Update on developmental therapeutics for acute lymphoblastic leukemia

Smith, Malcolm A.

doi:10.1007/s11899-009-0024-3

Cited by 10 publications

(7 citation statements)

References 76 publications

(66 reference statements)

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“…Acute lymphoblastic leukemia (ALL) affects both adults and children (22, 23). Because cure rates have begun to plateau, new classes of therapeutic agents are needed, but these are difficult to evaluate systematically in patients especially in the context of polychemotherapy.…”

Section: Introductionmentioning

confidence: 99%

BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells

et al. 2015

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BH3 mimetic drugs may be useful to treat acute lymphoblastic leukemia (ALL) but the sensitivity of primary tumor cells has not been fully evaluated. Here B-lineage ALL cell cultures derived from a set of primary tumors were studied with respect to sensitivity to the BH3 mimetics ABT-263 and ABT-199 and to Bcl-2 dependence and function. These ALL cells each expressed high levels of Bcl-2 and exhibited great sensitivity to ABT-263 and ABT-199, which induced rapid apoptotic cell death. BH3 profiling indicated that the ALL cultures were Bcl-2 dependent. Co-immunoprecipitation studies revealed a multi-faceted role for Bcl-2 in binding pro-apoptotic partners including Bax, Bak, Bik and Bim. ABT-263 disrupted Bcl-2:Bim interaction in cells. Mcl-1 overexpression rendered ALL cells resistant to ABT-263 and ABT-199 with Mcl-1 assuming the role of Bcl-2 in binding Bim. Freshly isolated pediatric ALL blasts also expressed high levels of Bcl-2 and exhibited high sensitivity to Bcl-2 inhibition by the BH3 mimetic compounds. Overall our results showed that primary ALL cultures were both more sensitive to BH3 mimetics and more uniform in their response than established ALL cell lines which have been evaluated previously. Further, the primary cell model characterized here offers a powerful system for preclinical testing of novel drugs and drug combinations to treat ALL.

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Section: Introductionmentioning

confidence: 99%

BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells

et al. 2015

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“…The requirement of γ-secretase for NOTCH1 activation led to the clinical evaluation of γ-secretase inhibitors (GSIs) for the treatment of T-ALL. Treatment of patients with these inhibitors was unsuccessful because of limited anti-leukemic activity and severe gastrointestinal toxicity [12]. In humans and in animal models, transformation by Notch1 oncogenes blocks T cell development at the immature double-positive (DP) cell stage but not at the mature T cell stages [13], indicating that Notch1 oncogenes may utilize the genetic programs that operate in normal thymic progenitor cells for tumor transformation.…”

Section: Introductionmentioning

confidence: 99%

Modulating the Strength and Threshold of NOTCH Oncogenic Signals by mir-181a-1/b-1

et al. 2012

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Oncogenes, which are essential for tumor initiation, development, and maintenance, are valuable targets for cancer therapy. However, it remains a challenge to effectively inhibit oncogene activity by targeting their downstream pathways without causing significant toxicity to normal tissues. Here we show that deletion of mir-181a-1/b-1 expression inhibits the development of Notch1 oncogene-induced T cell acute lymphoblastic leukemia (T-ALL). mir-181a-1/b-1 controls the strength and threshold of Notch activity in tumorigenesis in part by dampening multiple negative feedback regulators downstream of NOTCH and pre-T cell receptor (TCR) signaling pathways. Importantly, although Notch oncogenes utilize normal thymic progenitor cell genetic programs for tumor transformation, comparative analyses of mir-181a-1/b-1 function in normal thymocyte and tumor development demonstrate that mir-181a-1/b-1 can be specifically targeted to inhibit tumor development with little toxicity to normal development. Finally, we demonstrate that mir-181a-1/b-1, but not mir-181a-2b-2 and mir-181-c/d, controls the development of normal thymic T cells and leukemia cells. Together, these results illustrate that NOTCH oncogene activity in tumor development can be selectively inhibited by targeting the molecular networks controlled by mir-181a-1/b-1.

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“…A tumor immunological approach using humanized therapeutic monoclonal antibodies (mAbs; alemtuzumab, epratuzumab, rituximab, and SAR3419) has improved survival in cases of relapsed or refractory ALL, but only in combination with intensified chemotherapy 18 , 19 , 20 . These facts reinforce the notion that despite deleterious treatment‐related side effects in children treated for cancer, chemotherapy is essential to control disease progression and save lives.…”

Section: Acute Lymphoblastic Leukemia and The Chemotherapy Conundrummentioning

confidence: 98%

Clinical Nanomedicine: A Solution to the Chemotherapy Conundrum in Pediatric Leukemia Therapy

Krishnan

Rajasekaran

2013

Clin Pharmacol Ther

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Although chemotherapy-based treatment of leukemia has tremendously improved survival rates in children, induction of treatment-related side effects is a major concern in clinical oncology. The development of nanotechnology-based drug delivery techniques to target clinically approved anticancer agents specifically to leukemic cells should diminish toxic side effects. This review aims to address the rational design of nanotherapeutics in treating hematologic malignancies with a focus on acute lymphoblastic leukemia (ALL)--the most prominent form of pediatric cancer.

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Update on developmental therapeutics for acute lymphoblastic leukemia

Cited by 10 publications

References 76 publications

BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells

BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells

Modulating the Strength and Threshold of NOTCH Oncogenic Signals by mir-181a-1/b-1

Clinical Nanomedicine: A Solution to the Chemotherapy Conundrum in Pediatric Leukemia Therapy

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