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  • Deregulated Wnt signaling either due to pathway mutations or

    2020-02-15

    Deregulated Wnt signaling, either due to pathway mutations or otherwise aberrant pathway activity, is common in CLL [81], [82]. In addition to targets described above, alvocidib also inhibits glycogen synthase kinase 3 (GSK3)-β at higher nanomolar concentrations [37]. Despite intuition and experimental evidence that inhibiting GSK3-β might increase β-catenin–mediated survival signaling according to the canonical Wnt/β-catenin pathway [83], there is at least some evidence that GSK3-β can paradoxically drive cancer, including in leukemia, and that GSK3-β inhibition could be therapeutic [84]. As other known oncogenic drivers like the PI3K-AKT-mTOR axis have also been shown to be required for transcription of pro-apoptotic factors in lymphoid malignancy [85], this line of inquiry—namely, whether inhibition of GSK3-β by alvocidib is helpful or harmful, and how this might change in the context of other concomitant targeted therapy—is worth pursuing. CDK inhibitors have been combined with other novel non-chemotherapy agents. Rational combinations exploiting individual mechanisms of action or non-overlapping toxicities might provide enhanced benefits to patients. Lastly, exploiting what we now know about alvocidib’s mechanisms of action in terms of the mitochondria, we could combine it with another agent possessing anti-tumor activity mediated in some way through the mitochondrion like anti–HLA-DR anderson kpt australia or the anti–Bcl-2 agent navitoclax for synergy or to combat drug resistance [46], [86], [87].
    Summary Ultimately, we may conclude that CDK inhibitors are ineffective as monotherapy for CLL. This does not preclude their use in this disease, however, as they might instead be employed in either a transient fashion, taking advantage of the tumor lysis phenomenon to eliminate residual (or with caution, bulky) disease prior to transplant or the next line of therapy, or in rational combinations with other novel agents as we understand more of cancer cell and resistance biology. The finding that palbociclib is an active adjunct to ibrutinib in mantle cell lymphoma that is primarily resistant to ibrutinib [74] may have important implications for CLL and should be explored further. By extension, the future development of CDK inhibitors for CLL may be guided by our evolving understanding of the roles each CDK plays and how the modulation of CDKs synergizes with other therapeutics at different stages of the cancer’s clinical course.
    Conflicts of interest
    Acknowledgment
    Introduction Hepatocellular carcinoma (HCC) is one of the most prevalent neoplasm and it has become the third leading cause of cancer-related death worldwide (Bray et al., 2018). Since HCC was always diagnosed at advanced stage, five-year survival rate was very poor (Mah and Lee, 2014). Therefore, it is really required to explore the effective biomarker to improve the diagnosis of HCC. It was acknowledged that DNA methylation played a critical role in the progression of HCC by regulating the stabilization of genome and genes expressions (Liu et al., 2014). Furthermore, aberrant DNA methylation could provide additional options for tumor diagnosis (Zhang et al., 2018). Thus, DNA methylation detection could aid in identifying molecular biomarkers that may have potential clinical applications in HCC. Cyclin-dependent kinase-like 2 (CDKL2), located on chromosome 4q21, was classified as the member of the cdc2-related serine/threonine kinase subfamily according to its amino acid sequences similar to the kinase domain (Sassa et al., 2004). It has long been considered to be associated with behavioural and neurological disorders in brain (Milanesi et al., 2005; Gomi et al., 2010). Recently, CDKL2 has been reported to be concerned with neoplastic diseases, such as prostate cancer (Rubicz et al., 2016),breast cancer (Li et al., 2014), as well as HCC (Shen et al., 2012). Moreover, aberrant CDKL2 methylation was detected in HCC by genome-wide DNA methylation analysis, and further validated in few samples (Shen et al., 2015; Zheng et al., 2018). However, the correlations between CDKL2 methylation and clinical implication, mRNA expression remain unclear. Therefore, it is necessary to evaluate the methylation of CDKL2 in a larger cohort of clinical samples and explore its potential clinical implication.