Preclinical Characterization of AEG35156/GEM 640, a Second-Generation Antisense Oligonucleotide Targeting X-Linked Inhibitor of Apoptosis

LaCasse, Eric C.; Cherton-Horvat, Gabriele; Hewitt, Kim; Jerome, Lori; Morris, Stephen; Kandimalla, Ekambar R.; Yu, Dong; Wang, Hui; Wang, Wei; Zhang, Ruiwen; Agrawal, Sudhir; Gillard, John W.; Durkin, Jon P.

doi:10.1158/1078-0432.ccr-06-0608

Cited by 127 publications

(97 citation statements)

References 53 publications

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“…Furthermore, XIAP has been found to be overexpressed in several cancers, and small molecule and antisense approaches to target XIAP are in development (Hu et al, 2003;LaCasse et al, 2006). In addition, dysfunctional mitochondrial-mediated apoptosis, for example due to Bcl-2 or Bcl-X L overexpression (Adams and Cory, 2007;Verdine and Walensky, 2007) or loss of Bax expression (Jansson and Sun, 2002;Kang et al, 2007) is a common occurrence in human cancers.…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

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Section: Discussionmentioning

confidence: 99%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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“…A second approach for targeting XIAP, which is currently in early-phase clinical trials, involves the use of antisense oligonucleotides (33, 38, 41 -43). Specifically, AEG35156 is a second-generation XIAP antisense oligonucleotide that is currently undergoing evaluation as monotherapy, as well as in combination with docetaxel (Taxotere) and other agents, in solid cancers and in leukemia (44). Unlike small interfering RNAs, the antisense oligonucleotide approach seems to have had greater in vivo promise to date, and the results of these trials are eagerly awaited.…”

Section: Discussionmentioning

confidence: 99%

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

Karikari¹,

Roy²,

Tryggestad

et al. 2007

Molecular Cancer Therapeutics

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Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists (''XAntag''; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC 50 in the range of 2 to 5 Mmol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream ''effector'' caspases (caspase-3 and caspase-7) versus the upstream ''initiator'' caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation. [Mol Cancer Ther 2007;6(3):957 -66]

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“…[10][11][12][13][14][15][16] Not only is XIAP overexpressed in cancer, increased XIAP expression has been shown to contribute to apoptosis resistance and conversely, XIAP antagonism sensitizes cancer cells to multiple types of apoptotic stimuli in vitro and in vivo. 13,[17][18][19][20][21][22][23][24][25]28,[32][33][34][35][36][37] These apoptotic stimuli have included various chemotherapeutic agents, ionizing radiation, tumor necrosis factor-related apoptosis-inducing ligand, anoikis induction and immune clearance by cytotoxic lymphocytes. Despite these encouraging reports supporting a role for XIAP in the pathogenesis of cancer, there are data that are difficult to reconcile with the currently known functions of XIAP.…”

Section: Discussionmentioning

confidence: 99%

“…13,[17][18][19][20][21][22] Furthermore, antagonism of XIAP has been reported to have antitumor activity in a number of models, including prostate cancer. 21,[23][24][25] Consistent with an antiapoptotic role, high levels of XIAP have an adverse prognosis in certain cancers. 14,15 However, there was an unexpected favorable prognosis seen in prostate and non-small cell lung cancers with high levels of XIAP expression.…”

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confidence: 99%

X-linked inhibitor of apoptosis deficiency in the TRAMP mouse prostate cancer model

et al. 2008

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Deregulation of apoptotic pathways plays a central role in cancer pathogenesis. X-linked inhibitor of apoptosis protein (XIAP), is an antiapoptotic molecule, whose elevated expression has been observed in tumor specimens from patients with prostate carcinoma. Studies in human cancer cell culture models and xenograft tumor models have demonstrated that loss of XIAP sensitizes cancer cells to apoptotic stimuli and abrogates tumor growth. In view of these findings, XIAP represents an attractive antiapoptotic therapeutic target for prostate cancer. To examine the role of XIAP in an immunocompetent mouse cancer model, we have generated transgenic adenocarcinoma of the mouse prostate (TRAMP) mice that lack XIAP. We did not observe a protective effect of Xiap deficiency in TRAMP mice as measured by tumor onset and overall survival. In fact, there was an unexpected trend toward more aggressive disease in the Xiap-deficient mice. These findings suggest that alternative mechanisms of apoptosis resistance are playing a significant oncogenic role in the setting of Xiap deficiency. Our study has implications for XIAP-targeting therapies currently in development. Greater understanding of these mechanisms will aid in combating resistance to XIAP-targeting treatment, in addition to optimizing selection of patients who are most likely to respond to such treatment. Cell Death and Differentiation (2008) Apoptosis is a process of cell death that is tightly regulated by a cadre of both pro-and antiapoptotic proteins. In contrast to healthy cells, a hallmark of cancerous cells is the acquired capacity to evade this process of programmed cell death. 1,2 The acquisition of genetic lesions leading to oncogene activation normally triggers a program of apoptosis or senescence. Additionally, the tumor microenvironment often exposes malignant cells to apoptotic stimuli, such as hypoxia or activation of death receptors. Thus, suppression of the pathway leading to cell death has been suggested as a necessarily early event in the development of neoplasia.Execution of the apoptotic cell death process is carried out by caspases, a family of cysteine aspartate proteases. 3,4 During apoptosis, loss of mitochondrial integrity or engagement of death receptors leads to the activation of initiator caspase-9 or -8, respectively. In either case, the initiator caspases cleave and activate effector caspases, including caspase-3 or -7. The cascade of caspase cleavage is regulated by X-linked inhibitor of apoptosis protein (XIAP). XIAP belongs to the IAP family, characterized by containing at least one zinc-binding baculovirus IAP repeat. 5 The only member of the IAP family that potently inhibits caspase activity, XIAP has been demonstrated to directly inhibit caspases-3, -7 and -9, blocking both intrinsic and extrinsic apoptotic signals. 6 Given its role in apoptosis, there has been much interest in understanding the role of XIAP in cancer and evaluating XIAP as a therapeutic target. [7][8][9] XIAP overexpression has been reported in a variety of human ca...

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Preclinical Characterization of AEG35156/GEM 640, a Second-Generation Antisense Oligonucleotide Targeting X-Linked Inhibitor of Apoptosis

Cited by 127 publications

References 53 publications

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

X-linked inhibitor of apoptosis deficiency in the TRAMP mouse prostate cancer model

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