Mature plasma cells comprise the majority of tumor cells in multiple myeloma (MM), but we recently reported that these cells have little to no clonogenic growth potential either in vitro or in vivo. Instead, we found that MM growth was driven by clonally related memory B cells that are capable of recapitulating disease in immunodeficient mice and are relatively resistant to standard anti-MM therapies. These functional properties suggest that these clonotypic B cells are MM cancer stem cells (CSC) and play a central role in disease relapse and progression. However, it is unclear whether our laboratory findings apply to the pathogenesis of the disease since little data exists in MM or any human malignancy that CSCs are actually clinically relevant. Proof that the changes in the frequency and/or persistence of CSCs are associated with clinical outcomes or that the targeting and inhibition of CSCs improves survival rates would provide the strongest evidence for their clinical relevance and promote their further study. To this end, we have developed laboratory assays that are capable of serially quantifying MM CSCs over the course of treatment and our early data suggest that changes in MM CSC frequency are associated with progression free survival. We have also identified MM CSC targeting strategies based on their expression of CD20 and enhanced telomerase activity and have initiated pilot clinical trials utilizing the anti-CD20 antibody rituximab and the novel telomerase inhibitor imetelstat. Although clinical activity was limited in these early phase trials, results from our correlative studies have provided important insights regarding anti-CD20 and telomerase inhibitor based approaches in MM and allowed us to modify these approaches. The overall goal of this project is to determine whether or not MM CSCs are clinically relevant, and we believe that our previous studies now place us in an ideal position to address this question by both correlating their frequency with clinical outcomes and determining the clinical impact of novel CSC-targeting strategies. These findings may have important implications for both MM and the CSC field in general, and we propose to: 1). Examine the relationship between MM CSC frequency and clinical outcomes in patients treated with state of the therapies;2). Determine the effects of B cell directed radioimmunotherapy in MM;and 3). Determine the activity of telomerase inhibition in MM.
Virtually all patients with multiple myeloma will relapse and die from their disease. Our previous findings suggest that cancer stem cells possess functional properties implicating a central role in relapse. Therefore, we will determine whether these cells actually play a clinical role in the disease.
|Lombardi, Lindsey R; Kanakry, Christopher G; Zahurak, Marianna et al. (2016) Therapeutic drug monitoring for either oral or intravenous busulfan when combined with pre- and post-transplantation cyclophosphamide. Leuk Lymphoma 57:666-75|
|Meads, M B; Fang, B; Mathews, L et al. (2016) Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma. Oncogene 35:2723-34|
|Gocke, Christian B; McMillan, Ross; Wang, Qiuju et al. (2016) IQGAP1 Scaffold-MAP Kinase Interactions Enhance Multiple Myeloma Clonogenic Growth and Self-Renewal. Mol Cancer Ther 15:2733-2739|
|Lim, Yiting; Gondek, Lukasz; Li, Li et al. (2015) Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia. Sci Transl Med 7:291ra96|
|Kasamon, Yvette L; BolaÃ±os-Meade, Javier; Prince, Gabrielle T et al. (2015) Outcomes of Nonmyeloablative HLA-Haploidentical Blood or Marrow Transplantation With High-Dose Post-Transplantation Cyclophosphamide in Older Adults. J Clin Oncol 33:3152-61|
|Noonan, Kimberly A; Huff, Carol A; Davis, Janice et al. (2015) Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci Transl Med 7:288ra78|
|Xian, Lingling; Huff, Carol Ann; Resar, Linda M S (2015) IBRUTinib: BRUTe force against bortezomib-resistant myeloma cells. Cell Cycle 14:1349-50|
|Anderson, Kenneth C; Alsina, Melissa; Atanackovic, Djordje et al. (2015) Multiple Myeloma, Version 2.2016: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 13:1398-435|
|McCurdy, Shannon R; Kanakry, Jennifer A; Showel, Margaret M et al. (2015) Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood 125:3024-31|
|Tanno, Toshihiko; Lim, Yiting; Wang, Qiuju et al. (2014) Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells. Blood 123:725-33|
Showing the most recent 10 out of 12 publications