Targeting androgen receptor and the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in castration resistant prostate cancer.

BACKGROUND: Despite the advent of improved therapeutic options for advanced prostate cancer, the durability of clinical benefits is limited due to inevitable development of resistance. By constitutively sustaining androgen receptor (AR) signaling, expression of ligand-binding domain truncated AR variants (AR-V(ΔLBD)) accounts for the major mechanism underlying the resistance to anti-androgen drugs. Strategies to target AR and its LBD truncated variants are needed to prevent the emergence or overcome drug resistance. METHODS: We utilize Proteolysis Targeting Chimeras (PROTAC) technology to achieve induced degradation of both full-length AR (AR-FL) and AR-V(ΔLBD) proteins. In the ITRI-PROTAC design, an AR N-terminal domain (NTD) binding moiety is appended to von-Hippel-Lindau (VHL) or Cereblon (CRBN) E3 ligase binding ligand with linker. FINDINGS: In vitro studies demonstrate that ITRI-PROTAC compounds mechanistically degrade AR-FL and AR-V(ΔLBD) proteins via ubiquitin-proteasome system, leading to impaired AR transactivation on target gene expression, and inhibited cell proliferation accompanied by apoptosis activation. The compounds also significantly inhibit enzalutamide-resistant growth of castration resistant prostate cancer (CRPC) cells. In castration-, enzalutamide-resistant CWR22Rv1 xenograft model without hormone ablation, ITRI-90 displays a pharmacokinetic profile with decent oral bioavailability and strong antitumor efficacy. INTERPRETATION: AR NTD that governs the transcriptional activities of all active variants has been considered attractive therapeutic target to block AR signaling in prostate cancer cells. We demonstrated that utilizing PROTAC for induced AR protein degradation via NTD represents an efficient alternative therapeutic strategy for CRPC to overcome anti-androgen resistance. FUNDING: The funding detail can be found in the Acknowledgements section.

Spontaneous bilateral haemothorax with haemopericardium secondary to rivaroxaban.

WHAT IS KNOWN AND OBJECTIVE: Although the risk of major bleeding with non-vitamin K antagonist oral anticoagulant (NOAC) is low, life-threatening bleeding can occur. CASE SUMMARY: We report a case of an 81-year-old female with deep vein thrombosis who developed bilateral spontaneous haemothorax and haemopericardium after rivaroxaban therapy. Diagnostic thoracentesis revealed a grossly bloody pleural effusion. She was treated with factor eight inhibitor bypassing agent, but the result was not satisfactory. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first case report of a concomitant presentation of spontaneous bilateral haemothorax and haemopericardium due to rivaroxaban use. This case highlights the potential risk of major haemorrhagic complication of NOAC, which could be life-threatening and require emergent reversal.