Reduction in serum clusterin is a potential therapeutic biomarker in patients with castration-resistant prostate cancer treated with custirsen

Elevated levels of clusterin (CLU), a stress‐induced and secreted cytoprotective chaperone, are associated with advanced tumor stage, metastasis, treatment resistance, and adverse outcome in several cancers. Custirsen, a second‐generation antisense oligonucleotide, inhibits CLU production in tumor cells and reduces serum CLU levels. A Phase 2 study evaluated custirsen in combination with second‐line chemotherapy in men with metastatic castration‐resistant prostate cancer (mCRPC) who had progressed while on or within 6 months of first‐line docetaxel‐based chemotherapy. Exploratory analyses evaluated serum CLU levels during custirsen treatment and correlative clinical effects on prostate‐specific antigen (PSA) response, overall survival, and any relationship between serum CLU and PSA. Men with mCRPC were treated with mitoxantrone/prednisone/custirsen (MPC, n = 22) or docetaxel retreatment/prednisone/custirsen (DPC plus DPC‐Assigned, n = 45) in an open‐label, multicenter study. Subject‐specific profiles of PSA and serum CLU levels during treatment were characterized using statistical modeling to compute subject‐specific summary measures; these measures were analyzed for relationship to survival using proportional hazard regression. Estimated individual serum CLU response profiles were scored as below or at/above the median level for the population through 100 days postrandomization. Median survival was longer for subjects scoring below the median serum CLU level compared with subjects at/above the median level, respectively (MPC: 15.1 months vs. 6.2 months; DPC‐Pooled: 17.0 months vs. 12.1 months). Lowered serum CLU levels during custirsen treatment when in combination with either chemotherapy regimen were predictive of longer survival in mCRPC. These results support further evaluation of serum CLU as a therapeutic biomarker.

[1]  M. Gleave,et al.  Phase I/II Trial of Custirsen (OGX-011), an Inhibitor of Clusterin, in Combination with a Gemcitabine and Platinum Regimen in Patients with Previously Untreated Advanced Non-small Cell Lung Cancer , 2012, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[2]  H. Miyake,et al.  544 Serum level of clusterin and its density in men with prostate cancer as novel biomarkers reflecting disease extension , 2012 .

[3]  M. Gleave,et al.  Randomized Phase II Trial of Custirsen (OGX-011) in Combination with Docetaxel or Mitoxantrone as Second-line Therapy in Patients with Metastatic Castrate-Resistant Prostate Cancer Progressing after First-line Docetaxel: CUOG Trial P-06c , 2011, Clinical Cancer Research.

[4]  S. Ekici,et al.  Clusterin Immunoreactivity as a Predictive Factor for Progression of Non-Muscle-Invasive Bladder Carcinoma , 2010, Urologia Internationalis.

[5]  I. Tannock,et al.  Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  M. Tenniswood,et al.  Effects of clusterin over-expression on metastatic progression and therapy in breast cancer , 2010, BMC Cancer.

[7]  O. Elashry,et al.  Clusterin as a Diagnostic and Prognostic Marker for Transitional Cell Carcinoma of the Bladder , 2010, Pathology & Oncology Research.

[8]  M. Gleave,et al.  Clusterin Facilitates COMMD1 and I-κB Degradation to Enhance NF-κB Activity in Prostate Cancer Cells , 2010, Molecular Cancer Research.

[9]  D. Xie,et al.  Overexpression of Clusterin in Ovarian Cancer is Correlated With Impaired Survival , 2009, International Journal of Gynecologic Cancer.

[10]  T. Xue,et al.  Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer , 2009, International journal of cancer.

[11]  M. Gleave,et al.  Chemosensitization of gemcitabine‐resistant human bladder cancer cell line both in vitro and in vivo using antisense oligonucleotide targeting the anti‐apoptotic gene, clusterin , 2009, BJU international.

[12]  L. Margaritis,et al.  Intracellular Clusterin Inhibits Mitochondrial Apoptosis by Suppressing p53-Activating Stress Signals and Stabilizing the Cytosolic Ku70-Bax Protein Complex , 2009, Clinical Cancer Research.

[13]  M. Gleave,et al.  Clusterin knockdown using the antisense oligonucleotide OGX‐011 re‐sensitizes docetaxel‐refractory prostate cancer PC‐3 cells to chemotherapy , 2008, BJU international.

[14]  J. Closset,et al.  Clusterin Activates Survival through the Phosphatidylinositol 3-Kinase/Akt Pathway* , 2008, Journal of Biological Chemistry.

[15]  J. Jeon,et al.  Clusterin, a novel modulator of TGF-β signaling, is involved in Smad2/3 stability , 2008 .

[16]  M. Gleave,et al.  A Phase I Study of OGX-011, a 2′-Methoxyethyl Phosphorothioate Antisense to Clusterin, in Combination with Docetaxel in Patients with Advanced Cancer , 2008, Clinical Cancer Research.

[17]  C. Dobson,et al.  The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with prefibrillar structures , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  D. Michel,et al.  Stress‐Induced Retrotranslocation of Clusterin/ApoJ into the Cytosol , 2007, Traffic.

[19]  C. Tangen,et al.  Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. , 2006, Journal of the National Cancer Institute.

[20]  D. Michel,et al.  Up-regulation of the clusterin gene after proteotoxic stress: implication of HSF1-HSF2 heterocomplexes. , 2006, The Biochemical journal.

[21]  M. Gleave,et al.  Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo , 2005, Molecular Cancer Therapeutics.

[22]  M. Gleave,et al.  A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. , 2005, Journal of the National Cancer Institute.

[23]  R. Taichman,et al.  Clusterin inhibits apoptosis by interacting with activated Bax , 2005, Nature Cell Biology.

[24]  H. Pehamberger,et al.  Clusterin regulates drug-resistance in melanoma cells. , 2005, The Journal of investigative dermatology.

[25]  M. Gleave,et al.  Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. , 2004, Molecular cancer therapeutics.

[26]  G. Hart,et al.  Glycobiology and Cancer: Meeting Summary and Future Directions , 2004, Cancer biology & therapy.

[27]  P. Kantoff,et al.  Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  M. Gleave,et al.  Enhanced radiation sensitivity in prostate cancer by inhibition of the cell survival protein clusterin. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[29]  M. Gleave,et al.  Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy , 2002, The Prostate.

[30]  H. Miyake,et al.  Over expression of clusterin is an independent prognostic factor for nonpapillary renal cell carcinoma. , 2002, The Journal of urology.

[31]  H. Miyake,et al.  Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  M. Gleave,et al.  Antitumor activity of antisense clusterin oligonucleotides is improved in vitro and in vivo by incorporation of 2'-O-(2-methoxy)ethyl chemistry. , 2001, The Journal of pharmacology and experimental therapeutics.

[33]  H. Miyake,et al.  Acquisition of chemoresistant phenotype by overexpression of the antiapoptotic gene testosterone-repressed prostate message-2 in prostate cancer xenograft models. , 2000, Cancer research.

[34]  S Senn,et al.  Repeated measures in clinical trials: simple strategies for analysis using summary measures. , 2000, Statistics in medicine.

[35]  M. Gleave,et al.  Chemosensitization and delayed androgen-independent recurrence of prostate cancer with the use of antisense Bcl-2 oligodeoxynucleotides. , 2000, Journal of the National Cancer Institute.

[36]  J. Carver,et al.  Clusterin Has Chaperone-like Activity Similar to That of Small Heat Shock Proteins* , 1999, The Journal of Biological Chemistry.

[37]  George E. P. Box,et al.  Empirical Model‐Building and Response Surfaces , 1988 .

[38]  J R Anderson,et al.  Analysis of survival by tumor response. , 1983, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  J. Jeon,et al.  Clusterin, a novel modulator of TGF-beta signaling, is involved in Smad2/3 stability. , 2008, Biochemical and biophysical research communications.

[40]  M. Gleave,et al.  Chemosensitization of human renal cell cancer using antisense oligonucleotides targeting the antiapoptotic gene clusterin. , 2001, Neoplasia.

[41]  H. Miyake,et al.  Acquisition of resistance to Fas-mediated apoptosis by overexpression of clusterin in human renal-cell carcinoma cells. , 2001, Molecular urology.

[42]  H. Miyake,et al.  Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. , 2000, Cancer research.