Abstract
Abstract 3512
Background:
CK2 is a highly conserved and constitutively active serine-threonine protein kinase that plays a fundamental role in maintaining cell survival through pro-proliferative, anti-apoptotic and pro-angiogenic signaling. It is comprised of two catalytic (α and α') and two regulatory (β) subunits.
Overexpression and hyperactivation of CK2 has been well described in a variety of human solid tumors, and more recently, in hematologic malignancies including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphocytic leukemia (T-ALL), and multiple myeloma (MM). CK2 is known to support the viability of cancer cells through increased activation of the downstream PI3K/AKT signaling pathway, which results in cell-cycle progression, and suppression of apoptosis. Inhibition of CK2 has been shown to lead to preferential apoptosis of CLL, AML and myeloma cells. Studies have also demonstrated that CK2 inhibition in MM enhances the cytotoxic effect of chemotherapeutic drugs. Therefore, CK2 appears to be a rational target for novel therapies to treat hematologic malignancies.
CX-4945 is a potent and orally bioavailable inhibitor of both isoforms of the CK2 catalytic subunits, and is the first small molecule inhibitor of CK2 to progress to human clinical trials. CX-4945 has been found to be highly selective for CK2 and has also been shown to inhibit phosphorylation of the CK2-specific S129 site of AKT and inhibit activation of the AKT pathway. Anti-tumor activity of CX-4945 has been validated in cancer cell lines and murine xenograft models, and biological activity was observed in early clinical trials with solid tumors and multiple myeloma. However, little is known about its possible effects in leukemias and lymphomas. Therefore, we explored the therapeutic potential of CX-4945 in 224 adult and pediatric patient samples across a wide spectrum of hematologic malignancies including AML, ALL, CLL, CML, CMML and leukemic phase lymphomas.
Methods:
Fresh primary cells from 224 patients were purified using a Ficoll gradient. Purified cells were then added to wells (5 × 104 per well) containing 10% serum containing media and four serial dilutions of CX-4945 (ranging from 10 nM to 10 μM). Three days after culturing cells in the presence or absence of each drug concentration, we performed a tetrazolium-based cell viability assay (MTS) to evaluate the effect of CX-4945 across a broad spectrum of primary hematologic malignancy samples. The viability data were normalized to untreated controls and used to calculate IC50 values.
Results:
Of the 7 categories of hematologic malignancies evaluated, all except for 2 (CMML and CML) demonstrated a subset of patients with significantly decreased viability (IC50 < 1 μM) in response to CX-4945 (Table 1).
Investigations evaluating the effect of CK2 on downstream targets such as AKT and other cellular protein kinases, as well as studies exploring CK2 expression in AML are ongoing and will be presented.
Conclusions:
Our data confirms that CX-4945 demonstrates significant pre-clinical activity across a broad range of hematologic malignancies, and also confirms previous findings that CK2 may play a significant role in the tumorigenesis of certain hematologic malignancies. CX-4945 may be an attractive compound for clinical development, particularly in lymphoid malignancies such as CLL. Future studies will focus on the identification of highly sensitive subsets of cells, further defining the mechanistic details of the CK2 pathway in hematologic malignancies, and exploring the specific features that drive response to CK2 inhibition.
Disclosures:
Druker: Cylene Pharmaceuticals: Consultancy. Loriaux:Cylene Pharmaceuticals: Research Funding.
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