Showing papers by "Thomas W. Flaig published in 2012"
TL;DR: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.
Abstract: Background Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor–signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. Methods In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. Results The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for de...
3,866 citations
TL;DR: Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk-benefit ratio and safety findings and tumour responses were consistent with those observed in RECORD-1.
84 citations
TL;DR: A significant difference was demonstrated in the incidence of hypothyroidism during treatment with sunitinib and sorafenib, with a higher incidence in patients treated with sun itinib, and the development of hyp Timothyroidism was associated with a longer progression-free survival.
51 citations
TL;DR: Novel evidence is provided that miR-125b is an important regulator of the AR with specific ramification for the effectiveness of antiandrogens and other hormonal therapies in prostate cancer.
Abstract: Recognition of micro-RNA function and their contribution to the biology of disease has given a new insight into disease mechanisms, with these discoveries potentially improving clinical diagnostic and therapeutic options. miR-125b has been identified as an important regulator in various cancers, including prostate cancer, but the mechanism of this regulation remains incompletely understood. In these studies, the effect of castration on miR-125b serum expression was evaluated in mice, simulating androgen deprivation. Furthermore, miR-125b expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LNCaP prostate cancer cells treated with the antiandrogen bicalutamide. Using LNCaP cells, the effect of miR-125b modulation on apoptotic protein and NCOR2, a co-repressor of androgen receptor (AR), was examined by Western blot. A 3′-untranslated region (UTR) luciferase-binding assay was performed to confirm that miR-125b targets NCOR2. We found that surgical castration induc...
25 citations
Journal Article•
TL;DR: The rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options, and the treatment paradigm for patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents.
Abstract: We have entered a period of accelerated drug development and optimism in the care of advanced prostate cancer. The treatment paradigm for these patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents.
16 citations
TL;DR: New advancements in medical therapy for prostate cancer have added to the hormonal therapy armamentarium, and new therapeutic agents not only provide a survival benefit but also show potential for reversing hormonal resistance in metastatic CRPC, and thus redefining hormonally sensitive disease.
Abstract: Prostate cancer is the most common cancer among men in the United States. For decades, the cornerstone of medical treatment for advanced prostate cancer has been hormonal therapy, intended to lower testosterone levels, known as Androgen Deprivation Therapy (ADT). The development of hormone-resistant prostate cancer (now termed castration-resistant prostate cancer:CRPC) remains the key roadblock in successful long-term management of prostate cancer. New advancements in medical therapy for prostate cancer have added to the hormonal therapy armamentarium. These new therapeutic agents not only provide a survival benefit but also show potential for reversing hormonal resistance in metastatic CRPC, and thus redefining hormonally sensitive disease.
14 citations
TL;DR: Axitinib is a small-molecule protein-tyrosine kinase receptor inhibitor specifically targeting this family of receptors, in addition to platelet-derived growth factor receptor and proto-oncogene c-Kit, for use in metastatic renal cell carcinoma.
Abstract: Axitinib is a small-molecule protein-tyrosine kinase receptor inhibitor specifically targeting this family of receptors, in addition to platelet-derived growth factor receptor and proto-oncogene c-Kit. Improved knowledge of kidney cancer development, and specifically mutations in the VHL gene, has supported the targeting of angiogenesis pathways. Axitinib is the most recently approved agent for use in metastatic renal cell carcinoma. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical activity of this agent, and describe its place in the current treatment of renal cell carcinoma.
11 citations
TL;DR: Treatment options for recurrent prostate cancer are focused on, keeping in mind the unique characteristics of the elderly population, and many of the newly approved agents used to treat castration-resistant prostate cancer, and exciting agents currently under investigation are discussed.
Abstract: With a large, aging population in the USA and continued prolongation of life expectancy, treatment of cancer in the elderly will continue to be of importance. The most common cancer in men is prostate cancer, which is most often diagnosed in those over the age of 65 years. Initial therapies for prostate cancer are local treatments in those with localized disease and for whom definitive therapy is appropriate. Optimal treatment of an older patient with recurrent prostate cancer now involves more of a decision process than treatment has in the past, with the recent approval of several new medical agents for advanced prostate cancer. Through this article we will focus on treatment options for recurrent prostate cancer, keeping in mind the unique characteristics of the elderly population. A majority of the discussion will focus on many of the newly approved agents used to treat castration-resistant prostate cancer, and exciting agents currently under investigation. Improved androgen blockade has improved overall survival in patients with metastatic disease but carries many of the same adverse effects as previous agents. Newer approaches with immunotherapy, radiopharmaceuticals, or second-generation androgen receptor blockers introduce a different adverse-effect profile for older patients. As data matures, these too may improve survival for patients with metastatic disease. Throughout all stages of disease, one must keep in mind the unique needs of an older patient population.
8 citations
TL;DR: Long awaited data from the clinical investigation of bladder cancer in both the neoadjuvant and adjuvant settings were released in 2011, setting the stage for the next generation of work in this area.
Abstract: Long awaited data from the clinical investigation of bladder cancer in both the neoadjuvant and adjuvant settings were released in 2011, setting the stage for the next generation of work in this area. The findings of a number of studies provide the first steps towards a personalized approach to this disease.
5 citations
TL;DR: Initial results from the STAMPEDE trial of androgen deprivation therapy with and without Celecoxib in patients with prostate cancer have shown that celecoxib does not confer benefit, and this multiarm, multistage trial will be informative of future clinical trial design.
Abstract: Initial results from the STAMPEDE trial of androgen deprivation therapy with and without celecoxib in patients with prostate cancer have shown that celecoxib does not confer benefit. Despite this negative finding, this multiarm, multistage trial will be informative of future clinical trial design, particularly as new agents become available for prostate cancer.
3 citations
01 May 2012
TL;DR: The administration of dietary glycine supplementation suppressed radiation-induced Hif-1α expression and created a favorable growth delay in the xenograft model, establishing the feasibility of this experimental model and confirming an increase in H if-1 α expression after ionizing radiation.
Abstract: : The project was intended to determine whether cytotoxic ionizing radiation induces upregulation of Hif1-alpha via a nitric oxide(NO)-mediated tumor stress response pathway and whether this effect can be inhibited by the administration of dietary glycine supplementation, which can suppress activation of the macrophages responsible for the NO. The ultimate goal was to test whether glycine effects tumor growth delay after ionizing radiation by suppressing this pathway. PC-3 cells transfected with a Hif-1 reporter detectable via bioluminescence imaging were implanted into nude mice and subjected to ionizing radiation (2-6 Gy), with or without prior and concurrent feeding with a glycine-rich diet. The results established the feasibility of this experimental model and confirm an increase in Hif-1α expression after ionizing radiation. Furthermore, the administration of dietary glycine supplementation suppressed radiation-induced Hif-1α expression and created a favorable growth delay in the xenograft model.