Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC)

Scher, Howard I.; Beer, T. M.; Higano, Celestia S.; Danila, Daniel C.; Montgomery, Bruce; Shelkey, Julia; Hirmand, M.; Hung, David T.; Sawyers, Charles L.

doi:10.1200/jco.2008.26.15_suppl.5006

Cited by 20 publications

(11 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In that study, PSA declines of >50% at 12 weeks were observed in 57% (37/65) of naïve and 45% (22/49) of post-chemotherapy patients, while radiographic control at 12 weeks was seen in 35/47 patients (74%) with soft tissue lesions and in 50/81 patients (62%) with bone lesions [112,114,115]. In addition, MDV-3100 had positive effects on two exploratory biomarker analyses: positron emission tomography (PET) imaging, and circulating prostate cancer tumor cell (CTC) analysis.…”

Section: Targeted Treatmentsmentioning

confidence: 97%

Novel targeted therapeutics for metastatic castration-resistant prostate cancer

2010

View full text Add to dashboard Cite

Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5 years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.

show abstract

Section: Targeted Treatmentsmentioning

confidence: 97%

Novel targeted therapeutics for metastatic castration-resistant prostate cancer

2010

View full text Add to dashboard Cite

show abstract

“…The reactivation of the AR is a common consequence of several mechanisms of resistance in prostate cancer, therefore a logical point of intervention is to develop more potent AR antagonists as compared with the existing agents. One such molecule, MDV-3100, blocks the nuclear translocation and DNA binding of AR and showed in phase I/II studies, PSA declines of 44% to 87% for 19+ weeks in three of three patients in the 30 mg cohort, and 74% to 96% for 14+ weeks in three of three patients in the 60 mg cohort (42). Another intervention is the inhibition of enzymes involved in steroidogenesis.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Castration-Resistant Prostate Cancer: Locking Up the Molecular Escape Routes

Attar¹,

Takimoto²,

Gottardis

2009

Clinical Cancer Research

189

159

View full text Add to dashboard Cite

The understanding of the key role that androgens play on the normal and pathological physiology of the prostate guided the development of different therapies for the treatment of locally advanced or metastatic prostate cancer (PCa). These so-called androgen deprivation therapies include surgical or chemical castration, achieved by the administration of gonadotropin-releasing hormone analogs; inhibition of steroidogenic enzymes; and finally, blocking of the binding of androgens to their receptor (AR) by the use of antiandrogens. Despite an excellent initial response, in approximately 2 to 3 years, most of these patients will succumb to the castration resistant form of the disease. Remarkably, even in the presence of castration levels of circulating androgens, these tumors are still dependent on a functional AR, and several molecular mechanisms have been proposed to explain this phenomenon. These include: (1) gene amplification and increased expression of the AR mRNA and protein, (2) selection of mutations in the AR that confer broader ligand specificity, (3) changes in the ratios or expression between the AR and its coregulators, (4) increased expression of steroidogenic enzymes, and (5) up-regulation of cross-talk signal transduction pathways that can activate the AR in a ligand-independent manner. We will summarize how these molecular hypotheses are being tested in the clinic by the latest therapeutic modalities.

show abstract

“…Further work to unravel the potential targets for chalcone 17 is in progress in our laboratory. In addition, initial data from the clinical trial of novel antiandrogen MDV-3100 show that patients who already failed treatment with a GnRH analogue in concert with bicalutamide or nilutamide respond well to MDV3100 with significant declines in PSA levels [35]. This is of exceptional significant as it demonstrated that patients who failed hormonal therapy with conventional antiandrogens respond to novel antiandrogens.…”

Section: Discussionmentioning

confidence: 89%

Synthesis and in vitro characterization of ionone-based chalcones as novel antiandrogens effective against multiple clinically relevant androgen receptor mutants

Zhou

Geng

2009

Invest New Drugs

View full text Add to dashboard Cite

A crucial event in prostate cancer progression is the transition from a hormone-sensitive to a lethal castration-refractory disease state. The antagonist-to-agonist conversion due to mutation in AR is a critical problem with the current clinically used antiandrogens. We aim to identify novel antiandrogens that remain as a pure antagonist even in the mutated ARs. By synthesizing a series of ionone-based chalcones, we have identified a novel chalcone (17) that is a pan-antagonist of the wild type and the clinically relevant T877A, W741C and H874Y mutated ARs in luciferase reporter assays in PC-3 cells. Further, chalcone 17 demonstrates sub-micromolar to low micromolar antiproliferative activity in LNCaP, MDA-PCa-2b, 22Rv1 and C4-2B prostate cancer cells, all of which express mutated ARs and confer resistance to the current clinically used antiandrogens. The results suggest that chalcone 17 could be a good candidate for further pre-clinical development as a novel antiandrogen for advanced prostate cancer.

show abstract

Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC)

Cited by 20 publications

References 0 publications

Novel targeted therapeutics for metastatic castration-resistant prostate cancer

Novel targeted therapeutics for metastatic castration-resistant prostate cancer

Castration-Resistant Prostate Cancer: Locking Up the Molecular Escape Routes

Synthesis and in vitro characterization of ionone-based chalcones as novel antiandrogens effective against multiple clinically relevant androgen receptor mutants

Contact Info

Product

Resources

About