Rodger Tiedemann

Research Synopsis

Novel Therapeutics to Overcome Drug Resistance and Cancer Stem Cells in Multiple Myeloma

We are focused on the development of novel therapeutic strategies for multiple myeloma from a comprehensive understanding of myeloma tumor biology and myeloma genomics.

Multiple Myeloma (MM) is a malignancy of differentiated B lymphocytes that accounts for 15% of all hematological cancer and which affects 1 in 200 individuals during their lifetime. Despite advances in treatment MM remains incurable and is over represented in cancer death rates. Every year approximately 1,300 Canadians die of this disease.

The failure to cure MM with conventional therapy has lead us to the discovery of a tumor cell hierarchy within MM and the existence of drug-resistant tumor re-initiating stem cell-like subpopulations. We are currently characterizing and developing in vitro and in vivo models of these drug-resistant MM tumor precursor subpopulations. One of our immediate research goals is to define all essential and potentially 'druggable' survival genes required by drug-resistant MM tumor stem cells. We are attempting to do this by conducting large-scale RNA interference genetic screens in a range of MM cellular models using pooled lentivirus libraries containing 80,000+ shRNA targeting the genome. To capture the genetic heterogeneity of myeloma tumors in our results, we are screening a diverse panel of tumor lines bearing genetic rearrangements and deletions commonly seen in the clinic. Having identified highly vulnerable highly selective Achilles heel targets within MM precursor or stem cells, we shall then seek to develop small molecule or biologic therapeutics against these targets, in order to rationally promote progress towards a cure for this disease.

In a similar fashion, we have previously used smaller scale RNA interference studies, including a 17,000 siRNA screen, to identify critical Achilles heel vulnerabilities within myeloma plasma cells. From these early siRNA screens we have identified G-protein coupled receptor kinase 6 (GRK6) as a tumor-selective drug target in myeloma plasma cells and are currently collaborating with the OICR to develop small molecule inhibitors of this kinase for exploration as novel therapeutics for MM. A variety of lead compounds have been developed and are currently being screened in cell based assays.

Recent Publications

• Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M, Braggio E, Henry T, Zhu YX, Fogle H, Price-Troska T, Ahmann G, Mancini C, Brents LA, Kumar S, Greipp P, Dispenzieri A, Bryant B, Mulligan G, Bruhn L, Barrett M, Valdez R, Trent J, Stewart AK, Carpten J, Bergsagel PL. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007 Aug; 12(2):131-44.
• Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann RE, Valdez R, Palmer SE, Haas SS, Stewart AK, Fonseca R, Kremer R, Cattoretti G, Bergsagel PL. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 2008 Feb; 13(2):167-180.
• Tiedemann RE, Mao X, Shi CX, Zhu YX, Palmer SE, Sebag M, Marler R, Chesi M, Fonseca R, Bergsagel PL, Schimmer A, Stewart AK. I dentification of Kinetin riboside as a repressor of CCND1 and CCND2 with pre-clinical anti-Myeloma activity. JCI 2008 May; 118(5):1750-64.
• Tiedemann RE, Schmidt J, Keats JJ, Shi CX, Mao X, Zhu YX, Schimmer A, Stewart AK. Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF- k B with anti-myeloma activity in vitro and in vivo. Blood 2009 Apr 23;113(17):4027-37.
• Tiedemann RE, Zhu YX, Yin H, Shi CX, Que Q, Basu G, Azorsa D, Giusti K, Perkins L, Fonseca R, Braggio E, Mousses S, Stewart AK. Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid restricted kinase, GRK6. Blood. 2010 Feb 25;115(8):1594-604.
• Zhu YX, Tiedemann R, Shi CX, Yin H, Schmidt J, Bruins L, Keats J, Braggio E, Sereduk C, Mousses S, Stewart AK. RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5. Blood 2011 Apr 7;117(14):3847-57.
• Tiedemann RE, Zhu YX, Schmidt J, Shi CX, Sereduk C, Yin H, Mousses S, Stewart AK. Identification of Molecular Vulnerabilities in Human Multiple Myeloma Cells by RNA Interference Lethality Screening of the Druggable Genome. Cancer Res 2012 Jan; 72(3): 1-12