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Castrate resistant

Silvana Giacinti, Paolo Carlini, Michela Roberto, Maria Bassanelli, Lidia Strigari, Francesco Pavese, Anna M Aschelter, Alessandra Felici, Maurizio Valeriani, Francesco Cognetti, Paolo Marchetti
Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments...
October 19, 2016: Anti-cancer Drugs
Claire Levrier, Martin C Sadowski, Anja Rockstroh, Brian Gabrielli, Maria Kavallaris, Melanie Lehman, Rohan A Davis, Colleen C Nelson
The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6α-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC-3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis...
October 19, 2016: Molecular Cancer Therapeutics
Shuai Gao, Yanfei Gao, Housheng Hansen He, Dong Han, Wanting Han, Amy Avery, Jill A Macoska, Xiaming Liu, Sen Chen, Fen Ma, Shaoyong Chen, Steven P Balk, Changmeng Cai
Although well characterized as a transcriptional activator that drives prostate cancer (PCa) growth, androgen receptor (AR) can function as a transcriptional repressor, and high-level androgens can suppress PCa proliferation. The molecular basis for this repression activity remains to be determined. Genes required for DNA replication are highly enriched among androgen-repressed genes, and AR is recruited to the majority of these genes, where it rapidly represses their transcription. This activity is enhanced in PCa cells expressing high AR levels and is mediated by recruitment of hypophosphorylated retinoblastoma protein (Rb)...
October 18, 2016: Cell Reports
Michael T Schweizer, Heather H Cheng, Maria S Tretiakova, Funda Vakar-Lopez, Nola Klemfuss, Eric Q Konnick, Elahe A Mostaghel, Peter S Nelson, Evan Y Yu, R Bruce Montgomery, Lawrence D True, Colin C Pritchard
Precision oncology entails making treatment decisions based on a tumor's molecular characteristics. For prostate cancer, identifying clinically relevant molecular subgroups is challenging, as molecular profiling is not routine outside of academic centers. Since histologic variants of other cancers correlates with specific genomic alterations, we sought to determine if ductal adenocarcinoma of the prostate (dPC) - a rare and aggressive histopathologic variant - was associated with any recurrent actionable mutations...
October 15, 2016: Oncotarget
Shabbir M H Alibhai, Salman Aziz, Tharsika Manokumar, Narhari Timilshina, Henriette Breunis
OBJECTIVE: Since the benefits of chemotherapy in treating older men with metastatic castration-resistant prostate cancer (mCRPC) are modest, validated tools that predict the risk of treatment toxicity may aid clinical decision-making. Whether these tools are better than oncologist judgment remains unclear. We compared the Cancer and Aging Research Group (CARG) tool, the Vulnerable Elders Survey-13 (VES-13), and oncologist judgment in predicting toxicity in men with mCRPC undergoing chemotherapy...
October 15, 2016: Journal of Geriatric Oncology
Yoko Yamada, Nobuaki Matsubara, Ken-Ichi Tabata, Takefumi Satoh, Naoto Kamiya, Hiroyoshi Suzuki, Takashi Kawahara, Hiroji Uemura, Akihiro Yano, Satoru Kawakami
BACKGROUND: Both abiraterone acetate (AA) and enzalutamide are promising agents for patients with pre- and post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC). Several retrospective analysis suggested clinical cross-resistance between these agents in patients previously treated with docetaxel. However, data on the antitumor activity of AA as a second androgen receptor-targeting new agent after the failure of enzalutamide in chemotherapy-naive mCRPC patients is unavailable...
October 18, 2016: BMC Research Notes
Chad R Ritch, Michael S Cookson
Docetaxel based chemotherapy showed survival benefit and emerged as the mainstay of treatment for castration resistant prostate cancer (CRPC) in 2004. However, therapeutic options have expanded rapidly since 2011. The spectrum of new agents is broad and includes drugs that target the androgen axis (enzalutamide, abiraterone), immunotherapy (sipuleucel-T), bone seeking radionuclides (radium-223), and second line chemotherapy (cabazitaxel). In addition, new agents have been developed to reduce skeletal related events (denosumab)...
October 17, 2016: BMJ: British Medical Journal
Luis Ramudo Cela, Jesús Balea Filgueiras, José Ramón Vizoso Hermida, Isabel Martín Herranz
Abiraterone acetate is a potent and irreversible inhibitor of cytochrome p450 17A1 that suppresses androgen synthesis. It is approved for chemotherapy-naive and docetaxel-treated patients with metastatic castration-resistant prostate cancer. We describe the protocol for use of abiraterone in metastatic castration-resistant prostate cancer chemotherapy naive patients has been implanted in our centre and we review the cases of those patients whose adverse effects have forced the discontinuation of treatment. The side effects fit the safety profile of abiraterone, speed of their appearance and severity indicate that you should perform a thorough follow-up of these patients especially in the early phases of treatment...
October 16, 2016: Journal of Oncology Pharmacy Practice
Axel Bode, Kambiz Rahbar, Julia Konnert, Martin Bögemann, Lars Stegger
A 66-year-old man with castration-resistant prostate carcinoma and multiple symptomatic bone mestastases was considered for Ra-dichloride (Xofigo) therapy. Staging with Ga-PSMA-PET/CT revealed additional extensive tumor involvement of the spine without relevant uptake in bone scintigraphy. Based on this imaging result, the patient was rescheduled for a PSMA-targeted therapy. Additional Ga-PSMA-PET/CT may have a considerable benefit for patients considered for Xofigo.
October 5, 2016: Clinical Nuclear Medicine
Daniel H Hovelson, Scott A Tomlins
Molecular biomarkers play little role in the current treatment of metastatic castration-resistant prostate cancer (CRPC). The advent of next-generation sequencing (NGS) has enabled the comprehensive molecular characterization of the genomic and transcriptomic landscape of both untreated primary prostate cancer and CRPC. Recent studies demonstrating the feasibility of interinstitution studies obtaining and NGS profiling of metastatic biopsies, targeted NGS approaches applicable to routine formalin-fixed, paraffin-embedded specimens, and NGS approaches applicable to circulating DNA and circulating tumor cells portend near-term adoption of NGS approaches in the management and treatment of CRPC...
September 2016: Cancer Journal
Elena Castro, Joaquin Mateo, David Olmos, Johann S de Bono
Several genomic studies have identified DNA repair gene defects in prostate cancer in the last 5 years. The mechanisms by which these DNA repair defects promote carcinogenesis and tumor progression in the prostate have not been fully elucidated, but their presence in at least 20-25% of metastatic castration-resistant prostate cancers (CRPCs) provides an opportunity for a therapeutic strategy that turns a tumor strength into its weakness and may lead to arguably the first molecularly stratified treatment for this disease...
September 2016: Cancer Journal
Min Yuen Teo, Michael J Morris
Prostate-specific membrane antigen (PSMA) is highly expressed on both benign and malignant prostatic tissue. Prostate-specific membrane antigen-directed therapy is conceptually promising, with a potential to additionally serve as a theranostic model in management of advanced prostate cancer. To date, various approaches have been devised and tested, including radiolabeled PSMA antibodies and inhibitor and antibody-drug conjugates. However, development and progress have faced challenges in determining the optimal combination of payload, PSMA-binding moiety, and linker technology...
September 2016: Cancer Journal
Oliver Sartor
Radiopharmaceuticals used in the treatment of castrate-resistant prostate cancer are reviewed herein with an emphasis on sequential and combination therapies. Four bone-seeking radiopharmaceuticals had been approved in the United States. Three of these are β-emitters (phosphorus-32, strontium-89, samarium-153-ethylenediaminetetramethylene-phosphonic acid) that are approved for palliative purposes. One α-emitter (radium-223 [Ra]) is approved for prolongation of survival in bone metastatic castrate-resistant prostate cancer...
September 2016: Cancer Journal
Oladapo Yeku, Susan F Slovin
Immunotherapy for castration-resistant prostate cancer has continued to be an area of active research over the last several years. The enthusiasm of this approach has been based on the assumption of better tolerability and that using the body's own immune system may be more effective than either hormonal or chemotherapy. Sipuleucel-T, a dendritic cell-based vaccine, is the only approved agent in this class for the management of castrate-resistant prostate cancer. Although sipuleucel-T increases overall survival without any significant changes in progression-free survival, other forms of immunotherapy such as PSA-TRICOM, ipilimumab, and chimeric antigen receptor T cell therapy are in advanced stages of clinical development...
September 2016: Cancer Journal
Michael W Drazer, Walter M Stadler
Most men with metastatic prostate cancer who are treated with androgen deprivation therapy will eventually develop castration-resistant disease. In this review, we examine the molecular mechanisms that constitute castration resistance and how these processes may be exploited using testosterone-based therapies. We detail how the utilization of superphysiologic doses of testosterone at regular intervals, followed by a rapid clearance of testosterone through continued chemical castration, also known as bipolar androgen therapy, offers an especially promising therapeutic approach...
September 2016: Cancer Journal
Zachery R Reichert, Maha Hussain
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival...
September 2016: Cancer Journal
Daniel C Danila, Aliaksandra Samoila, Chintan Patel, Nicole Schreiber, Amrita Herkal, Aseem Anand, Diogo Bastos, Glenn Heller, Martin Fleisher, Howard I Scher
Circulating tumor cell (CTC) number measured with the CellSearch assay is prognostic for survival in metastatic castration-resistant prostate cancer before and after therapy. Using a standard operating protocol for sample collection, processing, and analysis, we compared detection rates of CellSearch performed using US Food and Drug Administration-cleared methodology with a second positive selection assay, AdnaTest, and a nonselection polymerase chain reaction (PCR)-based (direct detection PCR [DDPCR]) assay in 55 blood samples from 47 men with progressive metastatic castration-resistant prostate cancer...
September 2016: Cancer Journal
Sankar N Maity, Mark A Titus, Revekka Gyftaki, Guanglin Wu, Jing-Fang Lu, S Ramachandran, Elsa M Li-Ning-Tapia, Christopher J Logothetis, John C Araujo, Eleni Efstathiou
Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation...
October 17, 2016: Scientific Reports
Sanjoy Kumar Sureka, Ruchir Maheshwari, Shalini Agnihotri, Nilay Mitash, Shamim Ahmad, Anil Mandhani
BACKGROUND & OBJECTIVES: There is lack of data on natural history and progression of prostate cancer (PC) which have implications in the management of the disease. We undertook this retrospective study to analyze factors predicting progression of metastatic PC to castration-resistant prostate cancer (CRPC) in Indian men. METHODS: Complete records of 223 of the 489 patients with metastatic PC were obtained from computerized data based system in a tertiary care hospital in north India between January 2000 to June 2012...
May 2016: Indian Journal of Medical Research
Che-Kai Tsao, John Sfakianos, Bobby Liaw, Kiev Gimpel-Tetra, Margaret Kemeny, Linda Bulone, Mohammad Shahin, William Kyu Oh, Matthew David Galsky
LESSONS LEARNED: The safety and activity findings of abiraterone acetate plus prednisone treatment in black men with mCRPC were similar to results from previously conducted studies with largely white populations.Poor trial accrual continues to be a challenge in black men with mCRPC and further efforts are needed to address such underrepresentation. BACKGROUND: Self-identified black men have higher incidence and mortality from prostate cancer in the United States compared with white men but are dramatically underrepresented in clinical trials exploring novel therapies for metastatic castration-resistant prostate cancer (mCRPC)...
October 14, 2016: Oncologist
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