scholarly journals ZRSR2 overexpression is a frequent and early event in castration-resistant prostate cancer development

2021 ◽  
Author(s):  
Haiqing He ◽  
Jun Hao ◽  
Xin Dong ◽  
Yu Wang ◽  
Hui Xue ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle Progression ◽  
Locally Advanced ◽  
Patient Treatment ◽  
Early Event ◽  
Driver Gene ◽  
Castration Resistant Prostate Cancer ◽  
Driver Genes ◽  
Castration Resistant ◽  
Pdx Models

Abstract Background Androgen deprivation therapy (ADT) remains the leading systemic therapy for locally advanced and metastatic prostate cancers (PCa). While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development. Methods We have developed a unique panel of hormone-naïve PCa (HNPC) patient-derived xenograft (PDX) models at the Living Tumor Laboratory. The PDXs provide a unique platform for driver gene discovery as they allow for the analysis of differentially expressed genes via transcriptomic profiling at various time points after mouse host castration. In the present study, we focused on genes with expression changes shortly after castration but before CRPC has fully developed. These are likely to be potential early drivers of CRPC development. Such genes were further validated for their clinical relevance using data from PCa patient databases. ZRSR2 was identified as a top gene candidate and selected for further functional studies. Results ZRSR2 is significantly upregulated in our PDX models during the early phases of CRPC development after mouse host castration and remains consistently high in fully developed CRPC PDX models. Moreover, high ZRSR2 expression is also observed in clinical CRPC samples. Importantly, elevated ZRSR2 in PCa samples is correlated with poor patient treatment outcomes. ZRSR2 knockdown reduced PCa cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway. Conclusion Using our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.

Studies of a novel modified E2F-targeted peptide with activity against castration-resistant prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 205-205
Author(s):  
Joseph R. Bertino ◽  
Zoltan Szekely ◽  
Kathleen W Scotto
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Replication Proteins ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Stability

205 Background: The E2F family of genes encodes transcription factors that are key to the regulation of a number of target genes, including those encoding cyclins , CDKs , checkpoints regulators, and DNA repair and replication proteins. One of the primary functions of the E2Fs is to control the cell cycle, playing a major role in regulating the G1/S transition. One of the primary regulators of E2F expression is the retinoblastoma gene, RB, a chromatin associated protein that, in its unphosphorylated state, binds to and negatively regulates E2F; hyperphosphorylation of RB releases E2F, allowing cell cycle progression. Many tumor cells have mutant or dysfunctional RB, allowing the aberrant overexpression of the E2Fs and tumor cell proliferation; this aberrant overexpression is better tolerated when p53 is mutated, suppressing subsequent apoptosis. Overexpression of E2F, particularly E2F1, has thus been an attractive target for therapeutic intervention. However, this approach has not yet been successful, most likely due to the redundancy of the E2Fs and the lack of biomarkers for sensitivity. Methods: Using phage display, we have previously identified a novel peptide that, when coupled with penetratin (PEP) to enhance uptake), targets the E2F consensus site in E2F1,2 and 3a, leading to the downregulation of the activating E2Fs and their downstream targets. We have recently enhanced the stability and potency of this peptide by substituting L-Arg within the peptide with D-Arg. Results: Castrate resistant prostate cancer (CRPC) cells, DU-145, lack functional RB, have mutant p53, and are more sensitive to the D-Arg PEP than LnCap or PC-3 cells, with functional RB. Xenograft studies in mice show that the PEP, when encapsulated in PEGylated liposomes (PL-D-Arg PEP) , regresses DU-145 tumors without toxicity. Current studies are examining the combination of the (PL-D-Arg PEP) with taxotere, cisplatin and irradiation in prostate cancer xenografts and organoids from patients. Conclusions: A peptide that inhibits transcription of the activating E2Fs has promise to treat CRPC.

scholarly journals PD25-11 MULTIVISCERAL SURGERY IN MEN WITH LOCALLY ADVANCED, SYMPTOMATIC CASTRATION RESISTANT PROSTATE CANCER

2019 ◽  
Vol 201 (Supplement 4) ◽  
Author(s):  
Friederike Haidl* ◽  
David Pfister ◽  
Daniel Porres ◽  
Leonidas Karapanos ◽  
Johannes Salem ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Locally Advanced ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Multivisceral Surgery

New Options for the Management of Castration-Resistant Prostate Cancer: A Case Perspective

2011 ◽  
Vol 9 (Suppl_3) ◽  
pp. S-13-S-24 ◽  
Author(s):  
Dawn Goetz
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Locally Advanced ◽  
Castration Resistant Prostate Cancer ◽  
Study Approach ◽  
Castration Resistant ◽  
Localized Disease ◽  
Hormone Refractory ◽  
The Cost

Prostate cancer is the leading cause of cancer and second leading cause of death among men. Management of localized disease is fairly straight-forward, but treatment for locally advanced or metastatic disease is much less so. Androgen-deprivation therapy serves as the foundation of treatment for patients with locally advanced or metastatic disease. Although most patients with prostate cancer show a response to medical or surgical castration, many eventually experience a hormone-refractory, incurable state. Until recently, therapeutic options for CRPC have been limited and focused on systemic chemotherapeutic options. Unfortunately, however, this provides a minimal increase in overall survival, at the cost of significant additional toxicities. Therefore, much research has gone into developing other suitable therapies with potentially less toxicity. This article uses a case study approach to discuss new options for the treatment of castration-resistant prostate cancer.

scholarly journals Current opportunities of therapy for patients with non-metastatic castration-resistant prostate cancer

2020 ◽  
Vol 16 (3) ◽  
pp. 190-197
Author(s):  
B. Ya. Alekseev ◽  
K. M. Nushko ◽  
P. S. Kozlova ◽  
A. D. Kaprin ◽  
O. I. Mailyan
Keyword(s):  
Prostate Cancer ◽  
Locally Advanced ◽  
Specific Antigen ◽  
Distant Metastases ◽  
Diagnostic Methods ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Testing ◽  
Urological Malignancies ◽  
And Control

Prostate cancer is one of the most common urological malignancies. Improved diagnostic methods and widespread implementation of mandatory prostate specific antigen (PSA) testing in a number of clinics have led to an increase in the number of timely diagnosed cases of localized and locally advanced prostate cancer, as well as to the expansion of indications for radical therapies. Nevertheless, 30 % to 50 % of patients (depending on their risk) develop biochemical relapse after surgery or radiotherapy. Non-metastatic castration-resistant prostate cancer is usually a result of disease progression after radical treatment and long-term androgen-deprivation therapy, which manifests by constant increase in the PSA level along with castrate level of testosterone and no distant metastases according to the results of comprehensive radiological examination. A number of large clinical studies have demonstrated that regular examinations and control of PSA doubling time (main prognostic factor associated with poor disease outcome) are crucial to increase survival and prevent the development of distant metastases.This paper aims to provide an overview of existing literature on the problems associated with diagnosis and treatment of non-metastatic castration-resistant prostate cancer. We have analyzed large randomized studies that demonstrated an increase in the overall survival of patients receiving selective androgen receptor antagonists.

Pelvic exenteration in patients with nonmetastatic, locally advanced castration-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 168-168
Author(s):  
Timothy F. Donahue ◽  
Michael J. Morris ◽  
William M. Hilton ◽  
Howard I. Scher ◽  
Bernard H. Bochner
Keyword(s):  
Prostate Cancer ◽  
Median Time ◽  
Pelvic Exenteration ◽  
Performance Status ◽  
Locally Advanced ◽  
Primary Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Symptomatic Disease ◽  
Castration Resistant ◽  
Definitive Therapy

168 Background: A subset of patients who present with localized prostate cancer (PCa) do not develop metastatic disease and recur locally after definitive primary therapy, local salvage therapy, hormones, and systemic intervention. We report our experience in patients with non-metastatic, locally advanced castration resistant prostate cancer (CRPC) treated with radical cystectomy or pelvic exenteration (RC/PEx). Methods: Institutional review board (IRB) approved retrospective review of all patients undergoing RC/PEx for non-metastatic, locally recurrent CRPC after definitive and salvage therapies. Patients were excluded if RC/PEx was for complications of definitive therapy alone. Results: Of 31 patients who had RC/PEx for PCa, 20 met inclusion criteria. Initial therapy was RP (4), XRT (6), brachytherapy (4), brachy/XRT (3), ADT/chemo (2), and ADT alone (1). Five patients had salvage XRT. All received ADT at relapse and 11 had chemotherapy prior to RC/PEx. RC/PEx was performed a median of 8.16 years (0.7 to 24.5) after PCa diagnosis. Patients had pT2b (1), pT3 (5), and pT4 (14) disease at surgery. Lymph nodes were clinically negative in all patients but pathologically positive in six, negative in nine, and not resected in five. Concurrent resections included rectum (12), pelvic wall (6), pubis (1), and iliac vein (1). Eighty five percent of patients had symptoms attributable to locally progressive PCa at RC/PEx including pain, genitourinary or gastrointestinal obstruction and bleeding. All symptomatic patients had relief of disease-related symptoms until recurrence. After a median follow-up of 3.12 years (0.7 to 13.4), nine patients are alive (four have no evidence of disease, five alive with disease), nine dead of disease, and two dead of other causes. Median time to death after RC/PEx was 2.8 years (0.8 to 5.9). For 14 patients who relapsed, metastases developed a median of 398 days (110 to 1,679) after RC/PEx. Ten patients received chemotherapy and 16 had androgen-deprivation therapy after surgery for local recurrence or distant metastases. Median time to chemotherapy after RC/PEx was 346 days (96 to 1,709). Conclusions: For patients with non-metastatic, locally advanced CRPC, RC/PEx to resect symptomatic disease is feasible and appears clinically beneficial. In addition to local control, it may confer significant disease free intervals and relief of symptoms. Even after relapse, performance status was sufficient to undergo systemic therapy.

New Pharmacotherapies in the Treatment of Advanced Prostate Cancer

2010 ◽  
Vol 4 ◽  
pp. CMU.S5075
Author(s):  
Walid El-Ayass ◽  
Joelle El-Amm ◽  
Maneesh Jain ◽  
Jeanny B. Aragon-Ching
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Standard Treatment ◽  
Locally Advanced ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Safety ◽  
Treatment Practice ◽  
Castration Resistant ◽  
Prostate Cancer Therapy ◽  
The Right

Recent drug approvals in the field of prostate cancer therapy have brought about a change in the treatment landscape of locally advanced and metastatic castration-resistant prostate cancer. While this improvement offers a welcoming change in the standard treatment practice of prostate cancer, questions remain with regard to the proper sequencing of the right therapy for the appropriate patient. This review highlights the pre-clinical, safety and clinical studies that help bring to the forefront the drugs recently approved for the treatment of advanced prostate cancer and offer some insights to its use.

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