Improving the outcome of patients with castration-resistant prostate cancer through rational drug development

The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen–AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide.

Download Full-text

Novel Strategies to Test Biological Hypotheses in Early Drug Development for Advanced Prostate Cancer

Clinical Chemistry ◽

10.1373/clinchem.2012.185157 ◽

2013 ◽

Vol 59 (1) ◽

pp. 75-84 ◽

Cited By ~ 10

Author(s):

Roberta Ferraldeschi ◽

Gerhardt Attard ◽

Johann S de Bono

Keyword(s):

Prostate Cancer ◽

Drug Development ◽

Novel Agents ◽

Castration Resistant Prostate Cancer ◽

New Agents ◽

New Era ◽

Castration Resistant ◽

Clinical Trial Designs ◽

Early Drug ◽

Scientific Hypotheses

BACKGROUND Major advances in our understanding of the underlying biology of prostate cancer have helped to herald a new era in the treatment of castration-resistant prostate cancer (CRPC), with 5 new agents having shown a survival advantage in the last 3 years and an impressive number of promising novel agents now entering the clinic. CONTENT We discuss the challenges facing drug development for CRPC and strategies to meet these challenges, with a focus not only on the development of predictive and intermediate endpoint biomarkers, but also on novel hypothesis-testing, biomarker-driven clinical trial designs. SUMMARY With several promising agents now entering the clinic, there is increasing pressure to rethink drug development for CRPC to ensure that novel agents are appropriately evaluated and that patients and resources are appropriately allocated. We envision that biomarker-driven, reiterative clinical trials will have a major impact on CRPC treatment through the testing of robust scientific hypotheses with rationally designed drugs and drug combinations administered to selected patients.

Download Full-text

Improved Therapeutic Targeting of the Androgen Receptor: Rational Drug Design Improves Survival in Castration-Resistant Prostate Cancer

Current Drug Targets ◽

10.2174/1389450111314040003 ◽

2013 ◽

Vol 14 (4) ◽

pp. 408-419 ◽

Cited By ~ 9

Author(s):

Ai Chiin Lim ◽

Gerhardt Attard

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Drug Design ◽

Rational Drug Design ◽

Castration Resistant Prostate Cancer ◽

Therapeutic Targeting ◽

Castration Resistant ◽

Rational Drug

Download Full-text

Radiographic progression by Prostate Cancer Working Group (PCWG)-2 criteria as an intermediate endpoint for drug development in metastatic castration-resistant prostate cancer

BJU International ◽

10.1111/bju.12589 ◽

2014 ◽

Vol 114 (6b) ◽

pp. E25-E31 ◽

Cited By ~ 23

Author(s):

Guru Sonpavde ◽

Gregory R. Pond ◽

Andrew J. Armstrong ◽

Matthew D. Galsky ◽

Lance Leopold ◽

...

Keyword(s):

Prostate Cancer ◽

Drug Development ◽

Working Group ◽

Radiographic Progression ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

Download Full-text

Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3

Journal of Clinical Oncology ◽

10.1200/jco.2015.64.2702 ◽

2016 ◽

Vol 34 (12) ◽

pp. 1402-1418 ◽

Cited By ~ 430

Author(s):

Howard I. Scher ◽

Michael J. Morris ◽

Walter M. Stadler ◽

Celestia Higano ◽

Ethan Basch ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

Drug Development ◽

Working Group ◽

Expert Committee ◽

Cancer Clinical Trials ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Systemic Treatments ◽

Group 3

Purpose Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups. Methods An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations. Results PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials. Conclusion PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

Download Full-text