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The 23rd Annual Meeting of the American Urological Oncology Society (SUO) in 2022 was held
in San Diego, USA from November 30 to December 2, local time.
As an internationally influential urological oncology conference, the 2022 SUO Annual Meeting has announced the conference schedule
recently.
Many internationally renowned urological oncology experts, doctors and scientists gathered together to focus on the cutting-edge progress in the field of conversion therapy for prostate, kidney and bladder cancer, bringing us a wonderful academic feast
.
This article summarizes the preclinical research progress of emerging drugs in the field of prostate cancer for readers
.
First author: Ramesh Narayanan
Summary number: Poster #71
Chinese: Androgen receptor double-acting inhibitors are N-terminal domain-bound androgen receptor (AR) antagonists and degradants for the treatment of castration-resistant prostate cancer with positive AR and AR splicing variants
Research background
Advanced castration-resistant prostate cancer (CRPC) is the leading cause
of prostate cancer-related death.
Although CRPC can benefit from initial therapy with AR antagonists and androgen synthesis inhibitors, patients develop
resistance due to multiple mechanisms, such as AR amplification, AR ligand binding domain (LBD) mutations, and AR splicing variants (AR-SVs).
Since all approved AR antagonists and many AR antagonists currently in clinical development target LBD, they are ineffective
in many CRPC patients who carry mutations and variants.
Androgen receptor double-acting inhibitors (DAARIs) ONCT-534 and ONCT-505 are small molecule AR antagonists that interact with LBD and bind to the N-terminal domain (NTD) of AR, resulting in signal antagonism and degradation of AR and AR-SV
proteins.
Research methods
The investigators evaluated the role of DAARIs in AR, AR-SV-positive cell lines, and patient-derived tumor tissue xenografts (PDX), while also testing
DAARIs in patient-derived organoids (PDOs).
In preclinical studies, ONCT-534 and ONCT-505 showed strong antitumor activity in castrated and normal animal models of xenografts of enzalutamide-resistant AR and AR-SV-positive cell lines (22RV1 and LuCaP 86.
2), with tumor growth inhibition rates ranging from 50% to 100%.
The investigators further evaluated ONCT-534 and ONCT-505 in PDOs resistant to various AR antagonists, and also compared the role of DAARIs with PROTAC ARV-110 in xenograft models, the results of which are detailed in the original article
.
The results of preclinical studies show that DAARIs have excellent preclinical efficacy and druglikeness, which supports further preclinical studies and final clinical studies
.
DAARIs are expected to be a new paradigm
for the treatment of CRPC patients with AR and AR-SV positivity who do not benefit from existing standard treatments.
The cover image and accompanying pictures are from: SUO conference official
Reference source:
https://suonet.
org/meetings/upcoming-meetings/program-schedule.
aspx
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