Triple-arm androgen blockade for advanced prostate cancer: a review

Desai, Milap H; Parsi, Meghana; Potdar, Rashmika

doi:10.1007/s12032-021-01520-y

Cited by 5 publications

(3 citation statements)

References 62 publications

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“…Prostate cancer is currently a prevalent disease, the second most common cause of cancer death in the UK and the USA [ 1 , 2 , 3 , 4 , 5 ]. The androgen receptor (AR), a hormone-inducible transcription factor, represents an important therapeutic target in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Investigation of the Androgen Receptor DNA-Binding Domain and Modulation via Direct Interactions with DNA Abasic Sites: Understanding the Mechanisms Involved in Castration-Resistant Prostate Cancer

Kondal

Ahmad

et al. 2023

IJMS

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The androgen receptor (AR) is an important drug target in prostate cancer and a driver of castration-resistant prostate cancer (CRPC). A significant challenge in designing effective drugs lies in targeting constitutively active AR variants and, most importantly, nearly all AR variants lacking the ligand-binding domain (LBD). Recent findings show that an AR’s constitutive activity may occur in the presence of somatic DNA mutations within non-coding regions, but the role of these mutations remains elusive. The discovery of new drugs targeting CRPC is hampered by the limited molecular understanding of how AR binds mutated DNA sequences, frequently observed in prostate cancer, and how mutations within the protein and DNA regulate AR-DNA interactions. Using atomistic molecular dynamics (MD) simulations and quantum mechanical calculations, we focused our efforts on (i) rationalising the role of several activating DBD mutations linked to prostate cancer, and (ii) DBD interactions in the presence of abasic DNA lesions, which frequently occur in CRPC. Our results elucidate the role of mutations within DBD through their modulation of the intrinsic dynamics of the DBD-DNA ternary complex. Furthermore, our results indicate that the DNA apurinic lesions occurring in the androgen-responsive element (ARE) enhance direct AR-DNA interactions and stabilise the DBD homodimerisation interface. Moreover, our results strongly suggest that those abasic lesions may form reversible covalent crosslinks between DNA and lysine residues of an AR via a Schiff base. In addition to providing an atomistic model explaining how protein mutations within the AR DNA-binding domain affect AR dimerisation and AR-DNA interactions, our findings provide insight into how somatic mutations occurring in DNA non-coding regions may activate ARs. These mutations are frequently observed in prostate cancer and may contribute to disease progression by enhancing direct AR-DNA interactions.

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Section: Introductionmentioning

confidence: 99%

Mechanistic Investigation of the Androgen Receptor DNA-Binding Domain and Modulation via Direct Interactions with DNA Abasic Sites: Understanding the Mechanisms Involved in Castration-Resistant Prostate Cancer

Kondal

Ahmad

et al. 2023

IJMS

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“…Prostate cancer (PCa), which is featured with elevated levels of prostate-specific antigen (PSA) and driven by hormone, ranks as the second most prevalent malignancy in males with insidious onset and poor prognosis. − Generally, androgen-deprivation therapy (ADT) remains the mainstay for PCa management especially in the advanced setting, covering orchiectomy and medical approaches like estrogen treatment, which results in impaired androgen generation and relief in disease progression. − Unfortunately, the patients receiving ADT gain the clinical benefit temporarily and ultimately succumb to castration-resistant PCa (CRPC) where tumor cells aggressively proliferate and even metastasize to distal organs independent of androgen level. − Nevertheless, emerging pieces of evidence demonstrate that the androgen receptor (AR) signaling pathway plays a decisive role in the pathogenesis and progression of both androgen-sensitive and -resistant stages of PCa . Compared with androgen-sensitive PCa, CRPC exhibit splice variants of AR (AR-V) with lack of a ligand-binding site, which is activated via other factors rather than the circulating androgens. − Thus, the AR signaling pathway provides a therapeutic target for treating both PCa and CRPC.…”

Section: Introductionmentioning

confidence: 99%

Two-in-One Polymeric NO-Donor Prodrugs Mediate Precision and Synergistic Prostate Cancer Treatment

Zhao

Wan

Zhou

et al. 2023

ACS Appl. Mater. Interfaces

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Chemotherapy predominates in clinical treatment of prostate cancer (PCa), while irreversible resistance to chemotherapeutics and severe side effects hinder the therapeutic efficacy, especially in castration-resistant PCa (CRPC). Herein, a bombesin (BBN)-decorated two-in-one prodrug (T-NO/E 2 -PMs) incorporating a polymeric nitric oxide (NO) donor and acetal-linked 17β-estradiol (E 2 ) in one backbone is developed, aiming to inhibit androgen receptor (AR) expression, reprogram the tumor microenvironment of CRPC, and enhance estradiol-mediated hypoxic CRPC therapy. Following efficient internalization mediated by BBN, T-NO/ E 2 -PMs releases estradiol and NO in response to the unique intracellular environments. Both in vitro and in vivo studies demonstrate that the T-NO/E 2 -PMs nano-prodrug along with NO release potently downregulates AR levels to reverse CRPC and further enhances the chemo-sensitization of estradiol to PCa PC-3 cell apoptosis and the inhibition of metastasis. Collectively, this two-in-one nano-prodrug strategy offers a promising platform for construction of advanced nanomedicine to boost the therapeutic efficacy.

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“…Likewise, the second generation ARSI (enzalutamide, apalutamide and darolutamide) is a potent androgen receptor (AR) inhibitor 13 . The mechanism of actions includes competitive binding to AR, inhibiting androgen receptor nuclear translocation and androgen-receptors-mediated DNA binding 14 .…”

Section: Introductionmentioning

confidence: 99%

Assessment of androgen receptor signaling inhibitors therapy in metastatic hormone-sensitive prostate cancer

Yoodee¹,

Detma²,

Lappanawan³

et al. 2022

Pharm Sci Asia

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Androgen receptor signaling inhibitor (ARSI) therapy plays an important role in treating advanced prostate cancer. However, in Thailand, the efficacy and safety data of ARSI therapy remain limited. This study aimed to assess the efficacy and safety of ARSI therapy to treat patients with metastatic castration naïve prostate cancer. We collected data from electronic medical records based on disease progression and any reported adverse events. The primary outcome was progression-free survival (PFS) after initiating ARSI therapy. Secondary outcome was PFS according to abiraterone and enzalutamide, risk factors associated with PFS of ARSI therapy and adverse events. A total of 49 eligible patients were enrolled having received ARSI therapy (abiraterone or enzalutamide) to treat metastatic prostate cancer. The median time to follow-up was 17 months (interquartile range, 12-31). PFS among patients treated with ARSI therapy was 22 months (95% confidence interval [CI], 17-33), PFS among patients with abiraterone and enzalutamide was 21 and 23 months, respectively (hazard ratio [HR], 0.48; 95% CI, 0.17-1.41, P=0.185). Patients with Eastern Cooperative Group status 1-2 exhibited significantly decreased risk of disease progression (HR, 0.44; 95% CI, 0.20-0.96, P=0.038). The common adverse events included hypertension and fluid retention and edema. In conclusion, abiraterone and enzalutamide showed a trend to improve PFS among patients with metastatic castration naïve prostate cancer. Adverse events were rarely reported, and patients were able to tolerate treatment.

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Triple-arm androgen blockade for advanced prostate cancer: a review

Cited by 5 publications

References 62 publications

Mechanistic Investigation of the Androgen Receptor DNA-Binding Domain and Modulation via Direct Interactions with DNA Abasic Sites: Understanding the Mechanisms Involved in Castration-Resistant Prostate Cancer

Mechanistic Investigation of the Androgen Receptor DNA-Binding Domain and Modulation via Direct Interactions with DNA Abasic Sites: Understanding the Mechanisms Involved in Castration-Resistant Prostate Cancer

Two-in-One Polymeric NO-Donor Prodrugs Mediate Precision and Synergistic Prostate Cancer Treatment

Assessment of androgen receptor signaling inhibitors therapy in metastatic hormone-sensitive prostate cancer

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