Treatment Of Metastatic Castration-resistant Prostate Cancer Research Articles

Vaccines as treatments for prostate cancer.

Prostate cancer is a leading cause of death in men worldwide. For over 30 years, growing interest has focused on the development of vaccines as treatments for prostate cancer, with the goal of using vaccines to activate immune cells capable of targeting prostate cancer to either eradicate recurrent disease or at least delay disease progression. This interest has been prompted by the prevalence and long natural history of the disease and by the fact that the prostate is an expendable organ. Thus, an immune response elicited by vaccination might not need to target the tumour uniquely but could theoretically target any prostate tissue. To date, different vaccine approaches and targets for prostate cancer have been evaluated in clinical trials. Overall, five approaches have been assessed in randomized phase III trials and sipuleucel-T was approved as a treatment for metastaticcastration-resistant prostate cancer, being the only vaccine approved to date by the FDA as a treatment for cancer. Most vaccine approaches showed safety and some evidence of immunological activity but had poor clinical activity when used as monotherapies. However, increased activity has been observed when these vaccines were used in combination with other immune-modulating therapies. This evidence suggests that, in the future, prostate cancer vaccines might be used to activate and expand tumour-specific T cells as part of combination approacheswith agents that target tumour-associated immune mechanisms of resistance.

Real-world clinical outcomes and cost estimates of metastatic castration-resistant prostate cancer treatment: does sequencing of taxanes and androgen receptor-targeted agents matter?

ABSTRACT Introduction Health economic outcomes of real-world treatment sequencing of androgen receptor-targeted agents (ARTA) and docetaxel (DOC) remain unclear. Material and Methods Data from the electronic Castration-resistant Prostate cancer Australian Database (ePAD) were analyzed including median overall survival (mOS) and median time-to-treatment failure (mTTF). Mean total costs (mTC) and incremental cost-effectiveness ratios (ICER) of treatment sequences were estimated using the average sample method and Zhao and Tian estimator. Results Of 752 men, 441 received ARTA, 194 DOC, and 175 both sequentially. Of participants treated with both, first-line DOC followed by ARTA was the more common sequence (n = 125, 71%). mOS for first-line ARTA was 8.38 years (95% CI: 3.48, not-estimated) vs. 3.29 years (95% CI: 2.92, 4.02) for DOC. mTTF was 15.7 months (95% CI: 14.2, 23.7) for the ARTA-DOC sequence and 18.2 months (95% CI: 16.2, 23.2) for DOC-ARTA. In first-line, ARTA cost an additional $13,244 per mTTF month compared to DOC. In second-line, ARTA cost $6726 per mTTF month. The DOC-ARTA sequence saved $2139 per mTTF compared to ARTA-DOC, though not statistically significant. Conclusion ICERs show ARTA had improved clinical benefit compared to DOC but at higher cost. There were no significant cost differences between combined sequences.

Germline mutations in prostate cancer: a systematic review of the evidence for personalized medicine.

The goal of precision medicine in prostate cancer (PCa) is to individualize the treatment according to the patient's germline mutation status. PCa has a very high rate of genetic predisposition compared with other cancers in men, with an estimated rate of cancers ascribable to hereditary factors of 5-15%. A systematic search (PubMed, Web of Science, and ClinicalTrials.gov) of English literature from 2000 to 2022, using the keywords "prostate cancer", "germline mutations", "family history", and "inheritance" was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The search identified 980 publications. Of these, 200 papers were removed before screening (duplicates, non-English literature, and publication year before 2000) and 245 records were excluded after title/abstract screening. Finally, 50 articles were included in the final analysis. We analyze the latest evidence on the genetic basis of PCa predisposition and clinical implications for more personalized screening protocols and therapeutic management of this high-prevalent cancer. Emerging data show that germline mutations in homologous recombination genes (BRCA1/2, ATM, CHECK2), in mismatch repair genes (MLH1, MLH2, MSH6), and other additional genes are associated with the development and aggressiveness of PCa. Germline testing and genetic counseling have increasingly important implications in cancer screening and therapeutic decisions making for patients affected by PCa. Patients with localized PCa and some gene mutations are more likely to develop aggressive cancer, so active treatment may be preferable to active surveillance for these patients. Moreover, in patients with metastatic PCa, these gene alterations may be useful biomarkers for predicting response to specific therapy such as PARP inhibitors, recently approved for the treatment of metastatic castration-resistant PCa. The evidence supports recent guidelines and recommendations considering germline genetic testing for patients with a positive family history of PCa or men with high risk or metastatic disease.

The Role of PSMA PET Imaging in Prostate Cancer Theranostics: A Nationwide Survey

Introduction: Prostate-specific membrane antigen (PSMA)-based imaging and theranostics have played an important role in the diagnosis, staging, and treatment of prostate cancer (PCa). We aimed to evaluate the acceptance and use of PSMA theranostics among German urologists. Methods: An anonymous online questionnaire was sent via survio.com to the members of the German Society of Urology (DGU). Results: Seventy-two percent of participants performed PSMA positron emission tomography (PET) imaging regularly in biochemically recurrent PCa. Overall, 61% of participants considered PSMA-radioligand therapy to be very useful or extremely useful. PSMA PET imaging in high-risk PCa is more often considered by urologists working in a university setting than in nonuniversity settings or medical practices (51% vs. 25%, p < 0.001). Most perform PSMA-radioligand therapy as an option after all approved systemic treatments for metastatic castration-resistant PCa (56%) or after cabazitaxel (14%). A total of 93.9% and 70.3% of respondents consider the lack of reimbursement by health insurance to be the main obstacle to using PSMA PET imaging or radioligand therapy, respectively. Discussion/Conclusion: PSMA-based imaging/theranostics are already widely applied but would find even more widespread use if reimbursement is clearly regulated by health insurance in Germany.

Androgen receptor antagonists produced by Streptomyces overcome resistance to enzalutamide.

Prostate cancer (PC) is a leading cause of cancer-related death in men in Western countries. Androgen receptor (AR) signaling is a major driver of PC; therefore, androgen deprivation by medical and surgical castration is the standard treatment for patients with PC. However, over time, most patients will progress to metastatic castration-resistant PC. Enzalutamide is the only AR antagonist approved by the Food and Drug Administration for the treatment of metastatic castration-resistant PC. However, resistance to enzalutamide also develops in most patients with castration-resistant PC. Thus, there is an urgent need to develop new AR antagonists with new structures. For this purpose, we conducted both in silico and natural product screenings. From the in silico screening, we obtained T5853872 and more potent compound, STK765173. From the natural product screening, the novel compound arabilin was isolated from Streptomyces sp. MK756-CF1. Unlike STK765173, arabilin could overcome resistance to enzalutamide. Furthermore, we also extracted a novel compound, antarlide A, and its geometric isomers from Streptomyces sp. BB47. Antarlides A-F have novel 22-membered-ring macrocyclic structures, while antarlides G and H have 20-membered-ring structures. Both antarlides B and G showed potent AR antagonist activity in prostate cancer cells and could overcome resistance to enzalutamide.

Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer.

Introduction: Castration resistant prostate cancer (CRPC) has been characterized by a reactivation of the androgen receptor (AR) signaling pathway via alterations in androgen metabolism and AR aberrations. High-dose testosterone (HDT) is emerging as an active treatment in metastatic CRPC, however, biomarkers of response are unknown. We hypothesized that responses to HDT might impact the genomic expression of AR alterations found in circulating-tumor DNA (ctDNA).Methods: Retrospective analysis of mCRPC patients treated with HDT (testosterone cypionate q 2–4 weeks) with available clinical and somatic genomic data using a commercially available assay (Guardant360, Redwood City, CA). Clinical outcomes included PSA response (PSA50), time to PSA progression (TPP) and safety.Results: A total of 33 mCRPC patients were treated with ≥2 testosterone cypionate injections. ctDNA testing revealed alterations in AR (39%), TP53 (48%), and DNA repair genes (12%). HDT was given for median of 4.0 months (95% CI, 2.6–5.3) with 24% of PSA50. Twenty patients were re-challenged with abiraterone (n = 2) or enzalutamide (n = 18) with 30% PSA50. Significant (grade ≥3) adverse events were observed in 5% of patients (grade 4 thrombocytopenia and asthenia). Patients with median baseline ctDNA% of ≥1.10 had numerically worse TPP outcomes and all patients with AR alterations exhibited decreased AR expression post-HDT (n = 9), yet no association between clinical outcomes and ctDNA findings was observed.Conclusions: HDT led to a decrease in AR copy number and mutations which was independent from responses to therapy. Further understanding of the genomic alterations as potential predictor of response to HDT is needed.

Modern drug therapy of prostate cancer through the example of Moscow

Background. The average annual increment (5,09 %) of the prostate cancer (PC) incidence was highest across male oncological diseases registered in Russia from 2007 to 2017. 4643 new cases of PC were diagnosed in Moscow in 2017. As of 1st January 2018, the total number of living males with PC registered within Moscow healthcare system was 31,567.The study objective was to obtain the structure of factual costs related to medicine therapy of PC covered by the budget funds of the Moscow Healthcare Department in 2016–2017, that would help to further improve the system of subsidized drug provision for Moscow residents.Materials and methods. Using data from the information database of the Center for Medicine Provision of the Moscow City Department of Healthcare the following parameters were determined: total sum of expenses on drug purchase, mean treatment cost per 1 patient, number of patients receiving therapy, number of prescriptions, number of prescribed drug packs, mean pack cost, and others. The analyzed medicines were classified based on pharmacological and clinical groups. Costs for each class of therapies were studied.Results. During studied period (2016–2017), the most funds in Moscow were spent on abiraterone and goserelin. In 2016–2017, the amounts of prescribed packs were highest for androgen deprivation therapy: luteinizing hormone-releasing hormone agonists – goserelin and buserelin. In the group comprising 10 therapeutic regimens associated with highest costs, the percentages of costs for hormonal therapy and chemotherapy were respectively as following: 80 % and 16 % in 2016 and 75 % and 23 % in 2017. In the simplified model of costs associated with androgen deprivation therapy and treatment of metastatic castration-resistant PC without consideration of androgen deprivation therapy constituted 39 % and 61 % in 2016 and 36 % and 64 % in 2017. In the population of patients with prostate cancer, zoledronic acid, abiraterone, docetaxel, cabazitaxel were the most used medications in 2017 and the rate of enzalutamide usage was lowest.Conclusion. The highest costs are associated with treatment of metastatic castration-resistant PC. There is a growing necessity for improvement of funds spending on medications for patients with castration-resistant PC. This improvement could be achieved through development of medical methodologies that facilitate the selection of the most cost-effective approaches for early diagnosis and treatment.

Impact of the introduction of novel hormonal agents on metastatic castration-resistant prostate cancer treatment choice.

Docetaxel-based chemotherapy has been the cornerstone of the management of symptomatic metastatic castration-resistant prostate cancer (mCRPC) since 2004. This study aimed to describe how real-world clinical practice was changed with the public funding of novel hormonal agents (abiraterone and enzalutamide) in Quebec. We conducted a retrospective cohort study in two McGill University hospitals. Hospital-based cancer registries were used to select mCRPC patients in medical oncology departments from January 2010 to June 2014. Two groups according to mCRPC diagnosis year were built, with 2012 chosen as the cut-off year, corresponding to the year abiraterone was approved for public reimbursement in second-line in Quebec. Kaplan-Meier analysis was used to estimate time to first docetaxel prescription since mCRPC diagnosis before and after 2012. Cox regression was used to identify predictive factors of docetaxel and novel hormonal agent use. In our cohort, 308 patients diagnosed with mCRPC were selected with 162 patients in the pre-2012 group and 146 patients in the post-2012 group. The median age at mCRPC was 74.0 years old. At 12 months from diagnosis, 69% of patients received a prescription for docetaxel in the pre-2012 group comparatively to 53% in the post-2012 group. Factors that decreased the likelihood of docetaxel utilization were: age older than 80 at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3-0.7), mCRPC diagnosis after 2012 (HR: 0.6; 95%CI: 0.4-0.8), and asymptomatic disease at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3-0.7). The introduction of novel hormonal agents reduced first-line and overall docetaxel utilization and delayed time to its initiation.

Chinese experts consensus on the treatment of metastatic prostate cancer 2018 edition

The prevalence of prostate cancer has shown a marked increase in China. Most patients are presented with metastasis at diagnosis.It has been proven by clinical trials that besides androgen deprivation therapy, Abiraterone and docetaxel can improve the overall survival of metastatic hormone sensitive prostate cancer patients with high risks.For metastatic castration-resistant prostate cancer treatment, docetaxel, abiraterone and enzalutamide, etc., have demonstrated significant overall survival benefit. Among them, docetaxel and abiraterone have accumulated adequate experience in Chinese patients. Therefore, it is quite important for Chinese physicians to make reasonable clinical decisions based on these treatment regimes. In order to improve patients' survival and life quality, Chinese Anticancer Association Genitourinary Oncology Committee composed this expert consensus to help physicians to make reasonable decisions.

Metastatic castration-resistant prostate cancer: a current view on drug therapy and alternative tumor cell regulation

Prostate cancer (PC) is one of the most common causes of death from malignant neoplasms in men in many countries around the world. Transmission of the signal in the androgenic axis of regulation is crucial for the development and progression of PC. Despite the constant dependence on androgen receptor signals in castration resistance, the use of new anti-androgenic drugs invariably leads to the stability of the ongoing treatment. The interaction of androgen receptor and alternative (phosphoinositide-3-kinases, PI3K) pathways in the regulation of cells can be one of the mechanisms of resistance to treatment. In this article, we describe current treatments for metastatic castration-resistant PC and the possible role of the PI3K pathway in the pathogenesis and progression of PC.

Dutch Economic Value of Radium-223 in Metastatic Castration-Resistant Prostate Cancer.

BackgroundThe treatment of metastatic castration-resistant prostate cancer has changed with the introduction of radium-223, cabazitaxel, abiraterone and enzalutamide. To assess value for money, their cost effectiveness in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective was investigated.MethodsA cost-effectiveness analysis was conducted using efficacy, symptomatic skeletal-related event and safety data obtained from indirect treatment comparisons. Missing skeletal-related event data for cabazitaxel were conservatively assumed to be identical to radium-223. A Markov model combined these clinical inputs with Dutch-specific resource use and costs for metastatic castration-resistant prostate cancer treatment from a societal perspective. Total quality-adjusted life-years and costs in 2017 euros were calculated over a 5-year (lifetime) time horizon.ResultsRadium-223 resulted in €6092 and €4465 lower costs and 0.02 and 0.01 higher quality-adjusted life-years compared with abiraterone and cabazitaxel, respectively, demonstrating dominance of radium-223. Sensitivity analyses reveal a 64% (54%) chance of radium-223 being cost effective compared with abiraterone (cabazitaxel) at the informal €80,000 willingness-to-pay threshold. Compared with enzalutamide, radium-223 resulted in slightly lower quality-adjusted life-years (−0.06) and €7390 lower costs, revealing a 61% chance of radium-223 being cost effective compared with enzalutamide. The lower costs of radium-223 compared with abiraterone and enzalutamide are driven by lower drug costs and prevention of expensive skeletal-related events. Compared with cabazitaxel, the lower costs of radium-223 are driven by lower costs of the drug, administration and adverse events.ConclusionRadium-223 may be a less costly treatment strategy offering similar gains in health benefits compared with abiraterone, cabazitaxel and enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective.Electronic supplementary materialThe online version of this article (doi:10.1007/s40258-017-0350-x) contains supplementary material, which is available to authorized users.

The role of bone-targeted therapies for prostate cancer in 2017.

Bone-targeted agents (BTAs), such as zoledronic acid and denosumab, delay the occurrence of skeletal-related events (SREs) in metastatic prostate cancer (PCa) patients. Recently, several agents, such as abiraterone acetate, enzalutamide and radium-223, were approved for the treatment of metastatic castration-resistant PCa (mCRPC). These agents resulted in improved overall survival (OS), pain control and had positive effects on bone health. Combining BTAs to the newly approved agents demonstrates additional benefits that warrant a review of available evidence looking at appropriate combination therapies and timing of BTAs for optimizing the management of advanced and metastatic PCa. Post-hoc analyses of randomized trials demonstrated some benefits from combination therapy, such as increased OS when denosumab was used concurrently with radium-223 and when BTAs were used with abiraterone acetate. BTAs were not beneficial for the prevention of bone metastases. There is a suggestion of synergy or additive effects between BTAs and new agents approved for the treatment of metastatic PCa, resulting in potential clinical benefits. Therefore, prospective randomized studies evaluating the safety and benefits of combination therapies to address gaps in the literature are needed to optimize treatment of mCRPC.

Vinculin and filamin-C are two potential prognostic biomarkers and therapeutic targets for prostate cancer cell migration.

Prostate cancer (PCa) is one of the most common diseases for male population, and the effective treatment for metastatic castration-resistant PCa is still lacking. To unravel the underlying mechanism of PCa cell migration, we plan to analyze the related crucial proteins and their roles. In our study, we firstly identify the differentially expressed proteins using quantitative proteomics, and confirm their mRNA expression using quantitative polymerase chain reaction (qPCR). The alterations of these proteins at DNA and mRNA levels are obtained from cBioPortal database. Furthermore, the functions of these proteins are evaluated using wound-healing assay. The quantitative proteomics identified vinculin (VCL) and filamin-C (FLNC) as two highly expressed proteins in PC3 cells, and the DNA and mRNA of these two proteins were amplified and upregulated in a part of PCa patients. Knockdown of VCL and FLNC gene expression significantly inhibit PCa cell migration. These findings suggest that VCL and FLNC identified by quantitative proteomics are highly expressed in PCa cells with high migration potential, and they could be effective targets for repressing PCa cell migration, paving a new avenue for the prognosis and treatment of advanced PCa.

A randomized study of enzalutamide in patients with localized prostate cancer undergoing active surveillance (ENACT).

TPS5097 Background: Prostate cancer (PC) patients (pts) who select active surveillance (AS) are a heterogeneous population with varying risks for disease progression. Studies have estimated that approximately 31–42% of pts electing AS have experienced disease progression (pathological or therapeutic) over 1.8 and 2.3 years. There is no evidence-based pharmacological intervention which has effectively lessened this progression event. Pharmacological intervention with enzalutamide (ENZ), an androgen receptor inhibitor approved for treatment of metastatic castration-resistant PC, may lessen this progression. The aims of this study are to evaluate the efficacy of ENZ versus AS alone for delaying time to progression in pts with clinically localized PC undergoing AS. This study examines the effects of ENZ on progression in a subset of pts with low- or intermediate-risk PC who would otherwise elect an AS protocol. Methods: This is a multicenter, randomized, open-label study (NCT02799745). Eligibility criteria include histologically confirmed prostate adenocarcinoma within 6 months of screening, low or intermediate risk PC (T1c−T2c, prostate-specific antigen [PSA] &lt; 20, N0, M0, Gleason score ≤7 [3+4 pattern only]), Eastern Cooperative Oncology Group status ≤2 and estimated life expectancy &gt; 5 years. Exclusion criteria include any prior PC intervention. Pts will be randomized to receive open-label oral ENZ 160 mg/day once daily or to AS during the 1-year study treatment period. After the first year, all pts will be followed for one additional year with no other intervention. All pts will undergo prostate biopsy at 1 and 2 years. The primary end point is time to PC progression (pathological or therapeutic). Secondary end points include safety, incidence of negative biopsies for cancer at 1 and 2 years, percentage of cancer positive cores at 1 and 2 years, time to PSA progression, incidence of secondary rise in serum PSA, and quality-of-life questionnaires. Exploratory end points include biomarker assessment and genomic analysis. Study enrolment commenced in June 2016, with study completion expected in March 2019. Planned total enrolment is 222 pts from ~60 United States/Canadian sites. Clinical trial information: NCT02799745.

Indomethacin to inhibit AKR1C3 intracrine androgen production and sensitizes prostate cancer (PCa) to enzalutamide.

161 Background: Enzalutamide (Enza) improves the treatment of metastatic castration-resistant PCa (mCRPC). Acquired resistance is the most common cause of treatment failure. Our objective was to determine mechanisms of resistance to Enza and develop novel therapy to overcome resistance. Methods: Enza-resistant PCa cells were established through continuous culture of C4-2B cells with Enza. Global gene expression array and western blots were used to assess gene expression in cell lines and validated in clinical specimens using Oncomine and GEO databases. The therapeutic effects of indomethacin were determined in cell culture and in mice carrying CWR22Rv1 xenografts. A Phase I/II clinical trial with Enza plus indomethacin has been approved by IRB. Results: Steroid biosynthesis pathways, especially AKR1C3, were significantly elevated in Enza resistant cells and was associated with high production of androgens. AKR1C3 was also highly expressed in metastatic and recurrent CaP and in Enza-resistant xenograft tumors. Overexpression of AKR1C3 conferred resistance to Enza. Inhibition of AKR1C3 expression by its specific shRNAs or AKR1C3 enzymatic activity by indomethacin re-sensitized Enza-resistant CaP cells to Enza treatment both in vitro and in vivo. Combination of indomethacin and Enza resulted in significant inhibition of Enza-resistant tumor growth. Indomethacin treatment in one patient with mCRPC induced tumor shrinkage and PSA decrease. In a Phase I/II trial funded by the Department of Defense, patients with mCRPC, good performance status (ECOG 0-2) and vital organ function, and no history of Enza or indomethacin treatment will be recruited. The co-primary objective is to assess the toxicity and prostate-specific antigen (PSA) response ( ≥ 50% reduction). We will also assess the overall response as determined by the Prostate Cancer Working Group 2 criteria, progression-free survival and molecular correlative studies. Conclusions: AKR1C3 activation is a critical resistance mechanism associated with Enza resistance. Indomethacin targets AKR1C3 and intratumor androgen synthesis, and can be potentially used as a therapeutic agent for mCRPC. Clinical trial results will be presented. Clinical trial information: to be registered.

Abstract 5069: p66Shc regulates the migration of castration-resistant prostate cancer

Abstract Purpose and Background: Prostate cancer (PCa) remains the most commonly diagnosed solid tumor and is the second leading cause of cancer-related death in United States men. While androgen deprivation therapy is the current standard-of-care treatment for metastatic PCa, most patients eventually relapse and develop castration-resistant (CR) tumors for which there is currently no effective treatment. p66Shc, a 66 kDa Src and collagen homologue oxidase, is elevated in clinical PCa as well as multiple PCa cell lines which correspond with advanced CR PCa. Additionally, p66Shc has been demonstrated to promote proliferation in PCa cell lines via generation of reactive oxygen species (ROS). This study is the first to demonstrate p66Shc also regulates PCa cell migration. Understanding of the mechanism through which p66Shc promotes migration may lead to the development of therapeutic strategies to treat metastatic CR PCa. Experimental Methods: Human prostate adenocarcinoma cell lines LNCaP C-33 and C-81, androgen-sensitive (AS) and androgen independent (AI) MDA PCa2b, PC-3, and DU145 were used to determine the role of p66Shc in PCa migration. Stable p66Shc cDNA transfected subclones S-31, S-32, and S-36 were established from LNCaP C-33 cells. p66Shc's impact on migration was determined using transwell migration assays. Immunoblotting was performed to profile potential proteins involved in the mechanism through which p66Shc influences migration. Small-molecule inhibitors were used to confirm these proteins’ involvement in migration. Results: Levels of p66Shc protein positively correlate with metastatic potential across multiple PCa cell lines as well as LNCaP and MDA call progressive models. p66Shc is an authentic oxidase and promotes ROS production. In this study, we further demonstrate peroxide treatment is able to induce C-33 cell migration in a dose-dependent manner, while antioxidants inhibit migration. Similarly, p66Shc subclones possess increased migratory ability which is abolished upon antioxidant treatment and demonstrates the involvement of ROS in p66Shc-mediated migration. Molecular profiling reveals the correlation of p66Shc protein level with the activation of ErbB-2, PYK2, AKT, ERK, p38, RAC1, STAT3, and STAT5 as well as suppression of cPAcP. Conclusions: Altogether, our results indicate p66Shc is involved in PCa cell migration, in part, by inducing ROS generation. Understanding the role p66Shc in advanced PCa progression will help to determine its potential as a therapeutic target, and elucidating its mechanism of intracellular signaling will enable us to design new treatments for metastatic CR PCa. Citation Format: Matthew A. Ingersoll, Sakthivel Muniyan, Fen-Fen Lin, Ta-Chun Yuan, Yu-Wei Chou, Surinder K. Batra, Ming-Fong Lin. p66Shc regulates the migration of castration-resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5069.

Patterns of metastatic disease progression after treatment with first-line enzalutamide or abiraterone in castration-resistant prostate cancer (CRPC).

e16539Background: Abiraterone (A) and enzalutamide (E) are life-prolonging treatments for metastatic CRPC, yet their potent activity against the androgen receptor (AR) axis often yields tumors that...

Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations.

Mutant p53 proteins (mutant p53s) have oncogenic gain-of-function properties correlated with tumor grade, castration resistance, and prostate cancer (PCa) tumor recurrence. Docetaxel is a standard first-line treatment for metastatic castration-resistant PCa (mCRPC) after the failure of hormone therapy. However, most mCRPC patients who receive docetaxel experience only transient benefits and rapidly develop incurable drug resistance, which is closely correlated with the p53 mutation status. Mutant p53s were recently reported to regulate the metabolic pathways via sterol regulatory element-binding proteins (SREBPs). Therefore, targeting the SREBP metabolic pathways with docetaxel as a combination therapy may offer a potential strategy to improve anti-tumor efficacy and delay cellular drug resistance in mCRPC harboring mutant p53s. Our previous data showed that fatostatin, a new SREBP inhibitor, inhibited cell proliferation and induced apoptosis in androgen receptor (AR)-positive PCa cell lines and xenograft mouse models. In this study, we demonstrated that mutant p53s activate the SREBP-mediated metabolic pathways in metastatic AR-negative PCa cells carrying mutant p53s. By blocking the SREBP pathways, fatostatin inhibited cell growth and induced apoptosis in metastatic AR-negative PCa cells harboring mutant p53s. Furthermore, the combination of fatostatin and docetaxel resulted in greater proliferation inhibition and apoptosis induction compared with single agent treatment in PCa cells in vitro and in vivo, especially those with mutant p53s. These data suggest for the first time that fatostatin alone or in combination with docetaxel could be exploited as a novel and promising therapy for metastatic PCa harboring p53 mutations.

Radium223—Where Does It Fit in the Metastatic Castration-resistant Prostate Cancer Treatment Landscape?

Radium223 is approved for symptomatic castration-resistant prostate cancer patients with osseous involvement. Selecting patients and defining sequence strategies are challenging, with the limited available data, but there is a trend toward greater impact in higher volume disease. Combination and/or consolidation strategies for Radium223 will be of significant interest as data emerge from ongoing trials.

Androgen deprivation therapy increases the sensitivity of human prostate carcinoma cells to T cell-mediated lysis through an androgen receptor dependent mechanism

Despite recent advances in diagnosis and therapy, prostate cancer remains the most frequently diagnosed non-skin cancer in the United States and the third leading cause of cancer deaths. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors Enzalutamide and Abiraterone are approved for treatment of metastatic CRPC. Enzalutamide is a second-generation androgen antagonist with no agonist activity. Abiraterone is a cytochrome P450 inhibitor that blocks adrenal and intratumoral androgen production. Here we show for the first time that both Enzalutamide and Abiraterone induce immunogenic modulation in human prostate tumor cells, rendering them more sensitive to T cell-mediated lysis, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, exposure in vitro and in vivo of human prostate carcinoma cells to Enzalutamide significantly down-regulated the anti-apoptotic NAIP gene. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that Enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of Enzalutamide and Abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, particularly for patients with minimal response to Enzalutamide or Abiraterone alone, or for patients who have developed resistance to ADT.