Abstract 4292: Parthenolide and structurally related natural products as anti-cancer stem cell agents: A new era in treatment of multiple myeloma

Abstract

Abstract Multiple myeloma (MM) is an incurable plasma cell malignancy where even patients in remission succumb to an inevitable relapse. Pre-clinical testing of emerging therapeutics is hindered by the failure of the standard models to sustain the ex vivo growth of the MM clone. We have recently described a 3-D culture system where the extracellular matrix and cellular compartments of the bone marrow (BM) are reconstructed in vitro, recapitulating the native microenvironment of the human BM where cells occupy distinct niches. Cells from the BM aspirates are grown in a fibronectin, laminin, and collagen rich extracellular matrix designed to reconstruct endosteal and central marrow compartments of the BM (rBM). In the rBM model, the MM undergoes up to 15-fold expansion of malignant cells harboring the clonotypic IgH VDJ. The currently used MM pre-clinical models only target the plasma cells, comprising the bulk of the tumor, leaving the cancer stem cells (CSCs) to repopulate the tumor and trigger the relapse. The localization of non-proliferating, drug resistant CD20+ B cells to the reconstructed endosteum, in contact with N-cadherin and osteocalcin positive osteoblastic cells, suggests the presence of MM-cancer stem cells (MM-CSC) in the endosteal niche of rBM; the niche known to harbor the hematopoietic stem cells. MM-CSCs exhibit tumorigenic and self-renewal potential, measured by their ability to generate clonotypic colonies and differentiate into plasma cells in colony forming unit assays. Thus, the rBM model provides biologically relevant pre-clinical paradigm enabling the evaluation of therapeutic vulnerabilities of all compartments of the MM clone, including the drug-resistant MM-CSC. We have previously demonstrated that melphalan, dexamethasone, vincristine, and bortezomib therapies are not curative because these drugs target CD138+CD56+ MM plasma cells, thus failing to eliminate the MM-CSC. Here we show that parthenolide and structurally related natural product inhibitors of NFkB are potent anti-MM-CSC agents (LC50=5μM), inducing apoptosis in MM-CSCs through the activation of caspases 8 and 3. Combination treatment with conventional chemotherapeutic agents melphalan or bortezomib and parthenolide were cytotoxic and eliminated both the plasma cell burden and the MM-CSC, implying that such combinations may have curative potential. We determined that an analog of parthenolide, 13-(3-trifluoromethyl-phenyl)-parthenolide, has MM-CSC activity (LC50=15μM). The lower cytotoxicity of the fluorinated analog makes it a candidate to be used as an imaging probe. Therefore, we plan to test this compound as a labeling reagent for PET detection of MM-CSCs. This is a first report of an anti-CSC agent in MM, suggesting that parthenolide and its analogs could improve the survival of patients with MM by eliminating the relapse causing MM-CSCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4292.