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Therapeutic Utility of Proteasome Inhibitors for Acute Leukemia

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Book cover New Agents for the Treatment of Acute Lymphoblastic Leukemia

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Abstract

The proteasome inhibitors have emerged as a new and promising class of cancer therapeutics for hematological malignanices. In multiple myeloma and mantle cell lymphoma, bortezomib is the first-in-class proteasome inhibitor to be approved by the US Food and Drug Administration for treatment of these malignancies. In vitro and in vivo data are suggestive of the utility of proteasome inhibitors for acute leukemias and importantly, a Phase-I clinical trial in adult leukemia patients demonstrated biological activity (Cortes et al., Clin Cancer Res. 10:3371-3376, 2004). Here, we describe the rationale for targeting the proteasome, the molecular pharmacology of the proteasome inhibitors and summarize results from clinical trials using proteasome inhibitors as single agents and as a component of multidrug combination therapies. In acute lymphoblastic leukemia (ALL) patients with refractory disease and poor outcomes, the proteasome inhibitors represent an untapped therapeutic resource. Since low doses of proteasome inhibitors display striking synergy with low doses of other agents such as epigenetically targeted drugs (Miller et al. (Blood. 110:267-277, 2007) (Blood. 113(18):4289-4299, 2009)), these investigations hold promise for pediatric and young adult patients, where long-term toxicities and late effects could be minimized by optimizing the use of this class of drugs.

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Authors and Affiliations

  1. Department of Pediatrics Research, Children’s Cancer Hospital at M.D. Anderson, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Joya Chandra

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  1. Joya Chandra
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  2. Claudia P. Miller
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Correspondence to Joya Chandra .

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  1. Christie Hospital, Dept. Paediatric & Adolescent Oncology, University of Manchester, Manchester, M20 4BX, United Kingdom

    Vaskar Saha

  2. , School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom

    Pamela Kearns

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Chandra, J., Miller, C.P. (2011). Therapeutic Utility of Proteasome Inhibitors for Acute Leukemia. In: Saha, V., Kearns, P. (eds) New Agents for the Treatment of Acute Lymphoblastic Leukemia. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-8459-3_13

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