Sex Hormones and Prostate Cancer

2020 ◽  
Vol 71 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Richard J. Auchus ◽  
Nima Sharifi
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Current Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
History Of ◽  
Prostate Cancer Research ◽  
Prostate Cancers ◽  
Androgen Independent ◽  
Transition Studies

The prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths. Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease. Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms. This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm.

Beyond the Androgen Receptor: The Sequence, the Mutants, and New Avengers in the Treatment of Castrate-Resistant Metastatic Prostate Cancer

2021 ◽  
pp. e190-e202
Author(s):  
Daniel Westaby ◽  
Paul V. Viscuse ◽  
Rahul Ravilla ◽  
Maria de los Dolores Fenor de la Maza ◽  
Andrew Hahn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Metastatic Prostate Cancer ◽  
Clinical State ◽  
Castration Resistant Prostate Cancer ◽  
Resistance Development ◽  
Castration Resistant ◽  
Variant Histology ◽  
Prostate Cancers ◽  
Castrate Resistant

Targeting the androgen receptor by depriving testosterone with gonadotropin-releasing hormone agonists or antagonists, or surgical castration, has been the backbone of metastatic prostate cancer treatment. Although most prostate cancers initially respond to androgen deprivation, metastatic castration-resistant prostate cancer evolves into a heterogeneous disease with diverse drivers of progression and mechanisms of therapeutic resistance. Development of castrate resistance phenotype is associated with lethality despite the recent noteworthy strides gained via increase in therapeutic options. Identification of novel therapeutics to further improve survival and achieve durable responses in metastatic castration-resistant prostate cancer is a clinical necessity. In this review, we outline the existing avengers for treatment of metastatic castration-resistant prostate cancer by clinical presentation, placing into context the clinical state of the patient, such as burden of disease and symptoms. Doing so might aid in the ability to optimize the sequence of agents and allow for maximal exposure to life-prolonging therapeutics. Realizing the limitations of the androgen signaling inhibition, we explore the androgen-indifferent prostate cancer: the mutants. Classically, these subtypes have been associated with variant histology, but androgen-indifferent prostate cancer features are now frequently observed in association with heterogeneous morphologies, including double-negative prostate cancers, lacking both androgen receptor and neuroendocrine features, or clinicopathologic criteria, such as the aggressive variant prostate cancer criteria. The framework of new avengers against metastatic castration-resistant prostate cancer based on mechanism, including DNA repair, immune checkpoint inhibition, PTEN/PI3K/AKT pathway, prostate-specific membrane antigen targets, bispecific T-cell engagers, and radionuclide therapies, is summarized in this review.

scholarly journals Changing the History of Prostate Cancer with New Targeted Therapies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 392
Author(s):  
Susana Hernando Polo ◽  
Diana Moreno Muñoz ◽  
Adriana Carolina Rosero Rodríguez ◽  
Jorge Silva Ruiz ◽  
Diana Isabel Rosero Rodríguez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapies ◽  
Synthetic Lethality ◽  
Castration Resistant Prostate Cancer ◽  
Phosphatidylinositol 3 Kinase ◽  
Castration Resistant ◽  
Therapeutic Landscape ◽  
Important Benefit ◽  
History Of ◽  
Repair Genes

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is changing due to the emergence of new targeted therapies for the treatment of different molecular subtypes. Some biomarkers are described as potential molecular targets different from classic androgen receptors (AR). Approximately 20–25% of mCRPCs have somatic or germline alterations in DNA repair genes involved in homologous recombination. These subtypes are usually associated with more aggressive disease. Inhibitors of the enzyme poly ADP ribose polymerase (PARPi) have demonstrated an important benefit in the treatment of these subtypes of tumors. However, tumors that resistant to PARPi and wildtype BRCA tumors do not benefit from these therapies. Recent studies are exploring drug combinations with phosphatidylinositol-3-kinase (PI3K) or protein kinase B (AKT) inhibitors, as mechanisms to overcome resistance or to induce BRCAness and synthetic lethality. This article reviews various different novel strategies to improve outcomes in patients with prostate cancer.

scholarly journals Predictors for progression of metastatic prostate cancer to castration-resistant prostate cancer in Indians

2016 ◽  
Vol 143 (7) ◽  
pp. 68
Author(s):  
Anil Mandhani ◽  
SanjoyKumar Sureka ◽  
Ruchir Maheshwari ◽  
Shalini Agnihotri ◽  
Nilay Mitash ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals Incidence of Skeletal-Related Events in Patients with Castration-Resistant Prostate Cancer: An Observational Retrospective Cohort Study in the US

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Alison Tse Kawai ◽  
David Martinez ◽  
Catherine W. Saltus ◽  
Zdravko P. Vassilev ◽  
Montse Soriano-Gabarró ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Incidence Rate ◽  
Incidence Rates ◽  
Negative Consequences ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Castration Resistant ◽  
The Us ◽  
History Of ◽  
Skeletal Related Events

Background and Objective. Skeletal-related events (SREs) are common in men with bone metastases and have negative consequences for patients with castration-resistant prostate cancer (CRPC), including pain, reduced quality of life, and increased mortality. We estimated incidence rates of first SREs in a cohort of men with CRPC in the Surveillance, Epidemiology, and End Results-Medicare database. Methods. We included men aged ≥ 65 years with a prostate cancer diagnosis in 2000-2011 if they had no prior malignancy (other than nonmelanoma skin cancer) and had surgical or medical castration with subsequent second-line systemic therapy, which was used to infer castration resistance. The first occurrence of an SRE (fracture, bone surgery, radiation therapy, or spinal cord compression) in Medicare claims was identified. Incidence rates of SREs were estimated in all eligible person-time and, in secondary analyses, stratified by any use of bone-targeted agents (BTAs) and history of SRE. Results. Of 2,234 men with CRPC (84% white, mean age = 76.6 years), 896 (40%) had an SRE during follow-up, with 74% occurring within a year after cohort entry. Overall, the incidence rate of SREs was 3.78 (95% CI, 3.53-4.03) per 100 person-months. The incidence rate of SREs before any BTA use was 4.16 (95% CI, 3.71-4.65) per 100 person-months, and after any BTA use was 3.60 (95% CI, 3.32-3.91) per 100 person-months. The incidence rate in patients with no history of SRE was 3.33 (95% CI 3.01-3.68) per 100 person-months, and in patients who had such a history, it was 4.20 (95% CI 3.84-4.58) per 100 person-months. Conclusions. In this large cohort of elderly men with CRPC in the US, SREs were common. A decrease in incidence of SREs after starting BTA is suggested, but the magnitude of the effect may be confounded by indication and other factors such as age and prior SRE.

scholarly journals Inhibition of LOXL2 Enhances the Radiosensitivity of Castration-Resistant Prostate Cancer Cells Associated with the Reversal of the EMT Process

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Peng Xie ◽  
Hongliang Yu ◽  
Feijiang Wang ◽  
Feng Yan ◽  
Xia He
Keyword(s):  
Prostate Cancer ◽  
Cell Apoptosis ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Du145 Cells ◽  
Androgen Independent

Introduction. Radiotherapy is the mainstay in the treatment of prostate cancer. However, significant radioresistance of castration-resistant prostate cancer (CRPC) cells constitutes a main obstacle in the treatment of this disease. By using bioinformatic data mining methods, LOXL2 was found to be upregulated in both androgen-independent prostate cancer cell lines and radioresistant tumor samples collected from patients with prostate cancer. We speculate that LOXL2 may play an important role in the radioresistance of CRPC cells. Methods. The effect of LOXL2 knockdown on the radiosensitivity of androgen-independent prostate cancer cells lines was measured by the clonogenic assay and xenograft tumor experiments under in vitro and in vivo conditions, respectively. In studies on the mechanism, we focused on the EMT phenotype changes and cell apoptosis changes induced by LOXL2 knockdown in DU145 cells. The protein levels of three EMT biomarkers, namely, E-cadherin, vimentin, and N-cadherin, were measured by western blotting and immunohistochemical staining. Cell apoptosis after irradiation was measured by flow cytometry and caspase-3 activity assay. Salvage experiment was also conducted to confirm the possible role of EMT in the radiosensitization effect of LOXL2 knockdown in CRPC cells. Results. LOXL2 knockdown in CRPC cells enhanced cellular radiosensitivity under both in vitro and in vivo conditions. A significant reversal of EMT was observed in LOXL2-silenced DU145 cells. Cell apoptosis after irradiation was significantly enhanced by LOXL2 knockdown in DU145 cells. Results from the salvage experiment confirmed the key role of EMT process reversal in the radiosensitization effect of LOXL2 knockdown in DU145 cells. Conclusions. LOXL2 plays an important role in the development of cellular radioresistance in CRPC cells. Targeting LOXL2 may be a rational avenue to overcome radioresistance in CRPC cells. A LOXL2-targeting strategy for CRPC treatment warrants detailed investigation in the future.

Use of epirubicin, carboplatin, and 5-fluorouracil (ECarboF) as a second-line treatment in metastatic castration-resistant prostate cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 173-173
Author(s):  
U. B. McGovern ◽  
S. J. Harland
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Performance Status ◽  
Median Number ◽  
Second Line ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Castration Resistant ◽  
Docetaxel Chemotherapy ◽  
Line Chemotherapy

173 Background: ECarboF chemotherapy is an active first line chemotherapy treatment for metastatic prostate cancer. We have now investigated its efficacy and toxicity in patients who have progressed during or after docetaxel chemotherapy. Methods: 37 patients with metastatic prostate cancer who had received ECarboF chemotherapy were retrospectively reviewed from a five year period (2005-2010). All patients had previously received first-line docetaxel chemotherapy and had either progressed following treatment (n=17) or were docetaxel refractory (n=20). Patients received epirubicin 50mg/m2 iv d1, carboplatin (AUC 5) d1, fluorouracil 440mg/m2 d1, d15 and folinic acid 20mg/m2 d1, d15 on a q4w cycle. 20% dose reductions were made for the first cycle in patients with poorer performance status. PSA was measured before each cycle of treatment and all patients were assessed for toxicity. Results: Patients had a median age of 70 years (range 48-77), median baseline PSA of 226.5 ng/mL (range 9.6-1,580) and the median number of ECarboF chemotherapy cycles received was 6 (range 1-10). 65% (n=24) of patients were ECOG 0-1, the remaining 35% (n=13) were ECOG 2-3. 16% (n=6) patients had a ≥ 30% decline in PSA and 16% (n=6) patients had a ≥ 50% decline in PSA. 35% (n=13) of patients experienced grade 3/4 toxicity, most commonly anaemia (13.5%), neutropenia (13.5%) and thrombocytopenia (8.1%) with one treatment related death (neutropenic sepsis) during the five year period analysed. Median time to PSA progression was 5.1 months. Conclusions: ECarboF has activity with acceptable toxicity post docetaxel in the treatment of metastatic castration resistant prostate cancer. Although PSA response rates are modest, the time to progression is comparable to that of more toxic regimens. ECarboF should be considered as an active second-line chemotherapy regimen. No significant financial relationships to disclose.

Presence of myeloid-derived suppressor cells (MDSC) in patients with metastatic castration-sensitive and castration-resistant prostate cancer.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 222-222 ◽  
Author(s):  
Karen A. Autio ◽  
Phillip Wong ◽  
Angel Rabinowitz ◽  
Jianda Yuan ◽  
Lauryn Michelle Slavin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Whole Blood ◽  
Geometric Mean ◽  
Suppressor Cells ◽  
Current Treatment ◽  
Clinical State ◽  
Cancer Center ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

222 Background: MDSC contribute to an immune suppressive environment and have been implicated in cancer progression. Measurement (identification and enumeration) is challenged by the lack of analytically valid assays limiting data interpretation between groups. This impacts our understanding of rationale immune targets and design of clinical trials. We employed a novel biomarker based assay in whole blood to enumerate MDSC from patients with metastatic castration sensitive (CSPC) and castration resistant prostate cancer (CRPC). Methods: Whole blood was collected in Cyto-Chex (Streck) tubes. A published computational algorithm-based approach (developed by Memorial Sloan Kettering Cancer Center and commercialized by Serametrix) was employed to determine the %MDSC-monocytic and coefficient of variance (CV=ratio of SD and geometric mean fluorescence intensity) to assess HLA-DR spread on CD14+CD11b cells. Samples were performed in duplicate. Clinical variables including clinical state, past and current treatment, metastatic sites, PSA, and standard prognostic markers were collected. Results: 36 pts with metastatic prostate cancer (29 CRPC; 7 CSPC) were included. Median (SD) %MDSC in 29 CRPC pts was 21.15 (5.33) and median (SD) CV was1.29 (0.25); 7 CSPC demonstrated a median (SD) %MDSC 19.15 (4.86) and median (SD) CV 1.22 (0.25). MDSC did not differ between chemotherapy exposed (n=13) and chemotherapy naive (n=16) CRPC (23.3 vs 19.5, p=ns). MDSC were not significantly higher in those with visceral mets, though a trend existed (20.3 vs 24.0, p=0.076). PSA did not appear to correlate with MDSC or CV. Conclusions: Understanding the distribution and characterization of MDSC in various clinical states in prostate cancer is relevant to the development of immune targets in this disease. MDSC were quantifiable in both CSPC and CRPC. There was a trend for higher MDSC values in patients with visceral metastases, which historically are associated with worse prognoses. Presence of MDSC in metastatic CSPC and CRPC has important therapeutic and trial implications. Further discovery in larger cohorts and earlier disease states is underway.

scholarly journals Extracellular Microenvironment in Patient-derived Hydrogel Organoids of Prostate Cancer Regulates Therapeutic Response

2020 ◽  
Author(s):  
Matthew J Mosquera ◽  
Rohan Bareja ◽  
Jacob M Bernheim ◽  
Muhammad Asad ◽  
Cynthia Cheung ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Inflammatory Cells ◽  
Cellular Reprogramming ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Prostate Cells ◽  
Synthetic Hydrogel ◽  
Neuroendocrine Prostate Cancer ◽  
Prostate Cancers ◽  
Novel Target

Following treatment with androgen receptor (AR) pathway inhibitors, ~20% of prostate cancer patients progress by shedding their dependence on AR. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs. A major hurdle in the development of new therapies and treatment of CRPC-NEPC is the lack of accurate models to test candidate treatments. Such models would ideally capture components of the tumor microenvironment (TME) factors, which likely regulate the phenotypic, genetic, and epigenetic underpinnings of this aggressive subset. The TME is a complex system comprised not only of malignant prostate cells but also stromal and inflammatory cells and a scaffold of extracellular matrix (ECM). ECM proteins are implicated in the survival and progression of cancer and development of chemoresistance, while are equally integral to the development of prostate cancer organoids. Here, using a combination of patient tumor proteomics and RNA sequencing, we define putative ECM cues that may guide the growth of prostate tumors in patients. Using this molecular information, we developed synthetic hydrogels that recapitulate the tumor ECM. Organoids cultured in the synthetic hydrogel niches demonstrate that ECM subtypes regulate the morphology, transcriptome, and epigenetics hallmarks of CRPC-Adeno and CRPC-NEPC. CRPC-NEPC organoid showed a differential response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being a novel target in CRPC-NEPC when grown in tumor-specific ECM. Finally, in those synthetic ECM niches where drug resistance was observed in CRPC-NEPCs, cellular reprogramming by a synergistic combination of EZH2 inhibitors with DRD2 antagonists inhibited tumor growth. The synthetic platform can provide a more realistic prostate-specific microenvironment and subsequently enable the development of effective targeted therapeutics for prostate cancers.

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