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Potential use of custirsen to treat prostate cancer.

ABSTRACT: Over the last few years, five agents have demonstrated a survival benefit over a comparator treatment or placebo in the treatment of metastatic castration-resistant prostate cancer and have been approved by the US Food and Drug Administration: sipuleucel-T (a dendritic cell immunotherapy); cabazitaxel; abiraterone acetate and enzalutamide (both hormonal agents); and radium 223 (an alpha emitter). The development of these agents pivoted on whether patients had been treated with docetaxel, which remains the first-line chemotherapy of choice. To date, no combination of docetaxel and another active agent has demonstrated superiority to docetaxel alone despite numerous Phase III trials. Clusterin is a cytoprotective chaperone protein that is upregulated in response to various anticancer therapies. When overexpressed, clusterin interferes with apoptotic signaling, thereby promoting cell survival and conferring broad-spectrum resistance in cancer cell lines. Custirsen (OGX-011) is a second-generation 2'-methoxyethyl modified phosphorothioate antisense oligonucleotide that inhibits expression of clusterin. This review presents the preclinical and clinical data that provided the rationale for the combination of custirsen with chemotherapy in ongoing Phase III trials.

SUBMITTER: Higano CS

PROVIDER: S-EPMC3699352 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Potential use of custirsen to treat prostate cancer.

Higano Celestia S CS

OncoTargets and therapy 20130625

Over the last few years, five agents have demonstrated a survival benefit over a comparator treatment or placebo in the treatment of metastatic castration-resistant prostate cancer and have been approved by the US Food and Drug Administration: sipuleucel-T (a dendritic cell immunotherapy); cabazitaxel; abiraterone acetate and enzalutamide (both hormonal agents); and radium 223 (an alpha emitter). The development of these agents pivoted on whether patients had been treated with docetaxel, which r ...[more]

PMID: 23836992

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Project description:ImportanceSipuleucel-T is an immunotherapy that has been approved for use in patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). However, sipuleucel-T may not be available to some patients because of logistics, cost, and practice structure.ObjectiveTo identify factors associated with the adoption of sipuleucel-T across the United States.Design, setting, and participantsIn this retrospective cohort study, patients with prostate cancer who received therapy for mCRPC (docetaxel, abiraterone acetate, enzalutamide, cabazitaxel, radium 223, or sipuleucel-T) from January 1, 2010, through June 30, 2016, were identified in a large claims database of commercially insured patients. Patients who received sipuleucel-T were compared with patients who received any of the other treatments for mCRPC but did not receive sipuleucel-T. Data were analyzed from May 3, 2018, to February 24, 2019.ExposuresSipuleucel-T treatment.Main outcomes and measuresPatterns of treatment that involved the use of sipuleucel-T were elucidated, and binomial logistic regression was conducted to determine patient and physician factors that were associated with the use of sipuleucel-T and whether patients received sipuleucel-T in isolation or concurrently with other therapies.ResultsAmong 7272 patients who received a treatment for mCRPC, 730 (10.0%) received sipuleucel-T. Mean (SD) age of patients in the entire cohort was 73.2 (9.2) years; 6739 (92.7%) were non-Hispanic and 975 (13.4%) were black. In multivariable analysis, patients who were Hispanic (odds ratio [OR], 0.57; 95% CI, 0.38-0.86) or lived in the Pacific region (OR, 0.66; 95% CI, 0.45-0.97) had lower odds of receiving sipuleucel-T than patients who were not Hispanic or who lived in the South Atlantic region. Patients with higher incomes had greater odds of receiving sipuleucel-T than patients with incomes of less than $50?000 (OR, 1.29 [95% CI, 1.04-1.61] for $50?000-$99?000; OR, 1.43 [95% CI, 1.10-1.85] for >$99?000). Patients treated by a urologist had greater odds of receiving sipuleucel-T than patients not treated by a urologist (OR, 8.89; 95% CI, 7.10-11.11). Sixty-seven patients received concurrent therapies with sipuleucel-T, most commonly abiraterone or enzalutamide, but no factors were independently associated with patients receiving sipuleucel-T concurrent with other therapies for mCRPC.Conclusions and relevanceIn this study, 1 of 10 patients with prostate cancer who were treated for mCRPC received sipuleucel-T, with several variables associated with its use. Identifying disparities in receipt of sipuleucel-T may affect future access to this and other highly specialized cancer therapies by defining barriers to treatment that could be addressed in future studies.

Project description:Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor's androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat castration-resistant prostate cancer.

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Potential use of custirsen to treat prostate cancer.

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Potential use of custirsen to treat prostate cancer.

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