A Report on the Molly and David Bloom Chair in Multiple Myeloma Research at the Princess Margaret Cancer Centre

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1 A Report on the Molly and David Bloom Chair in Multiple Myeloma Research at the Princess Margaret Cancer Centre April 2013

2 Table of Contents 1 Introduction 2 Your Support 3 Thank you 10 The Princess Margaret Cancer Centre and its research arm, Ontario Cancer Institute, have achieved an international reputation as global leaders in the fight against cancer. The Princess Margaret Cancer Centre is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital and Toronto Rehabilitation Institute. All are research hospitals affiliated with the University of Toronto. For more information, please visit thepmcf.ca.

3 Introduction 2 As one of the top 5 cancer research centres in the world, the Princess Margaret Cancer Centre continues to attract and retain the best physicians and researchers. Endowed Chairs allow us to do this by investing in human capital. Over the past few years, Dr. Donna Reece and her team have used funds from the Molly and David Bloom Chair in Multiple Myeloma Research towards improving the outcomes of cancer patients. In this report, Dr. Reece will illustrate how she is conducting Personalized Cancer Medicine, in both clinical and laboratory research, that will spell new hope for individuals at The Princess Margaret, in Canada and around the world. Thank you for your loyalty and commitment to us over the years for this initiative. Donors like you are helping us move one step closer in our goal to Conquer Cancer in our Lifetime. Believe it. Dr. Donna Reece

4 3 Dr. Reece s Update Research supported by the Bloom Chair fosters "bench to bedside" innovation in myeloma therapy. Such research focuses on our ultimate goal: Personalized Cancer Medicine directed against the different subtypes of multiple myeloma. We continue our two-pronged effort, consisting of clinical and basic laboratory research, in our goal to eventually cure this disease. There are two routes to pursue the development of new therapies for multiple myeloma. One involves the selection of our Princess Margaret Cancer Centre Myeloma Clinical Research Program as a site for the investigation of new drugs that have been brought into clinical trials by the pharmaceutical industry. The second, more challenging but more innovative, involves our own development of novel agents that have a solid laboratory basis for efficacy in a not-for-profit academic setting. This in turn requires 3 critical steps: 1) Identification of a potential vulnerable target in the myeloma cell that will cause its death 2) Validation of that target in laboratory models 3) Introduction of the drug into clinical trials for patients with this disease

5 4 1. Clinical Research New Drug Development with the Myeloma Clinical Research Program Our Clinical Research Program (consisting of 13 research nurses and coordinators) continues to evaluate new drugs and treatment approaches in myeloma. In 2012, 32 research trials were ongoing, including nine that were opened last year. These trials span the spectrum of newly diagnosed myeloma, early relapsed myeloma and advanced relapsed myeloma (now often referred to as "double refractory" myeloma as it has progressed through the two most powerful drugs on the market, bortezomib [velcade] and lenalidomide [revlimid]). Eight of these trials have allowed Canadian myeloma patients access to new drugs that are showing clear activity in multiple myeloma and over time will likely be approved by Health Canada (pomalidomide, carfilzomib, ixazomib and elotuzumab). The selection by the pharmaceutical industry of centres to study such drugs is highly competitive, and our Myeloma Program was chosen based on our excellent clinical research infrastructure. As a result, our myeloma patients have had access to these agents several years in advance of commercial availability. Importantly, four other studies also utilized completely new drugs that were developed by pharmaceuticals with novel mechanisms to kill myeloma cells. Again, our Myeloma Program was selected, among many other potential institutions internationally, as a preferred site in which to evaluate them.

6 5 Two of the previously mentioned studies are being spearheaded by the Myeloma Clinical Research Program which will supervise the collaborating sites in Canada and the U.S. The unique classes of drugs used include an FGFR3 inhibitor for t(4;14) myeloma, an AKT inhibitor, a nuclear export inhibitor, and an IGF-1 receptor inhibitor. Correlative lab work to investigate the mechanisms of action for these agents, and to identify biomarkers for response, are underway in the laboratory of Dr. Suzanne Trudel. Dr. Trudel is an Associate Scientist at the Ontario Cancer Institute who performs validation work on potentially effective new drugs and the development of novel agents. She has recently turned her attention to immune therapy for myeloma. The new classes of anti-myeloma drugs have the potential to overcome poor prognostic subtypes of myeloma and "double refractory" myeloma, although further testing is required. Abstracts produced from this research can be found in Appendix 1. Dr. Suzanne Trudel Introduction of National Myeloma Trials managed by The Princess Margaret Myeloma Program A new trend for conducting multicentre myeloma trials is being embraced by our industry partners. These are investigatorinitiated studies in which money is provided by pharmaceuticals, but the actual trial design and conductance are performed by academic centres. Such trials are advantageous because they allow us to drive the scientific questions, with the drugs being provided free of charge. The advantage for industry is that the trials are much less costly than if they were to run them themselves. Our Princess Margaret Cancer Centre Myeloma Clinical Trials Program is the only academic centre with the expertise and personnel to conduct such myeloma trials in Canada. We have designed and successfully completed our first Canadian study of high-risk patients with t(4;14) myeloma throughout 8 centres. Positive results will be presented at the International Myeloma Workshop in Kyoto, Japan in April 2013 and then submitted for publication.

7 6 Our second coast to coast study is about to begin in 10 centres, using a novel stem cell transplant regimen. An important part of this study is the introduction across Canada of two newer tests for monitoring the levels of myeloma in patients - MRD by multiparameter flow cytometry (discussed below) and the HevyLite blood test. A third trial which uses sequential targeted agents (an AKT inhibitor followed by the addition of a MEK inhibitor) is under development. Although we have funding through industry for these studies, shortfalls are possible. If this happens, we will use Bloom Chair funds to be sure they are completed successfully. A poster presentation has resulted from this work. Please see Appendix 1. Proposed Myeloma Diagnostic Program A new initiative, which will be funded by the Bloom Chair, that will be introduced this year is the development of a comprehensive Myeloma Diagnostic Program. We now have access to more sophisticated methods of characterizing the tumour cells of new myeloma patients, in addition to the routine cytogenetic testing that is currently performed at The Princess Margaret using FISH (fluorescence in situ hybridization) to identify known high-risk myeloma: del 17p (p53 deletion), t(4;14), t(14;16) and del 13q. The newer assessments that will be obtained at diagnosis include: 1) Genomic characterization; We are now implementing sophisticated new methods of characterizing tumour cells in new myeloma patients (above image: cytogenetic testing using FISH (fluorescence in situ hybridization) Mutational changes in myeloma cells 2) Identification of patient-specific flow cytometry markers (by multiparameter flow cytometry) that can be used throughout the course of the disease to monitor minimal residual disease (MRD) after therapy; and 3) Tests for cancer-related mutational changes present in myeloma cells

8 7 Currently, the ability to rapidly perform marrow biopsies is limited by space and lack of staff in our Myeloma Clinics. Funds from the Bloom Chair are being earmarked for the creation of a program to obtain marrow quickly in patients suspected of having this disease, as well as to cover the costs of the MRD assay and mutational screens. These tests will allow the application of more individualized treatment approaches for myeloma patients based on the patterns of abnormalities identified by these new and exciting ways to subtype myeloma cells. Myeloma Database Thanks to your generous support, we will be able to obtain patients marrow in a more timely manner Considerable groundwork for the Myeloma Database has been laid this past year, and detailed information fields have been designed. The cost of this enterprise is $140,000 and funds from the Bloom Chair will cover the majority of this ($80,000), with the additional money provided via an institutional grant. This exciting comprehensive program will "go live" later this year, but it is already in a form usable for retrospective analyses to help define risk groups and assess treatment outcomes. Bloom Chair funds cover the salary of our data entry research assistant (Ben Chu), who enters relevant data on all new referrals into our Myeloma Program (approximately 300 per year). Subsequent outcomes with sequential lines of therapy as these patients receive treatment over time is also inputted. Since myeloma patients now routinely live many years, the amount of data generated by our Program has grown substantially. The Bloom Chair assists in funding contract salaries for special projects The Bloom Chair also funds contract salaries for special projects. One upcoming venture will examine the outcome of patients with a high-risk of myeloma, often characterized by the presence of deletion 17p: plasma cell leukemia. (See Appendix 1 for a list of publications resulting from the Myeloma Database.)

9 8 2. Laboratory Research Dr. Rodger Tiedemann is a clinician-scientist with the Ontario Cancer Institute who conducts dedicated bench research in the field of myeloma. Part of Dr. Tiedemann s laboratory start-up costs have been underwritten by the Bloom Chair for him, which currently funds a laboratory technician (Natalie Erdmann) and postdoctoral candidate (Dr. Kim Chan Chung completing maternity leave). His laboratory is involved in the direct development of new drugs for myeloma in an academic setting, outside the pharmaceutical industry, that can be introduced into clinical trials. Highlights of his research include: Dr. Rodger Tiedemann 1. Identification of points of vulnerability in myeloma cell genes (i.e., "Achilles heel" targets), the inhibition of which will lead to their death. To do this, he studies myeloma cell models, including those with deletion 17p (p53 deletion) by conducting large-scale RNA interference genetic screens using pooled lentivirus libraries containing 80,000+ shrna targeting the genome. Once vulnerable targets are found, small molecule drugs against these targets can be constructed. His work so far has identified an Achilles heel target, called G-protein, coupled receptor kinase 6 (GRK6). In order to design a specific drug to inhibit it, he is collaborating with the Medicinal Chemistry Platform at the Ontario Institute of Cancer Research to develop compounds that are suitable for myeloma therapy in humans. Several lead compounds have been found and further studies are ongoing. Natalie Erdmann A paper from Dr. Tiedemann s work in this area entitled, Identification of molecular vulnerabilities in human multiple myeloma cells by RNA interference lethality screening of the druggable genome was published in the journal Cancer Research in 2012.

10 9 2. Identification of mechanisms of drug resistance or "how myeloma cells become resistant to one of the main drugs used in this disease, bortezomib (velcade)." Dr. Tiedemann has found that the transcription factor XBP1 in very immature myeloma cells (progenitor cells) mediates bortezomib resistance. Therefore, these early myeloma progenitor cells must be eradicated in order to cure the disease. The article related to this work, XBP1s-negative tumor B cells and pre-plasmablasts cells mediate therapeutic proteasome inhibitor resistance in multple myeloma, has been submitted for publication. Dr. Tiedemann s team have discovered that myeloma cells become resistant to Bortezomib (velcade)

11 Thank you 10 The Princess Margaret Cancer Centre is developing and implementing new procedures and setting targets for drug development for multiple myeloma patients through Personalized Cancer Medicine. Dr. Reece, and the work that is being undertaken by her team and funded by the Molly and David Bloom Chair in Multiple Myeloma Research, exemplifies this vision. Thank you for the generosity you have shown and your commitment to the cause which will ultimately help our researchers find the next stabilizing drug to assist Multiple Myeloma patients until a cure is found.