First human dose study evaluating safety and pharmacokinetics of LY2181308, an antisense oligonucleotide designed to inhibit survivin

Talbot, Denis; Davies, J.; Callies, Sophie; Andre, Valérie; Lahn, Michael; Ang, Joo Ern; Bono, Johann S. de; Ranson, Malcolm R

doi:10.1200/jco.2008.26.15_suppl.3518

Cited by 20 publications

(16 citation statements)

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“…Two phase I trials of this compound in combination with docetaxel in advanced solid tumours are ongoing (clinicaltrials.gov ID; NCT00372736 and NCT00357747). A survivin ASO (LY2181308) was also well tolerated in 24 patients with refractory tumours and no grade 3 or 4 toxicities were seen (Talbot et al 2008). A randomised phase II trial of firstline therapy with docetaxel and LY2181308 or placebo in CRPC is in progress (NCT00642018).…”

Section: Inhibitors Of Apoptosis Proteinsmentioning

confidence: 99%

Pathways of chemotherapy resistance in castration-resistant prostate cancer

Mahon¹,

Henshall²,

Sutherland³

et al. 2011

Endocrine-Related Cancer

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Chemotherapy remains the major treatment option for castration-resistant prostate cancer (CRPC) and limited cytotoxic options are available. Inherent chemotherapy resistance occurs in half of all patients and inevitably develops even in those who initially respond. Docetaxel has been the mainstay of therapy for 6 years, providing a small survival benefit at the cost of significant toxicity. Cabazitaxel is a promising second-line agent; however, it is no less toxic, whereas mitoxantrone provides only symptomatic benefit. Multiple cellular pathways involving apoptosis, inflammation, angiogenesis, signalling intermediaries, drug efflux pumps and tubulin are implicated in the development of chemoresistance. A thorough understanding of these pathways is needed to identify biomarkers that predict chemotherapy resistance with the aim to avoid unwarranted toxicities in patients who will not benefit from treatment. Until recently, the search for predictive biomarkers has been disappointing; however, the recent discovery of macrophage inhibitory cytokine 1 as a marker of chemoresistance may herald a new era of biomarker discovery in CRPC. Understanding the interface between this complex array of chemoresistance pathways rather than their study in isolation will be required to effectively predict response and target the late stages of advanced disease. The pre-clinical evidence for these resistance pathways and their progress through clinical trials as therapeutic targets is reviewed in this study.

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Section: Inhibitors Of Apoptosis Proteinsmentioning

confidence: 99%

Pathways of chemotherapy resistance in castration-resistant prostate cancer

Mahon¹,

Henshall²,

Sutherland³

et al. 2011

Endocrine-Related Cancer

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“…Preliminary evidence on the clinical activity of LY2181308 ASO derived from a phase I study in which twenty-four patients with advanced tumors, including breastor colon cancer and melanoma, were treated with three consecutive daily 3-hr intravenous loading doses (750 mg) followed by weekly maintenance doses [113,114]. In these patients, 10 % stable disease was reported.…”

Section: Clinical Application Of Survivin Inhibi-torsmentioning

confidence: 99%

The Role of Survivin for Radiation Oncology: Moving Beyond Apoptosis Inhibition

Rödel

Reichert²,

Sprenger³

et al. 2011

CMC

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Alterations in the expression of apoptosis-related proteins, like the inhibitor of apoptosis (IAP) protein family, display a pivotal pathway by which cancer cells acquire resistance to therapeutic treatment. Among this family, survivin, the smallest and structural unique member, deserves growing attention due to its universal over-expression in human tumors, and its prominent role in disparate networks of cellular division, intracellular signaling and apoptosis. Several preclinical studies have demonstrated that targeting survivin expression by the use of small interfering RNAs, dominant negative mutants, antisense-oligonucleotides and small molecule repressors sensitized tumor cells towards chemotherapy and irradiation and reduced tumor growth potential. Due to these properties, survivin has been proposed as a molecular target for anticancer therapies. Recent studies further revealed that radio-sensitization achieved by survivin inhibition seems to be multifaceted and involves caspase-dependent and caspase-independent mechanisms. In general, an enhanced rate of apoptosis, and pronounced cell cycle arrest have been observed. More recently, a hampered DNA-damage response has been noted, indicating a distinct role of the protein in radiation-induced double strand break repair. These properties were linked to a nuclear import and physical interrelationship with members of the DNA-DSB repair machinery such as phospho-histone H2AX and DNA dependent Protein Kinase (DNA-PKcs). The applicability of survivin-driven strategies in clinical practice is currently under investigation as the first survivin inhibitors successfully entered phase I/II trials. Although these trials do not include radiation therapy at present, survivin inhibitors may represent a novel type of molecular antagonists to improve the effectiveness of radiation therapy or chemoradio-therapy.

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“…[31] Two other smallmolecule transcriptional repressors of survivin (YM155 and EM-1421) have been described. Preliminary activity of YM155, has been noted in Phase 1 trials in prostate cancer and large-cell lymphoma [29,32] and in a Phase 2 trial in patients with non-small-cell lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…[29,30] Direct inhibitors of survivin include gene-therapy approaches and antisense oligonucleotides (AsODNs). Currently, one AsODN (LY2181308 [31] ) and one small-molecule inhibitor (YM155 [29,32,33] ) are being evaluated in early-stage clinical programs in patients with cancer.…”

Section: Introductionmentioning

confidence: 99%

Down-Modulation of Survivin Expression and Inhibition of Tumor Growth In Vivo by EZN-3042, A Locked Nucleic Acid Antisense Oligonucleotide

Sapra

Wang

Bandaru

et al. 2010

Nucleosides, Nucleotides & Nucleic Acids

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Survivin plays an important role in preventing apoptosis and permitting mitosis, and is highly expressed in various human cancers. EZN-3042 is a locked nucleic acid antisense oligonucleotide (LNA-AsODN) against survivin. We report the effects of EZN-3042 in animal models. In a chemical-induced liver regeneration model, treatment with a mouse homolog of EZN-3042 resulted in 80% down-modulation of survivin mRNA. In A549 and Calu-6 lung xenograft models, treatment with EZN-3042 single agent induced 60% down-modulation of survivin mRNA in tumors and 37-45% tumor growth inhibition (TGI). In Calu-6 model, when EZN-3042 was combined with paclitaxel, an 83% TGI was obtained. EZN-3042 is currently being evaluated in a Phase 1 clinical trial as a single agent and in combination with docetaxel.

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First human dose study evaluating safety and pharmacokinetics of LY2181308, an antisense oligonucleotide designed to inhibit survivin

Cited by 20 publications

References 0 publications

Pathways of chemotherapy resistance in castration-resistant prostate cancer

Pathways of chemotherapy resistance in castration-resistant prostate cancer

The Role of Survivin for Radiation Oncology: Moving Beyond Apoptosis Inhibition

Down-Modulation of Survivin Expression and Inhibition of Tumor Growth In Vivo by EZN-3042, A Locked Nucleic Acid Antisense Oligonucleotide

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