scholarly journals The heterogeneity of prostate cancers lacking AR activity will require diverse treatment approaches

2021 ◽  
Author(s):  
Mark P Labrecque ◽  
Joshi J Alumkal ◽  
Ilsa M Coleman ◽  
Peter S Nelson ◽  
Colm Morrissey
Keyword(s):  
Prostate Cancer ◽  
Treatment Strategies ◽  
Small Cell ◽  
Cell Phenotype ◽  
Tumor Type ◽  
Castration Resistant Prostate Cancer ◽  
Treatment Approaches ◽  
Tumor Plasticity ◽  
Signaling Axis ◽  
Therapeutic Development

The use of androgen deprivation therapy and second line anti-androgens in prostate cancer has led to the emergence of tumors employing multiple androgen receptor (AR)-dependent and AR-independent mechanisms to resist AR targeted therapies in castration-resistant prostate cancer (CRPC). While the AR signaling axis remains the cornerstone for therapeutic development in CRPC, a clearer understanding of the heterogeneous biology of CRPC tumors is needed for inno-vative treatment strategies. In this review, we discuss the characteristics of CRPC tumors that lack AR activity and the temporal and spatial considerations for the conversion of an AR-dependent to an AR-independent tumor type. We describe the more prevalent treatment-emergent phenotypes aris-ing in the CRPC disease continuum, including amphicrine, AR-low, double-negative, neuroendo-crine and small cell phenotypes. We discuss the association between the loss of AR activity and tumor plasticity with a focus on the roles of transcription factors like SOX2, DNA methylation, alterna-tive splicing, and the activity of epigenetic modifiers like EZH2, BRD4, LSD1, and the nBAF complex in conversion to a neuroendocrine or small cell phenotype in CRPC. We hypothesize that only a subset of CRPC tumors have the propensity for tumor plasticity and conversion to the neuroendo-crine phenotype and outline how we might target these plastic and emergent phenotypes in CRPC. In conclusion, we assess the current and future avenues for treatment and determine that the heter-ogeneity of CRPCs lacking AR activity will require diverse treatment approaches.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

Anaplastic features (AnaF) and DNA-damage repair pathway (DDR) mutations in metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 92-92
Author(s):  
Vincent Chau ◽  
Ravi Amrit Madan ◽  
Marijo Bilusic ◽  
Lisa M. Cordes ◽  
Jennifer L. Marte ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Mutational Analysis ◽  
Short Interval ◽  
Elevated Serum ◽  
High Volume ◽  
Small Cell ◽  
Castration Resistant Prostate Cancer ◽  
Damage Repair ◽  
Serum Cea

92 Background: Anaplastic prostate cancer displays features of small-cell carcinoma, a type of neuroendocrine tumor. Treatments for anaplastic prostate cancer are based on small cell lung cancer regimens. Both AnaF and mutations in DDR pathways, including BRCA2 confer an aggressive phenotype. For patients (pts) with certain DDR mutations, olaparib (O) was recently FDA approved, and an ongoing study is evaluating whether the addition of durvalumab (D) confers additional benefit in mCRPC (NCT02484404). We evaluate a potential preliminary relationship between DDR mutations, treatment with D and O, and AnaF. Methods: This is a phase II study of O plus D in pts with mCRPC with disease that is amenable to biopsy. On-study core biopsies undergo mutational analysis. Prior treatment with enzalutamide (enza) and/or abiraterone (abi) is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Pts were categorized into those with and without AnaF as defined by Aparicio et al. (2013). AnaF include small-cell histology; exclusively visceral metastases; predominantly lytic bone metastases; bulky lymphadenopathy (≥5 cm) or high-grade (Gleason ≥8) mass in prostate/pelvis; low PSA (≤10 ng/mL) at initial presentation with high volume (≥20) bone metastases; neuroendocrine markers in histology or serum plus elevated LDH, malignant hypercalcemia, or elevated serum CEA; or short interval (≤6 months) to androgen-independent progression. Results: Of 55 pts accrued, 24 had prior abi and enza; 19 pts had prior taxane. Common adverse events include anemia, fatigue, and nausea. Also, 11 pts (20.0%) displayed clear AnaF (Table) and 43 pts lacked AnaF, including 8 (14.5%) with partial AnaF that did not meet the full criteria, 4 (7.3%) who likely did not have AnaF due to difficulty in quantifying disease burden, 29 (52.7%) who did not have AnaF, and 2 (3.6%) had unknown status. Four pts (36.4%) with clear AnaF had DDR aberrations, including 3 (27.3%) with BRCA2, 1 (9.1%) with both BRCA2 and CHEK2, and 1 (9.1%) with ATM. Conclusions: Pts with mCRPC with DDR mutations can also have AnaF. This preliminary data demonstrates that pts with anaplastic prostate cancer and pts with DDR mutations are two distinct populations with some degree of overlap. O+D is well-tolerated, and future studies should focus on finding optimal treatments for pts with AnaF without and without DDR mutations. Clinical trial information: NCT02484404. [Table: see text]

scholarly journals Clinicopathologic Diagnostic Approach to Aggressive Variant Prostate Cancer

2019 ◽  
Vol 144 (1) ◽  
pp. 18-23 ◽  
Author(s):  
Varsha Manucha ◽  
John Henegan
Keyword(s):  
Prostate Cancer ◽  
English Language ◽  
Treatment Strategies ◽  
Castration Resistant Prostate Cancer ◽  
Ongoing Research ◽  
Castration Resistant ◽  
Current Review ◽  
Pathologic Features ◽  
Neuroendocrine Carcinomas ◽  
Aggressive Variant

Context.— Aggressive variant prostate cancer (AVPCa) develops in a subset of patients with metastatic castration-resistant prostate cancer. The clinical and histologic overlap of AVPCa with other neuroendocrine carcinomas of the prostate has resulted in a lack of consensus on its terminology and treatment. Objective.— To review AVPCa to familiarize pathologists with this entity so they can actively participate in the detection, ongoing research, and evolving management of AVPCa. Data Sources.— The English language literature was reviewed. Conclusions.— The current review summarizes the pathologic features of AVPCa, describes how it has been defined clinically, and discusses how biomarkers may inform treatment strategies in the future.

Modern Management of Castration-resistant Prostate Cancer

2013 ◽  
Vol 09 (01) ◽  
pp. 34 ◽  
Author(s):  
Axel Heidenreich ◽  
David Pfister ◽  
Axel Merseburger ◽  
Georg Bartsch ◽  
◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Medical Treatment ◽  
Treatment Options ◽  
Treatment Strategies ◽  
New Drugs ◽  
Control Group ◽  
Daily Routine ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Radium 223

The approval or clinical evaluation of several new agents – cabazitaxel, enzalutamide, sipuleucel-T, radium-223 and abiraterone acetate – has significantly changed the management of patients with metastatic castration-resistant prostate cancer (mCRPC) prior to or after docetaxelbased chemotherapy. All of these agents have resulted in a significant survival benefit compared with their control group. However, treatment responses might differ depending on the associated comorbidities and the extent and the biological aggressiveness of the disease. Furthermore, treatment-associated side effects differ between the various drugs. As new drugs are approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. It is the aim of this article to (1) summarise the data of established treatment options in mCRPC, (2) highlight new developments of medical treatment, (3) provide clinically useful algorithms for the daily routine and to (4) point out future developments of medical treatment.

Association of neuroendocrine (NE) mRNA expression profiling in hormone-sensitive tumors samples with adverse clinical outcome in castration-resistant prostate cancer (CRPC) patients.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 165-165
Author(s):  
Mayra Orrillo ◽  
Natalia Jimenez ◽  
Oscar Reig ◽  
Giancarlo Castellano ◽  
Albert Font ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Outcome ◽  
Treatment Strategies ◽  
Gene Signature ◽  
Molecular Profile ◽  
Castration Resistant Prostate Cancer ◽  
Adverse Clinical Outcome ◽  
Related Gene ◽  
Primary Tumors ◽  
Hormone Sensitive

165 Background: NE dedifferentiation is associated to clinical aggressiveness and resistance to androgen receptor inhibition in prostate cancer. We investigated impact of a NE expression signature in the clinical outcome of mCRPC patients treated with taxanes. Methods: This is a multicenter retrospective study. A customized panel of 45 NE-related gene signature was tested in total RNA from formalin-fixed paraffin-embedded hormone-sensitive tumor samples, by the nCounter platform (Nanostring Technologies). Patients were grouped according to their molecular profile by unsupervised clustering. Expression levels were correlated with taxanes response and clinical outcome. Independent association with survival was evaluated by multivariate Cox modeling. Results: Eighty seven patients were included in the study, 79 were treated with docetaxel and 8 with cabazitaxel. Median age was 64.8 (44-88.3) years and median follow-up was 20.7 (1.17-74.4) months. High expression of the NE signature was associated with a shorter time of CRPC development (N=60, median 12.8 vs 21.6, HR 2.4, 95%CI 1.3-4.3, P=0.003) and shorter OS from CRPC diagnosis (median 24.1 vs 41.33, HR 2.3, 95%CI 1.4-3.8, P=0.001). Moreover, according to the outcome to taxanes, high NE signature correlated with lower PSA-PFS (median 6.6 vs 10.1 mo P=0.047, HR 1.6, 95%CI 1-2.7, P=0.05) and OS (median 19 vs 22 mo, HR 1.8, 95%CI 1.1-2.8, P=0.014), and it was independently associated to a lower OS (HR 1.9, 95%CI 1.1-3.2, P=0.016). Conclusions: NE-related gene expression in hormone-sensitive tumor samples is associated with adverse clinical outcome and lower taxane benefit in metastatic CRPC patients. Thus, molecular characterization of primary tumors may be useful to guide treatment strategies in metastatic prostate cancer.

scholarly journals Clinical Evaluation of Abiraterone in the Treatment of Metastatic Prostate Cancer

2013 ◽  
Vol 7 ◽  
pp. CMU.S8337
Author(s):  
Jatinder Goyal ◽  
Emmanuel S. Antonarakis
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Complex Disease ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Irreversible Inhibitor ◽  
Androgen Synthesis ◽  
Medical Need ◽  
The Us ◽  
Signaling Axis

Treatment of castration-resistant prostate cancer remains an area of unmet medical need. Evidence suggests that this entity continues to be driven by androgens and androgen receptor (AR) signaling. Abiraterone acetate, a pregnenolone derivative, is an oral selective and irreversible inhibitor of the key steroidogenic enzyme CYP17. It possesses dual 17-α hydroxylase and C17,20-lyase blocking activity, the result of which is decreased gonadal and extra-gonadal androgen synthesis. Abiraterone was first approved by the US Food and Drug Administration (FDA) in 2011 following the demonstration of superior survival compared with placebo in the post-docetaxel population. Since that time, more evidence has been generated from preclinical studies and clinical trials which have considerably enhanced our understanding of this complex disease. In this paper, we review the development of abiraterone acetate, its pharmacological characteristics, and its effects on the androgen-AR signaling axis, along with the combined experience from clinical trials. We also discuss some of the ongoing trials using this agent, as well as potential mechanisms of abiraterone resistance, novel biomarker development, and future directions using AR-directed therapies.

scholarly journals Understanding Treatment Strategies and Preferences in Nonmetastatic Castration-Resistant Prostate Cancer From the Japanese Physician Perspective

2021 ◽  
pp. 302-310
Author(s):  
Kazuhiro Suzuki ◽  
Vince Grillo ◽  
Yirong Chen ◽  
Shikha Singh ◽  
Dianne Athene Ledesma
Keyword(s):  
Prostate Cancer ◽  
Decision Making ◽  
Treatment Strategies ◽  
Patient Characteristics ◽  
Relative Importance ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Treatment Characteristics ◽  
Hypothetical Treatment ◽  
Preference Weights

PURPOSE Sixteen percent (16%) of patients with castration-resistant prostate cancer (CRPC) show no bone metastasis at diagnosis. However, 33% will become metastatic within 2 years. The goal of treatment in patients with nonmetastatic CRPC (nmCRPC), therefore, is to delay symptomatic metastases without undue toxicity. With novel antiandrogen treatments of different strengths and limitations available, physician preferences for nmCRPC treatment in Japan should be understood. METHODS A discrete choice experiment was conducted. Physicians chose between two hypothetical treatments in nmCRPC defined by six attributes: risk of fatigue, falls or fracture, cognitive impairment, hypertension, rashes as side effects of treatment, and extension of time until cancer-related pain occurs. Relative preference weights and relative importance were estimated by hierarchical Bayesian logistic regression. Physicians were also asked to make treatment decisions based on four hypothetical patient profiles to understand the most important factors driving decision making. RESULTS A total of 151 physicians completed the survey. Extension of time until cancer-related pain occurs was the most important attribute (relative importance, 32.3%; CI, 31.3% to 33.3%). Based on summed preference weights across all attributes, preferences for hypothetical treatment profiles I, II, and III were compared. A hypothetical treatment profile with better safety though shorter extension time was preferred (I: mean [standard deviation] = 1.7 [1.6 to 2.1]) over treatment profiles with lower safety but longer extension time (II: −2.7 [−2.8 to −2.6] and III: −0.2 [−0.3 to −0.1]). Treatment characteristics were more important factors for physicians' decision making than patient characteristics in prescribing treatment. CONCLUSION Physicians preferred a treatment with better safety profile, and treatment characteristics were the most important factors for decision making. This might have implications in physicians' decision making for nmCRPC treatment in the future in Japan.

scholarly journals Treatment Approaches for Nonmetastatic Castration-Resistant Prostate Cancer

2015 ◽  
Vol 14 (2) ◽  
pp. 120-127
Author(s):  
Mehmet Yıldızhan ◽  
Hakan Gemalmaz ◽  
Mehmet Şirin Ertek
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Treatment Approaches ◽  
Castration Resistant
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