News Article | May 4, 2017
New York, NY (May 4, 2017)--Columbia University Medical Center (CUMC) researchers have discovered a molecular mechanism that reprograms tumor cells in patients with advanced prostate cancer, reducing their response to anti-androgen therapy. The findings, based on a study in mice, could help to determine which patients should avoid anti-androgen therapy and identify new treatments for people with advanced prostate cancer. The study was published online April14th in the journal Cancer Discovery. Since androgens (male hormones) are known to drive prostate cancer, patients with recurrent or advanced disease are typically treated with anti-androgen medications. However, most patients fail treatment and develop an aggressive form of prostate cancer known as castration-resistant prostate cancer, or CRPC. "It's been a mystery why some patients do not respond to anti-androgens, and why a subset of these patients actually get worse after treatment," said study co-leader Cory Abate-Shen, PhD, the Michael and Stella Chernow Professor of Urological Oncology and professor of urology, medicine, systems biology, and pathology and cell biology at CUMC. "Our findings show that in many of these patients, the tumor cells are reprogrammed so that they are no longer dependent on androgens." To learn about the molecular mechanisms that drive resistance to anti-androgens, Drs. Abate-Shen and Michael Shen co-led a team to develop a strain of mice that lack two tumor-suppressor genes, Trp53 and Pten. These genes are both mutated in about 25 percent of patients with advanced prostate cancer. Mice that were treated with the anti-androgen drug abiraterone failed to respond and had accelerated tumor growth--similar to some humans with advanced prostate cancer who do not respond to anti-androgen therapy. "We found a number of genes that were overexpressed in mice with CRPC and also conserved in patients with the disease. Among the most interesting of these was SOX11, which regulates the development of the nervous system," said study co-leader Michael M. Shen, PhD, professor of medical sciences at CUMC. Most localized, slow-growing prostate cancers are largely composed of epithelial cells, which are rich in androgen receptors that increase their susceptibility to anti-androgen therapy. In contrast, aggressive prostate cancers, particularly those that fail treatment, often contain many neuroendocrine-like cells, which lack androgen receptors and are therefore less responsive to anti-androgen therapy. "This raised the question, where are the neuroendocrine-like cells in prostate tumors coming from?" said Dr. Abate-Shen. "While previous research hinted that epithelial tumor cells may be reprogrammed to become neuroendocrine-like cells, our study provides the first direct evidence that this reprogramming is actually occurring and that it is mediated, at least in part, by SOX11." The researchers also demonstrated that SOX11 acts in a similar fashion in human prostate cancer cells. "By giving anti-androgens to patients with CRPC, we are eliminating the cancer cells that need androgen to survive and enriching the tumor with the remaining neuroendocrine-like cells. The net effect is to create an even more aggressive tumor," said Dr. Shen. The researchers also identified several "master regulators"--genes that control SOX11 and other genes involved in prostate cancer reprogramming--that might be targeted for new prostate cancer treatments. "Based on our findings, genetic testing to identify SOX11 and the master regulators may be considered before embarking on anti-androgen therapy for patients with advanced prostate cancer," said Dr. Shen. The study is titled, "Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer." The other contributors are: Min Zou (CUMC), Roxanne Toivanen (CUMC), Antonina Mitrofanova (CUMC and State University of New Jersey, Newark, NJ), Nicolas Floch (CUMC), Sheida Hayati (State University of New Jersey, Newark, NJ), Yanping Sun (CUMC), Clémentine Le Magnen (CUMC), Daniel Chester (CUMC), Elahe A. Mostaghel (Fred Hutchinson Cancer Research Center, Seattle, WA), Andrea Califano (CUMC), and Mark A. Rubin (Weill Cornell Medicine/NewYork-Presbyterian, New York, NY). The study was supported by grants from the National Institutes of Health (P30 CA013696, UL1 TR00040, P01 CA173481, CA154293, DK076602, CA196662, U54 CA209997, R35 CA197745, UL1 TR001873), the Pacific Northwest Prostate Cancer SPORE (P50 CA097186), the DOD Prostate Cancer Research Program (PC150051, PC131821), the Prostate Cancer Foundation, the TJ Martell Foundation for Leukemia, Cancer and AIDS Research, the National Health and Medical Research Council of Australia, the Swiss National Science Foundation, and the FM Kirby Foundation. The authors declare no financial or other conflicts of interest. Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.
News Article | November 30, 2016
Munich, Germany: A strategy of alternately flooding and starving the body of testosterone is producing good results in patients who have metastatic prostate cancer that is resistant to treatment by chemical or surgical castration, according to new findings. In a presentation at the 28th EORTC-NCI-AACR  Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany, today (Thursday), researchers reported that results from 47 men who have completed at least three cycles of bipolar androgen therapy (BAT) showed that the strategy was safe and effective. Prostate specific antigen (PSA) levels  fell in the majority of the men, tumours shrank in some men, in several the disease did not progress and this included some whose disease continued to be stable for more than a year. One man appears to have been "cured", in that his PSA levels dropped to zero after three months and have remained so for 22 cycles of treatment, with no trace of the disease remaining. The researchers are planning to treat a group of 60 men in total. Sam Denmeade MD, professor of oncology at Johns Hopkins University School of Medicine (Baltimore, USA) told the Symposium: "We think the results are unexpected and exciting. We are still in the early stages of figuring out how this works and how to incorporate it into the treatment paradigm for prostate cancer." Traditionally, treatments for prostate cancer have involved lowering the levels of the male hormone (or androgen) testosterone using drugs called luteinising hormone-releasing hormone (LHRH) agonists, as it was thought that androgens stimulate the cancer cells to grow. However, Prof Denmeade says there is no evidence that testosterone promotes cancer. "Indeed, earlier research in prostate cancer cell lines has shown that treatment with high doses of testosterone could inhibit growth and kill cancer cells. The exact mechanism is not known and there may be many things happening since the androgen receptor is the key signalling pathway in prostate cancer," he said. "In our lab we have observed that testosterone interferes with part of the cell division process in cancer cells called DNA licensing; it also seems to cause prostate cancer cells to make breaks in their DNA. So too much testosterone can cause cancer cells to die. It can also induce something we call senescence, which means the cancer cells become like old men who sit around and tell stories but don't make much trouble." In an ongoing study called RESTORE, 47 men with castration resistant prostate cancer that had started to spread to other parts of the body (metastasise), who showed no symptoms but whose disease had become resistant to treatment with either abiraterone (17 patients) or enzalutamide (30 patients) receive a high dose of testosterone (400 mg), injected into the muscle every 28 days. At the same time the men continued on their LHRH agonist therapy to clamp down on testosterone produced naturally by the testicles. The men also stopped taking abiraterone or enzalutamide. These two anti-cancer therapies work by inhibiting androgen receptor signalling. "Our goal is to shock the cancer cells by exposing them rapidly to very high followed by very low levels of testosterone in the blood," explained Prof Denmeade. These alternating extremes in testosterone levels are why the researchers call the therapy "bipolar". Men with declining PSA levels or stable disease continued with BAT after three cycles, and if their disease started to progress they were treated again with abiraterone or enzalutamide. The study has completed enrolment of the required 30 men in the first arm of the study who were treated with testosterone after their disease became resistant to enzalutamide and started to progress. Presenting results from this group, Prof Denmeade said: "Thus far we have observed dramatic PSA response in a subset of men; PSA levels declined in about 40% of men and in about 30% of men levels fell by more than 50%. Some men also have objective responses with a decrease in the size of measurable disease, mostly in lymph nodes. Many of the men have stable disease that has not progressed for more than 12 months. I think we may have cured one man whose PSA dropped to zero after three months and has remained so now for 22 cycles. His disease has all disappeared." So far, 17 of the 30 men in the second arm of the study whose disease had started to progress again after treatment with abiraterone have received testosterone. Prof Denmeade said: "PSA responses were also observed in this group, but full results will not be presented until all 30 men have been enrolled over the next year." All men in the study were tested for circulating tumour cells in their blood and six of them were found to have a protein called androgen-receptor splice variant (AR-V7), which may be associated with resistance to treatment with enzalutamide. After BAT treatment, AR-V7 disappeared from the blood of all six men, and two of the men had declines in PSA levels of 50% and over. So far, BAT has been well-tolerated by patients with no dose-limiting toxicities. One patient had an increase in pain and one had a problem with retention of urine. "The benefits of the treatment are particularly evident in men who have had no sexual function for many years due to impotence caused by hormone deprivation. These men are quite happy with the new treatment. Other positives include increase in muscle strength, increased energy and decreased fatigue. This does not occur in every man and we are not sure exactly why." More research still needs to be conducted on BAT. Prof Denmeade said: "We caution that this is still experimental. In particular, this therapy should only be given to men who are asymptomatic. Testosterone treatment can definitely worsen pain in men with prostate cancer who have pain from their disease." A multi-centre randomised trial in the USA called TRANSFORMER is testing BAT versus enzalutamide in men with metastatic castrate-resistant prostate cancer whose disease had progressed after being treated with abiraterone. So far it has recruited 111 men with a target of 180. "If we find testosterone is superior then we would hope to move on to larger trials. Our problem is this is not a drug that is owned by a pharmaceutical company; it is generic testosterone. So moving forward is going to be difficult due to issues with finding funds to run a bigger trial," concluded Prof Denmeade. Chair of the scientific committee for the Symposium, Professor Jean Charles Soria from the Institut Gustave Roussy (France), commented: "The use of testosterone in men with castration-resistant prostate cancer is an intriguing concept that was previously advocated some years ago, but this is the first time we have clinical data in patients whose disease has progressed after treatment with abiraterone or enzalutamide."  EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].  PSA is a protein produced by normal cells in the prostate and also by prostate cancer cells. PSA levels rise as men get older, but abnormally high levels may be an indication of cancer and PSA levels are measured to see whether anti-cancer treatments are working or not.  The initial pilot study (in just 14 men in the era before abiraterone or enzalutamide) was funded by the One-in-Six Foundation, set up by one of Professor Denmeade's patients who was suffering from prostate cancer and wanted to make a difference. Based on the preliminary data, the researchers received funding from the USA's National Institutes of Health (NIH) to perform RESTORE and a Transformative Impact grant from the Department of Defense Prostate Cancer Research Program to perform TRANSFORMER.
News Article | December 19, 2016
PHILADELPHIA --(Dec. 19, 2016)-- Scientists at The Wistar Institute have identified a novel protein pathway across several types of cancer that controls how tumor cells acquire the energy necessary for movement, invasion and metastasis. This protein pathway was previously only observed in neurons and represents a potential therapeutic target for several types of cancer. Study results were published in the journal Nature Communications. Mitochondria serve as power generators of the cell, responsible for converting oxygen and nutrients into energy for cellular processes. Researchers have long observed that, instead of relying on mitochondria and oxygen, tumor cells switch to a different system of energy production to compensate for their increased energy needs and the low levels of oxygen typically found in tumor tissues. This process is known as the Warburg effect, and because it had been well-established in cancer cells, mitochondria were not regarded as major players in tumor biology until recently. This study confirms that mitochondria play an important role especially in disease progression, during which tumor cells break out of the primary mass and invade distant tissues in the body. "The scientific community has been missing a fundamental aspect of cancer cell metabolism because we have overlooked the role of mitochondria and oxidative metabolic processes in cancer," said Dario C. Altieri, M.D., president and CEO of The Wistar Institute, director of The Wistar Institute Cancer Center, the Robert & Penny Fox Distinguished Professor, and lead author of this study. "Our findings, along with those of others from the past few years, pave the way to a new research direction in the field, alluding to the need to further investigate the role of mitochondria in tumor metabolism." The Altieri Laboratory found that mitochondria in tumor cells are repositioned close to the cell membrane to provide energy for movement. While this type of cellular behavior had been previously only observed in neurons, the group showed how a network of proteins, including SNPH and its partners, that control mitochondria trafficking in neurons are reprogrammed to perform the same function in tumor cells. Using a genome-wide screening approach, Altieri and colleagues discovered that SNPH inhibits cell invasion by reducing cell movement in prostate cancer cells. They also found that when SNPH expression is inhibited, the mitochondria relocate from their typical position around the cell nucleus to the cell membrane. They evaluated the expression levels of SNPH and its partners in tissue samples from patients with epithelial and hematologic malignancies and found that reduced levels of SNPH correlate with disease progression and unfavorable prognosis across the tumor types. "We were able to establish a correlation between this protein pathway and disease progression and survival in several cancer types besides prostate cancer. This indicates that we are dealing with a general mechanism of metastasis suppression, not specific to one single tumor type," said M. Cecilia Caino, Ph.D., a postdoctoral researcher in The Altieri Laboratory and first author of the paper. "Our observations have strong clinical implications, as some of the proteins in this network are druggable, opening new potential therapeutic opportunities for metastatic diseases." This work was supported by the National Institutes of Health grants P01 CA140043, R01 CA78810, CA190027, R01 CA089720, R01 NS076709, F32 CA177018 and T32 CA009171, the Italian Minister of Health grant GR2011-02351626, the Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program under Award No. W81XWH-13-1-0193 and a Prostate Cancer Foundation Challenge Award. Core support for The Wistar Institute was provided by the Cancer Center Support Grant (CCSG) CA010815. Co-authors of this study from The Wistar Institute include: Jae Ho Seo, Kelly G. Bryant, Andrew V. Kossenkov, James E. Hayden and Dmitry I. Gabrilovich. Other co-authors include: Angeline Aguinaldo, Eric Wait and Andrew R. Cohen from Drexel University, Valentina Vaira, Annamaria Morotti, Stefano Ferrero, Silvano Bosari from the Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy, and Lucia Languino from Kimmel Cancer Center at Thomas Jefferson University. The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.
News Article | November 10, 2016
PHILADELPHIA--(Nov. 9, 2016)-- Scientists at The Wistar Institute have demonstrated how a protein called TRAP1 - an important regulator of energy production in healthy and cancerous cells - is an important driver of prostate cancer and appears to be a valuable therapeutic target for the disease. The findings were published in the Journal of Biological Chemistry. Mitochondria are known as the powerhouse of the cells because of their role in energy production, and in recent years, research has shown that different tumors are able to manipulate genes and proteins responsible for energy production in order to help them survive. TRAP1 is a chaperone protein that is structurally similar to heat shock protein 90 (HSP90), which is found in larger amounts in the mitochondria of cancer cells. In a prior study, Dario C. Altieri, M.D., president and CEO of The Wistar Institute, director of The Wistar Institute Cancer Center, the Robert & Penny Fox Distinguished Professor, and colleagues bred mice with the TRAP1 protein "knocked out" to determine what impact it may have on disease. These special mice lived longer and experienced fewer age-related illnesses, suggesting that the protein played an important role in disease. "In our prior study, while we had evidence that hinted at TRAP1's role in tumor growth, we lacked the direct evidence we needed to define the role of this protein in prostate cancer development," Altieri said. "As we better understand the role of mitochondria in cancer, it's important to thoroughly study the roles of the proteins involved in helping tumors receive the energy they desire for survival." In this study, instead of removing the TRAP1 protein, the Altieri laboratory generated mice with the TRAP1 protein overexpressed. Additionally, the mice were bred to lose one copy of the PTEN gene, which is an important tumor suppressor gene. At least one copy of PTEN is deleted in about 40 percent of cases of prostate cancer and is often found in more aggressive tumors, so mice without this gene more accurately simulate the behavior of the disease. The combination of increased TRAP1 coupled with the loss of PTEN resulted in aggressive, early-onset invasive prostate cancer, according to the study. Altieri and colleagues found increased tumor cell proliferation, inhibition of apoptosis (a form of programmed cell death that is thought to halt the progression of tumor cells), and increased epithelial cell invasion. These findings suggest that TRAP1 has a role in promoting the mitochondrial "fitness" of a prostate tumor, making it more aggressive and less responsive to treatment. "What is exciting about these findings is the fact that we believe TRAP1 is a druggable target," Altieri said. "We are continuing to advance our promising research and development program aimed at targeting the mitochondria in tumors." This work was supported by the National Institutes of Health/National Cancer Institute P01CA140043, R01CA78810, CA190027, and the Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program under Award No. W81XWH-13-1-0193, and a Challenge Award from the Prostate Cancer Foundation (PCF). Support for core facilities in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute and CA016672 to The University of Texas MD Anderson Cancer Center. Co-authors of this study from The Wistar Institute include Sofia Lisanti, David Garlick, Kelly Bryant, Michele Tavecchio, Andrew Kossenkov and Louise Showe. Other co-authors include Lucia Languino from Thomas Jefferson University and Gordon Mills and Yiling Lu from The University of Texas MD Anderson Cancer Center. The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.
Suzman D.L.,Prostate Cancer Research Program |
Boikos S.A.,Prostate Cancer Research Program |
Carducci M.A.,Prostate Cancer Research Program
Cancer and Metastasis Reviews | Year: 2014
Bone metastases are present in the vast majority of men with advanced prostate cancer, representing the main cause for morbidity and mortality. Recurrent or metastatic disease is managed initially with androgen deprivation but the majority of the patients eventually will progress to castration-resistant prostate cancer, with patients developing bone metastases in most of the cases. Survival and growth of the metastatic prostate cancer cells is dependent on a complex microenvironment (onco-niche) that includes the osteoblasts, the osteoclasts, the endothelium, and the stroma. This review summarizes agents that target the pathways involved in this complex interaction between prostate cancer and bone microenvironment and aim to transform lethal metastatic prostate cancer into a chronic disease. © 2014 Springer Science+Business Media.
Wozney J.L.,Johns Hopkins Sidney Kimmel Comprehensive Cancer Center |
Antonarakis E.S.,Prostate Cancer Research Program
Cancer and Metastasis Reviews | Year: 2014
Treatments that target the androgen axis represent an effective strategy for patients with advanced prostate cancer, but the disease remains incurable and new therapeutic approaches are necessary. Significant advances have recently occurred in our understanding of the growth factor and signaling pathways that are active in prostate cancer. In conjunction with this, many new targeted therapies with sound preclinical rationale have entered clinical development and are being tested in men with castration-resistant prostate cancer. Some of the most relevant pathways currently being exploited for therapeutic gain are HGF/c-Met signaling, the PI3K/AKT/mTOR pathway, Hedgehog signaling, the endothelin axis, Src kinase signaling, the IGF pathway, and angiogenesis. Here, we summarize the biological basis for the use of selected targeted agents and the results from available clinical trials of these drugs in men with prostate cancer. © 2014 Springer Science+Business Media.
Schweizer M.T.,Prostate Cancer Research Program |
Carducci M.A.,Prostate Cancer Research Program
Cancer Journal (United States) | Year: 2013
It was first posited in the 1970s that angiogenesis may prove to be a useful target for anticancer therapies. Since then, a number of agents have been developed and tested across a range of tumor types; however, to date, there have unfortunately been more failures than successes. Prostate cancer (PCa) is no exception in this regard, and despite a strong preclinical rationale for targeting angiogenesis in men with PCa, there has yet to be an antiangiogenic therapy proven to prolong survival in this group of patients. Drugs have been developed to target a host of angiogenesis mediators. These include vascular endothelial growth factor (VEGF), the VEGF receptors, antiangiogenic factors (e.g., thrombospondin-1), and downstream mediators of angiogenesis (e.g., hypoxia-inducible factor-1α and MET). At present, there are 2 drugs being tested in the phase III setting for men with PCa: cabozantinib and tasquinimod. Cabozantinib, a dual VEGF receptor-2/MET inhibitor, has shown dramatic beneficial effects on radiographically evident bone metastases and pain in the phase II setting. There are currently 2 large phase III trials underway to further investigate cabozantinib's role in treating men with PCa. Both trials randomize subjects to cabozantinib versus mitoxantrone: one is designed to evaluate overall survival, and the other, pain response durability. The other drug, tasquinimod, has a somewhat poorly understood mechanism of action. It is thought to exert an antiangiogenic effect through the inhibition of myeloid-derived suppressor cells, key to the support of an angiogenic environment, and down-regulation of hypoxia-inducible factor-1α. A phase II trial randomizing men to tasquinimod versus placebo revealed a median progression-free survival advantage in the experimental arm (7.6 vs. 3.3 months with placebo; P = 0.0042). Based on these encouraging phase II results, a randomized, double-blind, placebo-controlled trial in men with metastatic castration-resistant PCa was launched. That trial is powered for a primary endpoint of progression-free survival and is expected to enroll 1200 men. Copyright © 2013 Lippincott Williams &Wilkins.
Antonarakis E.S.,Prostate Cancer Research Program |
Armstrong A.J.,Duke University
Prostate Cancer and Prostatic Diseases | Year: 2011
The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forward in the past year, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel with prednisone and abiraterone acetate with prednisone), and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are showing preliminary signs of clinical benefit, leading to more definitive phase III confirmatory trials. In this review, which represents part 1 of a two-part series on metastatic CRPC, we will summarize the mechanisms of resistance to hormonal and chemotherapies and discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options following docetaxel administration, as well as prognostic factors in this post-docetaxel state. As docetaxel remains the standard initial systemic therapy for men with metastatic CRPC for both palliative and life-prolonging purposes, knowledge of these evolving standards will help to optimize delivery of care and long-term outcomes. © 2011 Macmillan Publishers Limited All rights reserved.
Schweizer M.T.,Prostate Cancer Research Program |
Zhou X.C.,Prostate Cancer Research Program |
Wang H.,Prostate Cancer Research Program |
Bassi S.,Prostate Cancer Research Program |
And 3 more authors.
European Urology | Year: 2014
Background Taxanes may partly mediate their effect in castration-resistant prostate cancer (CRPC) through disruption of androgen-receptor trafficking along microtubules. This raises the possibility of cross-resistance between androgen-directed agents and docetaxel. Objective To evaluate docetaxel efficacy after abiraterone treatment in CRPC patients. Design, setting, and participants This was a single-institution, retrospective analysis in CRPC patients (N = 119) who either received abiraterone before docetaxel (AD) (n = 24) or did not receive abiraterone before docetaxel (docetaxel-only; n = 95). Men initiated docetaxel between December 2007 (the date abiraterone was first used at our center) and May 2013. Outcome measurements and statistical analysis The primary efficacy end points were prostate-specific antigen progression-free survival (PSA-PFS) and clinical/radiographic progression-free survival (PFS) on docetaxel. Differences between groups were assessed using univariate and multivariable analyses. Results and limitations Men in the AD group had a significantly higher risk for progression than those in the docetaxel-only group. Median PSA-PFS was 4.1 mo in the AD group and 6.7 mo in the docetaxel-only group (p = 0.002). Median PFS was also shorter in the AD group (4.4 mo vs 7.6 mo; p = 0.003). In multivariable analysis, prior abiraterone treatment remained an independent predictor of shorter PSA-PFS (hazard ratio [HR]: 3.48; 95% confidence interval [CI], 1.36-8.94; p = 0.01) and PFS (HR: 3.62; 95% CI, 1.41-9.27; p = 0.008). PSA declines ≥50% were less frequent in the AD group (38% vs 63%; p = 0.02). The small size and retrospective nature of this study may have introduced bias. Conclusions Men receiving abiraterone before docetaxel were more likely to progress on docetaxel and less likely to achieve a PSA response than abiraterone-naïve patients. Cross-resistance between abiraterone and docetaxel may explain these findings; however, larger, more definitive studies are still needed to confirm this. Patient summary We examined the efficacy of docetaxel in castration-resistant prostate cancer patients who either did or did not receive prior abiraterone. We found that men receiving abiraterone before docetaxel were less likely to achieve a PSA response and were more likely to progress sooner on docetaxel than abiraterone-untreated patients. This may be due to cross-resistance. © 2014 European Association of Urology.
Antonarakis E.S.,Prostate Cancer Research Program
Expert Review of Anticancer Therapy | Year: 2015
There is an emerging interest in understanding mechanisms of response and resistance to next-generation hormonal therapies: abiraterone and enzalutamide. While many explanations for resistance to these agents have been postulated, the importance of androgen receptor splice variants is gaining momentum. Androgen receptor (AR) splice variants are constitutively active isoforms of the AR that lack the ligand-binding domain yet retain their transcriptional activity in a ligand-independent fashion. Of these, AR variant-7 may be the most important, and has been implicated in primary resistance to abiraterone and enzalutamide in men with advanced prostate cancer. In this editorial, the clinical relevance of AR splice variant-7 (AR-V7) will be reviewed within the context of AR-directed therapies, and next steps for the analytical and clinical validation of this potential biomarker will be proposed. © 2014 Informa UK, Ltd.