Myeloma Research Group, Division of Blood Cancers
2016. Back row L - R: Dr Jay Hocking, Dr Anna Kalff, Dr Tiffany Khong, Middle row L - R: Mr Sahan Chandrasekara, Prof Andrew Spencer, Dr Ioanna Savvidou, Ms Kelsey Man, Ms Malarmathy Ramachandran, Front row L - R: Ms Maria Papaioannou, Dr Krystal Bergin, Absent: Dr Samar Masoumi Moghaddam, Dr Sridurga Mithraprabhu, Dr Annie Reale, Dr Patricia Walker.
To identify better therapeutic strategies for the treatment of multiple myeloma (MM).
The MRG within the Division of Blood Cancers, ACBD, focuses on the pre-clinical development of novel therapeutic agents for multiple myeloma and the identification of new therapeutic targets through the study of disease resistance and disease progression mechanisms. Recent work has discovered that dysregulation of the NOTCH signaling pathway promotes a more malignant phenotype with features of ‘epithelial to mesenchymal transition’ that may provide a unique therapeutic approach for drug sensitization utilizing NOTCH inhibition. In addition, recent work with small molecule inhibitors targeting HSP90, JAK and MEK have informed the design of in-house clinical trials for relapsed myeloma patients. The group utilizes a wide range of myeloma cell lines, including unique cell lines propagated in-house, and has extensive experience in the procurement of primary myeloma tumour cells for biological studies and drug testing. In vivo studies involve the use of the 5T33 syngeneic murine model of systemic myelomatosis and a recently established human-murine xenograft in NSG mice. The MRG works in close collaboration with the Haematology CRU undertaking focused correlative studies with a particular emphasis on biomarker recognition and development.
Research Focus and Tools
- The role of CD45 and EMT in MM disease progression
- Optimisation of epigenetic modifiers in MM therapy
- RAS-MAPK signalling in MM
- 5T33 and NSG mouse models of MM
- Ex vivo primary MM cell drug evaluation
Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated B-cells characterised by a high level of de novo drug resistance and a remitting relapsing clinical course. The MRG is focused on the mechanisms underlying de novo MM cell drug resistance; the processes that drive acquired drug resistance with disease progression; and, the identification and optimisation of novel therapeutic strategies for MM.
Projects and Opportunities
- Determining the mechanisms of action of de-acetylase inhibitors in MM
- Evaluation of circulating free nucleic acids in myeloma dysregulation and role in MM
- Identification of biomarkers of novel drug responsiveness in MM
- Tumour heterogeneity in MM as a mechanism of drug resistance
- Loss of MM cell CD45 expression as a model of disease progression
- Testing novel drug combinations against primary MM cells and mouse models
- RAS-MAPK signalling in MM
For current project opportunity descriptions please visit our honours page.
Asvadi P, Cuddihy A, Dunn R, Jiang V, Wong M, Khong T, Spencer A. MDX-1097 induces antibody-dependent cellular cytotoxicity against kappa multiple myeloma cells and its activity is augmented by lenalidomide. British Journal of Haematology 2015 May; 169(3).
Scheid C, Reece D, Beksac M, Spencer A, Callander N, Sonneveld P, Kalimi G, Cai C, Shi M, Scott JW, Stewart K. Phase 2 study of dovitinib in patients with relapsed or refractory multiple myeloma with or without t(4;14) translocation. European Journal of Haematology 2015; 95(4); 316-324.
Seggewiss-Bernhardt R, Bargou R, Goh YT, Stewart K, Spencer A, Alegre A, Blade J, Ottman O, Fernandez-ibarra C, Lu H, Pain S, Akimov M, Iyer S. A Phase 1/1B Trial of the HSP90 Inhibitor NVP-AUY922 Monotherapy or in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma. Cancer 2015 March 24. doi: 10.1002/cncr.29339
Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Rollig C, Einsele H, Wu KL, Singhal A, San Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart E, Anderson KC, Richardson P. Elotuzumab therapy for relapsed or refractory multiple myeloma. New England Journal of Medicine 2015; 373(7): 621-631.
Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomized, multicenter, phase 3 trial. Lancet Oncology 2015; 16(16): 1617-1629.
Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, MD,Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht L, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for treatment of patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3 study. Lancet Oncology 2016; 17(1): 27-38.
Lee WTY, Cain JE, Cuddihy A, Johnson J, Dickinson A, Yeung K, Kumar B, Johns TG, Watkins N, Spencer A, St John JC. Mitochondrial DNA plasticity is an essential inducer of tumorigenesis. Cell Death Discovery 2016 (in press).
Levin N. Spencer A, Harrison SJ, Chauhan D, Burrows FJ, Anderson KC, Reich SD, Richardson P, Trikha M. Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients. British Journal of Haematology 2016 (in press).
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Cavo M, Dimopoulos MA, Durie BGM, Anderson KC, Sonneveld P, Miguel JS, Rajkumar SV, Moreau P. Revised International Staging System for Multiple Myeloma: a report from IMWG. Journal of Clinical Oncology 10.1200/JCO.2015.61.2267