, Kuijjer ML, Cleton-Jansen AM, Hinds PW, Smyth MJ, Thomas DM (2013). Immune response to RB1-regulated senescence limits radiation induced osteosarcoma formation. J Clinical Investigation 2013, Dec 2013, 123(12);5351.
Etemadmoghadam D, Au-Yeung G, Wall M, Mitchell C, Kansara M, Loehrer E, Batzios C, George J, Ftouni S, Weir BA, Carter SL, Gresshoff I, Mileshkin L, Rischin D, Hahn WC, Waring PM, Getz G, Cullinane C, Campbell LJ, Bowtell DD (2013) Clinical Cancer Research 2013 Sep 4, 1:19(21)5960-71.
Cain JE, McCaw A, Jayasekara WS, Rossello FJ, Marini KD, Irving AT, Kansara M, Thomas DM, Ashley DM, Watkins DN (2013) Sustained low-dose treatment with Histone deacetylase inhibitor LBH589 induces terminal differentiation of osteosarcoma cells, Sarcoma. 2013:608964.
Paget C, Duret H, Ngiow SF, Kansara M, Thomas DM, Smyth MJ Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma (2012) Oncoimmunology. 2012 Nov 1;1(8):1313-1322.
Etemadmoghadam D, George J, Cowin PA, Cullinane C, Kansara M; Australian Ovarian Cancer Study Group, Gorringe KL, Smyth GK, Bowtell DD (2010) Amplicon-dependent CCNE1 expression is critical for clonogenic survival after cisplatin treatment and is correlated with 20q11 gain in ovarian cancer. PLoS One. 2010 Nov 12;5(11):e15498.
Kansara M, Tsang M, Kodjabachian L, Sims NA, Trivett MK, Ehrich M, Dobrovic A, Slavin J, Choong PF, Simmons PJ, Dawid IB, Thomas DM (2009). Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clinical Investigation.2009 Apr;119(4):837-51.
Kansara M, Thomas DM (2007). Molecular pathogenesis of osteosarcoma. DNA and Cell Biology 2Jan;26(1):1-18. (I.P 2.3) Review.
Thomas D, Kansara M.Epigenetic modifications in osteogenic differentiation and transformation (2006). J Cell Biochem. 2006 Jul 1;98(4):757-69.
Cullinane C, Dorow DS, Kansara M, Conus N, Binns D, Hicks RJ, Ashman LK, McArthur GA, Thomas DM (2005) An in vivo tumor model exploiting metabolic response as a biomarker for targeted drug development. Cancer Research. 2005 Nov 1;65(21):9633-6.
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