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Cancers
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The Response of Prostate Cancers to Androgen Deprivation Therapies
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The Response of Prostate Cancers to Androgen Deprivation Therapies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (2 August 2024) | Viewed by 7439

Special Issue Editor

Dr. John J. Krolewski

E-Mail Website
Guest Editor
Buffalo State College, State University of New York, Buffalo, NY 14222, USA
Interests: prostate cancer; tumor immune microenvironment; androgen deprivation; immunogenomics; cell signaling

Special Issue Information

Dear Colleagues,

Most human prostate cancers are curable by surgery or radiation therapy, or are so slow-growing and occur so late in life that the cancer does not affect lifespan. However, 10–20% of cases progress or recur following curative therapies. Thus, given the very high incidence of this cancer, upwards of 30,000 men die of prostate cancer each year. The mainstay therapy for recurrent or progressing prostate cancer is androgen deprivation therapy (ADT), which has been in use for almost 80 years. ADT is apparently effective because nearly all prostate cancers are initiated by genetic events that ‘reprogram’ the androgen receptor cistrome, leading to the transcription of gene sets that drive the de-differentiation of prostate epithelial cells, enabling oncogenic transformation. Despite the effectiveness of ADT, this therapy is not curative, and those tumors which can evade ADT are eventually lethal, accounting for the majority of prostate cancer deaths. Thus, there is a need to: i) understand the mechanism of tumor death and recurrence following ADT; ii) identify curative therapies that synergize with or replace ADT; and iii) define the biology of ADT-resistant tumors as a first step to finding effective therapies for these lethal cancers. In this Special Issue, we invite contributions from investigators studying all aspects of the response of prostate cancers to ADT. We are particularly interested in studies that use relevant murine models and human prostate cancer tissue samples or model systems derived from human prostate cancers and consider the response of both tumor cells and the tumor microenvironment, including immune-cell populations.   

Dr. John J. Krolewski
Guest Editor

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Keywords

  • prostate cancer
  • androgen deprivation therapy
  • therapy resistance
  • tumor microenvironment
  • ADT

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Published Papers (4 papers)

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Research

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14 pages, 2993 KiB  
Article
LncRNA LOC730101 Promotes Darolutamide Resistance in Prostate Cancer by Suppressing miR-1-3p
by Tianyi Zhou, Steven Nguyen, Jacky Wu, Bin He and Qin Feng
Cancers 2024, 16(14), 2594; https://doi.org/10.3390/cancers16142594 - 20 Jul 2024
Cited by 1 | Viewed by 1043
Abstract
Antiandrogen is part of the standard-of-care treatment option for metastatic prostate cancer. However, prostate cancers frequently relapse, and the underlying resistance mechanism remains incompletely understood. This study seeks to investigate whether long non-coding RNAs (lncRNAs) contribute to the resistance against the latest antiandrogen [...] Read more.
Antiandrogen is part of the standard-of-care treatment option for metastatic prostate cancer. However, prostate cancers frequently relapse, and the underlying resistance mechanism remains incompletely understood. This study seeks to investigate whether long non-coding RNAs (lncRNAs) contribute to the resistance against the latest antiandrogen drug, darolutamide. Our RNA sequencing analysis revealed significant overexpression of LOC730101 in darolutamide-resistant cancer cells compared to the parental cells. Elevated LOC730101 levels were also observed in clinical samples of metastatic castration-resistant prostate cancer (CRPC) compared to primary prostate cancer samples. Silencing LOC730101 with siRNA significantly impaired the growth of darolutamide-resistant cells. Additional RNA sequencing analysis identified a set of genes regulated by LOC730101, including key players in the cell cycle regulatory pathway. We further demonstrated that LOC730101 promotes darolutamide resistance by competitively inhibiting microRNA miR-1-3p. Moreover, by Hi-C sequencing, we found that LOC730101 is located in a topologically associating domain (TAD) that undergoes specific gene induction in darolutamide-resistant cells. Collectively, our study demonstrates the crucial role of the lncRNA LOC730101 in darolutamide resistance and its potential as a target for overcoming antiandrogen resistance in CRPC. Full article
(This article belongs to the Special Issue The Response of Prostate Cancers to Androgen Deprivation Therapies)
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15 pages, 2641 KiB  
Article
Therapeutic Resistance Models and Treatment Sequencing in Advanced Prostate Cancer
by Zachary A. Schaaf, Shu Ning, Amy R. Leslie, Masuda Sharifi, Xianrui Han, Cameron Armstrong, Wei Lou, Alan P. Lombard, Chengfei Liu and Allen C. Gao
Cancers 2023, 15(21), 5273; https://doi.org/10.3390/cancers15215273 - 3 Nov 2023
Cited by 2 | Viewed by 2014
Abstract
Current common treatments for castration-resistant prostate cancer (CRPC) typically belong to one of three major categories: next-generation anti-androgen therapies (NGAT) including enzalutamide, abiraterone acetate, apalutamide, and darolutamide; taxane therapy represented by docetaxel; and PARP inhibitors (PARPi) like olaparib. Although these treatments have shown [...] Read more.
Current common treatments for castration-resistant prostate cancer (CRPC) typically belong to one of three major categories: next-generation anti-androgen therapies (NGAT) including enzalutamide, abiraterone acetate, apalutamide, and darolutamide; taxane therapy represented by docetaxel; and PARP inhibitors (PARPi) like olaparib. Although these treatments have shown efficacy and have improved outcomes for many patients, some do not survive due to the emergence of therapeutic resistance. The clinical landscape is further complicated by limited knowledge about how the sequence of treatments impacts the development of therapeutic cross-resistance in CRPC. We have developed multiple CRPC models of acquired therapeutic resistance cell sublines from C4-2B cells. These include C4-2B MDVR, C4-2B AbiR, C4-2B ApaR, C4-2B DaroR, TaxR, and 2B-olapR, which are resistant to enzalutamide, abiraterone, apalutamide, darolutamide, docetaxel, and olaparib, respectively. These models are instrumental for analyzing gene expression and assessing responses to various treatments. Our findings reveal distinct cross-resistance characteristics among NGAT-resistant cell sublines. Specifically, resistance to enzalutamide induces resistance to abiraterone and vice versa, while maintaining sensitivity to taxanes and olaparib. Conversely, cells with acquired resistance to docetaxel exhibit cross-resistance to both cabazitaxel and olaparib but retain sensitivity to NGATs like enzalutamide and abiraterone. OlapR cells, significantly resistant to olaparib compared to parental cells, are still responsive to NGATs and docetaxel. Moreover, OlapR models display cross-resistance to other clinically relevant PARP inhibitors, including rucaparib, niraparib, and talazoparib. RNA-sequencing analyses have revealed a complex network of altered gene expressions that influence signaling pathways, energy metabolism, and apoptotic signaling, pivotal to cancer’s evolution and progression. The data indicate that resistance mechanisms are distinct among different drug classes. Notably, NGAT-resistant sublines exhibited a significant downregulation of androgen-regulated genes, contrasting to the stable expression noted in olaparib and docetaxel-resistant sublines. These results may have clinical implications by showing that treatments of one class can be sequenced with those from another class, but caution should be taken when sequencing drugs of the same class. Full article
(This article belongs to the Special Issue The Response of Prostate Cancers to Androgen Deprivation Therapies)
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17 pages, 3147 KiB  
Article
TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression
by John J. Krolewski, Shalini Singh, Kai Sha, Neha Jaiswal, Steven G. Turowski, Chunliu Pan, Laurie J. Rich, Mukund Seshadri and Kent L. Nastiuk
Cancers 2022, 14(24), 6020; https://doi.org/10.3390/cancers14246020 - 7 Dec 2022
Cited by 2 | Viewed by 2068
Abstract
The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces [...] Read more.
The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. In addition to this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death, which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostates. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area, and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely by inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer microenvironment that mediates prostate cancer regression following androgen deprivation. Full article
(This article belongs to the Special Issue The Response of Prostate Cancers to Androgen Deprivation Therapies)
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Review

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15 pages, 1832 KiB  
Review
Metabolic Response to Androgen Deprivation Therapy of Prostate Cancer
by Yubin Chen, Pao-Hwa Lin, Stephen J. Freedland and Jen-Tsan Chi
Cancers 2024, 16(11), 1991; https://doi.org/10.3390/cancers16111991 - 24 May 2024
Cited by 1 | Viewed by 1637
Abstract
Prostate cancer (PC) stands as the most frequently diagnosed non-skin cancer and ranks as the second highest cause of cancer-related deaths among men in the United States. For those facing non-metastatic PC necessitating intervention, solely local treatments may not suffice, leading to a [...] Read more.
Prostate cancer (PC) stands as the most frequently diagnosed non-skin cancer and ranks as the second highest cause of cancer-related deaths among men in the United States. For those facing non-metastatic PC necessitating intervention, solely local treatments may not suffice, leading to a possible transition toward systemic therapies, including androgen deprivation therapy (ADT), chemotherapy, and therapies targeting androgen. Yet, these systemic treatments often bring about considerable adverse effects. Additionally, it is observed that overweight men are at a higher risk of developing aggressive forms of PC, advancing to metastatic stages, and succumbing to the disease. Consequently, there is a pressing demand for new treatment options that carry fewer side effects and enhance the current standard treatments, particularly for the majority of American men who are overweight or obese. In this article, we will review the metabolic response to ADT and how lifestyle modulation can mitigate these ADT-associated metabolic responses with a particular focus on the two clinical trials, Carbohydrate and Prostate Study 1 (CAPS1) and Carbohydrate and Prostate Study 2 (CAPS2), which tested the effects of low-carbohydrate diets on the metabolic side effects of ADT and PC progression, respectively. Furthermore, we will summarize the findings of serum metabolomic studies to elucidate the potential mechanisms by which ADT and low-carbohydrate diets can affect the metabolic response to mitigate the metabolic side effects while maximizing therapeutic efficacy. Full article
(This article belongs to the Special Issue The Response of Prostate Cancers to Androgen Deprivation Therapies)
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