A Trial Evaluating the Efficacy and Safety of HC-1119 Soft Capsules in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC).

Relevance: Prostate cancer (PC) is one of the most common malignant neoplasms in the male population. The widespread introduction of modern diagnostic methods and the determination of prostate-specific antigen (PSA) levels have increased the number of detected cases of localized and locally advanced PC forms. However, in some patients treated with radical methods and long-term androgen deprivation therapy (ADT), the disease continues to progress in the form of an increase in PSA levels with castration testosterone values and with no distant metastases. Such a course of the disease is referred to as non-metastatic castration-resistant prostate cancer (nmCRPC). Purpose: The article reports the results of a meeting of the Expert Council arranged by the Kazakh Research Institute of Oncology and Radiology on December 25, 2020, on non-metastatic castration-resistant prostate cancer diagnostics and treatment. Results: Large clinical studies highlight the critical importance of controlling the PSA doubling time as the main prognostic factor for an unfavorable outcome to increase patient survival and prevent the development of distant metastases. Based on the results of large randomized studies, experts recommended using new-generation androgen receptor antagonists in combination with ongoing ADT to improve the clinical outcomes in nmCRPC patients at high risk of metastatic progression. The Expert Council was presented with the data of a registration clinical study on darolutamide efficacy and safety. The advantages of introducing this drug into clinical practice to expand the choice of therapeutic options were identified. Personalized adjustment of a treatment regimen will increase the treatment efficacy and ensure higher survival in this category of patients. Conclusion: Increasing survival as the main objective in treating nmCRPC patients requires improved diagnostics through regular controlling of testosterone and PSA levels, calculation of PSA doubling time, and the use of radiological diagnostic methods to rule out distant metastases. The choice of therapy in patients at high risk of metastasis shall consider the patient’s status and the treatment efficacy and safety balance.

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Anti-Proliferative, Anti-Angiogenic and Safety Profiles of Novel HDAC Inhibitors for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Pharmaceuticals ◽

10.3390/ph14101020 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1020

Author(s):

Zohaib Rana ◽

Sarah Diermeier ◽

Fearghal P. Walsh ◽

Muhammad Hanif ◽

Christian G. Hartinger ◽

...

Keyword(s):

Prostate Cancer ◽

Histone Deacetylases ◽

Hdac Inhibitors ◽

Tube Formation ◽

In Vivo Studies ◽

Efficacy And Safety ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Pc3 Cells

Metastatic castration-resistant prostate cancer (CRPC) has a five-year survival rate of 28%. As histone deacetylases (HDACs) are overexpressed in CRPC, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was trialled in CRPC patients but found to be toxic and inefficacious. Previously, we showed that novel HDAC inhibitors (Jazz90 (N1-hydroxy-N8-(4-(pyridine-2-carbothioamido)phenyl)octanediamide) and Jazz167 ([chlorido(η5-pentamethylcyclopentadieny[1–4](N1-hydroxy-N8-(4-(pyridine-2-carbothioamido-κ2N,S)phenyl)octanediamide)rhodium(III)] chloride) had a higher cancer-to-normal-cell selectivity and superior anti-angiogenic effects in CRPC (PC3) cells than SAHA. Thus, this study aimed to further investigate the efficacy and toxicity of these compounds. HUVEC tube formation assays revealed that Jazz90 and Jazz167 significantly reduced meshes and segment lengths in the range of 55–88 and 43–64%, respectively. However, Jazz90 and Jazz167 did not affect the expression of epithelial-to-mesenchymal transitioning markers E-cadherin and vimentin. Jazz90 and Jazz167 significantly inhibited the growth of PC3 and DU145 spheroids and reduced PC3 spheroid branching. Jazz90 and Jazz167 (25, 50 and 75 mg/kg/day orally for 21 days) were non-toxic in male BALB/c mice. The efficacy and safety of these compounds demonstrate their potential for further in vivo studies in CRPC models.

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