HDAC inhibitors with potential to overcome drug resistance in castration-resistant prostate cancer

Biersack, Bernhard; Nitzsche, Bianca; Höpfner, Michael

doi:10.20517/cdr.2021.105

Cited by 13 publications

(15 citation statements)

References 89 publications

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“…Specifically, ONECUT2 regulates the signaling of hypoxia-inducing factors and consequently promotes prostate cancer differentiation and can also serve as a therapeutic target in mCRPC. Khalil et al (2022) summarize the multifaceted role of Tousled-like kinase 1 (TLK1) in mCRPC progression and development of therapeutic resistance [10] . The highlight of this review includes that DDR kinase TLK1 mediates an important aspect of adaptation to androgen deprivation and promotes cell cycle progression under unfavorable growth conditions such as ADT and reprograms prostate cancer cells to adapt to androgen-independent growth and resistance development.…”

Section: Article Descriptionmentioning

confidence: 99%

“…The final review article by Biersack et al (2022) demonstrated that epigenetic modification of histone deacetylase (HDAC) plays a significant role in different mechanisms contributing to the development and persistence of CRPC chemoresistance [ 11 ] . The clinical trials on HDAC inhibitors for the treatment of CRPC were reviewed and the major outcomes have been summarized.…”

Section: Article Descriptionmentioning

confidence: 99%

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New insights for drug resistance in metastatic castration-resistant prostate cancer

Kushwaha¹,

Gupta²

2022

Cancer Drug Resist

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Prostate cancer is the most common cancer and is the second leading cause of cancer-related deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard treatment for advanced-stage prostate cancer; however, this treatment eventually fails, leading to an incurable disease subtype known as metastatic castration-resistant prostate cancer (mCRPC). There are several molecular mechanisms that facilitate the development of mCRPC engaging androgen receptor (AR) growth axis, including AR amplification, gain of function AR mutations, and AR splice variants that are constitutively active and are a foremost factor for mCRPC development. AR-independent mechanisms with exceptionally low or absent AR expression found in cancer cells suppress ADT effectiveness and contribute to aggressive variants, including neuroendocrine differentiation. Several other AR regulatory factors such as epigenetic modification(s), and DNA damage response have been reported during post-ADT exposure and play a crucial role in mCRPC development. Therefore, targeting prostate cancer cells before their progression to mCRPC would improve patient outcomes. This special issue in “Cancer Drug Resistance” focuses on understanding the mechanism(s) and development of mCRPC resistance. This special issue also highlights the therapeutic strategies to combat against resistant subtype. This issue comprehensively reviews the mCRPC and delivers the update in the forum of mCRPC resistance development.

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Section: Article Descriptionmentioning

confidence: 99%

Section: Article Descriptionmentioning

confidence: 99%

New insights for drug resistance in metastatic castration-resistant prostate cancer

Kushwaha¹,

Gupta²

2022

Cancer Drug Resist

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“…Vorinostat has been previously reported to block proliferation of prostate cancer cells 56 and to synergize with the AR-antagonist bicalutamide 57 . Consequently, HDAC inhibitors have the potential to overcome resistance to established mCRPC treatments, including AR targeted drugs 58 . A significant increase in sensitivity to HDAC inhibition was observed in castration-resistant LNCaP-16D cells relative to hormone-sensitive parental LNCaP cells (Supplementary Figure 8.…”

Section: Resultsmentioning

confidence: 99%

Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients

Severson

Zhu

Prekovic

et al. 2023

Preprint

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Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness. These data were successfully validated in mCRPC patient-derived xenograft models (PDX).In silicoanalyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validatedin vitro. Using cell lines and mCRPC PDX tumorsin vitro, we identified drug-drug synergy between enzalutamide and the pan-HDAC inhibitor vorinostat, providing therapeutic proof-of-concept. These findings demonstrate rationale for new therapeutic strategies using a combination of AR and HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.

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“…For castration resistant prostate cancer in non-metastatic or metastatic variants, the therapy options are limited, and further improvements are urgently needed. Taken into account that histone deacetylases are upregulated in many cancer cell types including prostate cancer, molecules that inhibits these epigenetic enzymes have the potential to overcome drug resistance in prostate cancer and promising clinical trials are currently ongoing ( 6 ).…”

Section: Prostate Cancermentioning

confidence: 99%

Editorial: Advances in molecular targeted therapies of urologic cancers

Nitzsche

Höpfner²

2022

Front. Oncol.

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Editorial on the Research TopicAdvances in molecular targeted therapies of urologic cancers Urologic cancer is a generic term for distinct malignancies of the urogenital tract comprising of solid tumors of different organs such as bladder, prostate, kidney, urothelium and testicles. Except for testicular cancer rather showing an increased prevalence and incidence in younger adults, most urologic cancers develop in the older male population. All types of urologic cancers represent a problem of major concern and some of them (e.g. prostate cancer) rank among the three most frequent cancers, worldwide and account for a large number of cancer related deaths per year (1). And even more alarming the incidence of urologic cancer is rising due to demographic reasons such as population growth and aging but also due to environmental factors, which have been linked to the development and growth of single urologic cancers, too (e.g. kidney, prostate, bladder) (2).In the past decade, the understanding of dysregulated pathways in urologic cancers as well as the identification of potential biomarkers helped to identify new targets and pathways for novel therapeutic approaches. In this respect new immunomodulatory substances, antiangiogenic agents, growth factor receptor inhibitors or the targeting of epigenetically modulated signaling pathways have become interesting and promising starting points for future medical treatment of urologic cancer. Besides being more effective, targeted approaches also aim at reducing the severe short-and long-term side effects known for conventional chemo-and radiotherapies.The idea of the Research Topic "Advances in molecular targeted therapies of urologic cancers" was to bring together experts in the field reporting on recent (pre-)clinical findings and achievements and to give an overview on possible therapeutic developments and biomarker analysis in urologic cancer research.

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HDAC inhibitors with potential to overcome drug resistance in castration-resistant prostate cancer

Cited by 13 publications

References 89 publications

New insights for drug resistance in metastatic castration-resistant prostate cancer

New insights for drug resistance in metastatic castration-resistant prostate cancer

Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients

Editorial: Advances in molecular targeted therapies of urologic cancers

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