A phase I study of a second generation antisense oligonucleotide to clusterin (OGX-011) in combination with docetaxel: NCIC CTG IND.154

Chi, K. N.; Eisenhauer, E.; Siu, Lillian L.; Hirte, H.; Hotte, Sébastien J.; Chia, Stephen; Knox, Jennifer J.; Guns, Emma S. Tomlinson; Powers, Jean; Gleave, Martin

doi:10.1200/jco.2005.23.16_suppl.3085

Cited by 11 publications

(5 citation statements)

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“…Three representative samples are shown in each group. (52). Three phase II trials of OGX-011 in combination with chemotherapy are now under way in patients with prostate, breast, and lung cancers.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo

Sinnemann²,

Huntsman³

et al. 2005

Molecular Cancer Therapeutics

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Clusterin is a stress-associated cytoprotective chaperone up-regulated by various apoptotic triggers in many cancers and confers treatment resistance when overexpressed. The objectives of this study were to evaluate clusterin expression levels in human breast cancer and to determine whether antisense oligonucleotides or double-stranded small interfering RNAs (siRNA) targeting the clusterin gene enhance apoptosis induced by paclitaxel. Clusterin immunostaining was evaluated in a tissue microarray of 379 spotted breast cancers. The effect of hormone withdrawal, paclitaxel treatment, clusterin antisense oligonucleotide (OGX-011), and siRNA treatments on clusterin expression was examined in MCF-7 and MDA-MB-231 cells. Northern, quantitative real-time PCR, and Western analyses were used to measure change in clusterin mRNA and protein levels. The effect of OGX-011 or siRNA clusterin treatment on chemosensitivity to paclitaxel was done in both cell lines in vitro, whereas the ability of OGX-011 to chemosensitize in vivo was evaluated in athymic mice bearing MCF-7 tumors. Clusterin was expressed in 62.5% of tumors within the tissue microarray. Clusterin expression increased after estrogen withdrawal and paclitaxel treatment in vitro in MCF-7 cells. OGX-011 or siRNA clusterin decreased clusterin levels by >90% in a dose-dependent, sequencespecific manner and significantly enhanced chemosensitivity to paclitaxel in vitro. When combined, OGX-011 or siRNA clusterin reduced the IC 50 by 2-log compared with paclitaxel alone. In vivo administration of OGX-011 enhanced the effects of paclitaxel to significantly delay MCF-7 tumor growth. These data identify clusterin as a valid therapeutic target and provides preclinical proof-ofprinciple to test OGX-011 in multimodality therapies for breast cancer.

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Section: Discussionmentioning

confidence: 99%

Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo

Sinnemann²,

Huntsman³

et al. 2005

Molecular Cancer Therapeutics

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“…Concentrations of OGX-011 associated with preclinical effect were measured in tumor tissue, and 90% suppression in clusterin was achieved at 640 mg dose level. A second phase I trial combined increasing doses of OGX-011 with docetaxel in patients with metastatic breast, non-smallcell lung, and HRPCs established a phase II dose for OGX-011 of 640 mg in combination with weekly or every 3 week docetaxel [36]. Four phase II trials of OGX-011 in combination with chemotherapy are now underway in patients with prostate, breast, and lung cancers.…”

Section: Clusterinmentioning

confidence: 98%

Therapeutic options in advanced prostate cancer: Present and future

Sowery¹,

So²,

Gleave

2007

Curr Urol Rep

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Patients with advanced prostate cancer now have many treatment options available including first- and second-line hormonal therapy, radiotherapy, bisphosphonate therapy with zoledronic acid, and taxane-based chemotherapy. These options now give clinicians an opportunity to offer their patients symptomatic relief and most importantly improve overall survival. This article reviews the current treatment options available for men with advanced prostate cancer. In addition, novel treatment options under development, including calcitriol, immunotherapies, small molecule inhibitors, and nucleotide-based targeted therapy, are discussed.

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“…No dose-limiting toxicities were observed in the trial. A second phase I study was designed to determine recommended dose of OGX-011 in combination with docetaxel (TAXOTERE TM ) in various solid tumours [16,108]. OGX-011 is currently in phase II development for patients with prostate, breast and lung cancers.…”

Section: Newer Molecular Targets Clusterinmentioning

confidence: 99%

Antisense therapy in malignant diseases: status quo and quo vadis?

Tamm

2006

Clinical Science

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Preclinical and clinical studies indicate a role for AS ODNs (antisense oligonucleotides) as therapeutics for malignant diseases. The principle of antisense technology is the sequence-specific binding of an AS ODN to the target mRNA, resulting in a translational arrest. The specificity of hybridization makes antisense strategy attractive to selectively modulate the expression of genes involved in the pathogenesis of malignant diseases. One antisense drug has been approved for local therapy of CMV (cytomegalovirus) retinitis, and a number of AS ODNs are currently being tested in clinical trials, including AS ODN targeting Bcl-2, XIAP (X-linked inhibitor of apoptosis protein) and TGF-beta-2 (transforming growth factor beta-2). AS ODNs are well tolerated and may have therapeutic activity. In particular, an AS ODN to Bcl-2 has been tested in phase III clinical trials in chronic lymphocytic leukaemia, multiple myeloma and malignant melanoma. In this review, therapeutic concepts, clinical studies and new promising molecular targets to treat malignancies with AS ODNs are summarized.

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A phase I study of a second generation antisense oligonucleotide to clusterin (OGX-011) in combination with docetaxel: NCIC CTG IND.154

Cited by 11 publications

References 0 publications

Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo

Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo

Therapeutic options in advanced prostate cancer: Present and future

Antisense therapy in malignant diseases: status quo and quo vadis?

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