A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6

Cornell University, Итак, New York, United States
Cancer Research (Impact Factor: 9.33). 09/2006; 66(15):7661-7. DOI: 10.1158/0008-5472.CAN-06-1098
Source: PubMed


Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G(1) arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers.

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Available from: Scott Ely, Jan 08, 2015
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    • "Cell cycle regulators, such as cyclin-dependent kinases (CDKs), are appealing targets for MM therapy given the increased proliferative rates of tumor cells in advanced versus early stages of MM [47]. Specific inhibition of CDK4/6 by PD-0332991, an orally bioavailable small-molecule CDK inhibitor, has demonstrated only growth arrest in MM cells [48], suggesting that selective CDK inhibition may not be sufficient for inducing MM cell death. Rather, effective MM cytotoxicity may be best achieved when multiple CDKs are inhibited concurrently, as demonstrated in preclinical studies with multitargeted CDK inhibitors, such as seliciclib [49] and LCQ195 [50]. "
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    ABSTRACT: Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.
    04/2014; 2014(1):976567. DOI:10.1155/2014/976567
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    • "Gene expression studies have shown that the overexpression of CCND3 and CCND1 results in a clustering of downstream gene expression suggesting that activation of these two genes results in the deregulation of common downstream transcriptional events [27]. Due to the seeming importance of cyclin D gene deregulation in myeloma, cyclin D inhibitors with a variety of specificities have shown promise targeting myeloma in vitro [40] [41], with many of these inhibitors now entering early human trials. Unlike í µí±¡(4; 14), the overall prognostic impact of these two translocations is neutral [42], although í µí±¡(11; 14) patients do show considerable heterogeneity and in some instances the translocation may manifest with an aggressive phenotype such as PCL. "
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    ABSTRACT: Multiple myeloma is a malignant proliferation of monoclonal plasma cells leading to clinical features that include hypercalcaemia, renal dysfunction, anaemia, and bone disease (frequently referred to by the acronym CRAB) which represent evidence of end organ failure. Recent evidence has revealed myeloma to be a highly heterogeneous disease composed of multiple molecularly-defined subtypes each with varying clinicopathological features and disease outcomes. The major division within myeloma is between hyperdiploid and nonhyperdiploid subtypes. In this division, hyperdiploid myeloma is characterised by trisomies of certain odd numbered chromosomes, namely, 3, 5, 7, 9, 11, 15, 19, and 21 whereas nonhyperdiploid myeloma is characterised by translocations of the immunoglobulin heavy chain alleles at chromosome 14q32 with various partner chromosomes, the most important of which being 4, 6, 11, 16, and 20. Hyperdiploid and nonhyperdiploid changes appear to represent early or even initiating mutagenic events that are subsequently followed by secondary aberrations including copy number abnormalities, additional translocations, mutations, and epigenetic modifications which lead to plasma cell immortalisation and disease progression. The following review provides a comprehensive coverage of the genetic and epigenetic events contributing to the initiation and progression of multiple myeloma and where possible these abnormalities have been linked to disease prognosis.
    Advances in Hematology 04/2014; 2014(6):864058. DOI:10.1155/2014/864058
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    • "Similarly to other malignancies [8], virtually any innovative treatment for MM requires a pre-clinical assessment, which largely relies on the use of animal models to evaluate the anti-tumor potential and possible toxicities [9-12]. To this goal, sub-lethally irradiated immunodeficient NOD/SCID mice have been extensively used since they allow for human MM cell line xenografting after intravenous injection [13-23]. More recently, it has been shown that NOD/SCID mice carrying nonfunctional IL-2 receptor gamma chain (NOD/SCID/γcnull, NOG) are more permissive recipients than NOD/SCID and can be easily xenografted with human MM cell lines to produce a disease similar to that seen in patients, including multiple metastatic sites and bone lesions [24,25]. "
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    ABSTRACT: Multiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors. Continuous efforts are being made to develop innovative and more effective treatments. The preclinical evaluation of new therapies relies on the use of murine models of the disease. Here we describe a new MM animal model in NOD-Rag1null IL2rgnull (NRG) mice that supports the engraftment of cell lines and primary MM cells that can be tracked with the tumor antigen, AKAP-4. Human MM cell lines, U266 and H929, and primary MM cells were successfully engrafted in NRG mice after intravenous administration, and were found in the bone marrow, blood and spleen of tumor-challenged animals. The AKAP-4 expression pattern was similar to that of known MM markers, such as paraproteins, CD38 and CD45. We developed for the first time a murine model allowing for the growth of both MM cell lines and primary cells in multifocal sites, thus mimicking the disease seen in patients. Additionally, we validated the use of AKAP-4 antigen to track tumor growth in vivo and to specifically identify MM cells in mouse tissues. We expect that our model will significantly improve the pre-clinical evaluation of new anti-myeloma therapies.
    BMC Cancer 09/2011; 11(1):394. DOI:10.1186/1471-2407-11-394 · 3.36 Impact Factor
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