XIAP antisense therapy with AEG 35156 in acute myeloid leukemia

Katragadda, Lakshmikanth; Carter, Bing Z.; Borthakur, Gautam

doi:10.1517/13543784.2013.789498

Cited by 15 publications

(11 citation statements)

References 56 publications

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“…Administration of AEG35156 was correlated with decrease in XIAP mRNA and protein levels and induction of apoptosis in CD34 + 38 − AML stem cells [129,130]. However, a subsequent randomized phase II study of AEG35156 in combination with re-induction chemotherapy with cytarabine and idarubicin in AML showed no improvement in remission rate compared to treatment with cytarabine and idarubicin alone and the study was terminated early due to lack of benefit [131,132]. There are currently no active trials with AEG35156.…”

Section: Targeting the Apoptosis Pathwaymentioning

confidence: 99%

Targeting the apoptosis pathway in hematologic malignancies

Zaman¹,

Wang²,

Gandhi³

2014

Leukemia & Lymphoma

182

146

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Apoptosis is a cell death program that is well-orchestrated for normal tissue homeostasis and for removal of damaged, old, or infected cells. It is regulated by intrinsic and extrinsic pathways. The intrinsic pathway responds to signals such as ultraviolet radiation or DNA damage and activates “executioner” caspases through a mitochondria-dependent pathway. The extrinsic pathway is activated by death signals induced, for example, by an infection that activates the immune system or receptor-mediated pathways. The extrinsic pathway signals also cascade down to executioner caspases that cleave target proteins and lead to cell death. Strict control of cellular apoptosis is important for the hematopoietic system as it has a high turnover rate. However, the apoptosis program is often deregulated in hematologic malignancies leading to the accumulation of malignant cells. Therefore, apoptosis pathways have been identified for development of anticancer therapeutics. We review here the proteins that have been targeted for anticancer drug development in hematologic malignancies. These include BCL-2 family proteins, death ligands and receptors, inhibitor of apoptosis family proteins, and caspases. Except for caspase activators, drugs that target each of these classes of proteins have advanced into clinical trials.

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Section: Targeting the Apoptosis Pathwaymentioning

confidence: 99%

Targeting the apoptosis pathway in hematologic malignancies

Zaman¹,

Wang²,

Gandhi³

2014

Leukemia & Lymphoma

182

146

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“…It induced a decrease of XIAP expression in tumor cell lines and tumor xenograft models, and sensitized cells to various standard chemotherapeutic agents and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) receptor agonists 86. AEG35156 entered into clinical trials (http://www.clinicaltrials.gov/) in 2005, and to date, ten Phase 1,2, or 1/2 clinical trials have been completed in solid tumors and in acute myeloid leukemia (AML) (Table 2) (for review,86,87). In the trials, AEG35156 appeared to accumulate in the liver and to have efficiently downregulated XIAP messenger ribonucleic acid (mRNA) in peripheral blood mononuclear cells and hepatocytes.…”

Section: Targeting Iaps In Cancer Therapymentioning

confidence: 99%

IAP proteins as targets for drug development in oncology

Dubrez¹,

Berthelet²,

Glorian³

2013

OTT

107

124

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The inhibitors of apoptosis (IAPs) constitute a family of proteins involved in the regulation of various cellular processes, including cell death, immune and inflammatory responses, cell proliferation, cell differentiation, and cell motility. There is accumulating evidence supporting IAP-targeting in tumors: IAPs regulate various cellular processes that contribute to tumor development, such as cell death, cell proliferation, and cell migration; their expression is increased in a number of human tumor samples, and IAP overexpression has been correlated with tumor growth, and poor prognosis or low response to treatment; and IAP expression can be rapidly induced in response to chemotherapy or radiotherapy because of the presence of an internal ribosome entry site (IRES)-dependent mechanism of translation initiation, which could contribute to resistance to antitumor therapy. The development of IAP antagonists is an important challenge and was subject to intense research over the past decade. Six molecules are currently in clinical trials. This review focuses on the role of IAPs in tumors and the development of IAP-targeting molecules for anticancer therapy.

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“…FC1008, a neutralizing antibody that bind all isoforms of TGF-b, is undergoing a Phase I/II clinical trial to treat breast cancer and pleural mesothelioma [76]. Antisense inhibition of oncogene expression provides a potential therapeutic platform for treatment of several malignancies [77]. Specifically for prostate cancer, an antisense oligonucleotide targeting TGF-b1, AP11014, decreases TGF-b1 secretion by prostate cancer cells [74].…”

Section: Targeting Value Of Tgf-b Mechanisms In Prostate Tumor Progrementioning

confidence: 99%