ABSTRACT
The androgen receptor (AR) is an attractive target for treating prostate cancer, considering its role in the development and progression of localized and metastatic prostate cancer. The high global mortality burden of prostate cancer, despite medical treatments such as androgen deprivation or AR antagonist therapy, highlights the need to explore alternative strategies. One strategy involves the use of heterobifunctional degraders, also known as proteolysis-targeting chimeras, which are novel small-molecule therapeutics that inhibit amplified or mutated targets. Here, the study reports a novel cereblon-based AR degrader, UBX-390, and demonstrates its superior activity over established AR degraders, such as ARV-110 or ARCC-4, in prostate cancer cells under short- and long-term treatment conditions. UBX-390 suppresses chromatin binding and gene expression of AR and demonstrates substantial efficacy in the degradation of AR mutants in patients with treatment-resistant prostate cancer. UBX-390 is presented as an optimized AR degrader with remarkable potential for treating castration-resistant prostate cancer.
ABSTRACT
BACKGROUND: Simultaneous pancreas and kidney transplant (SPK) is the most common type of pancreas transplant performed worldwide. In contrast, there are a few drawbacks to pancreas after kidney transplant (PAK), such as the requirement for an additional operation, the immunologic risk, etc. SPK is the best option, but because of a lack of deceased donors and a lengthy waiting period, it is not always possible to use it. METHODS: From 2015 to 2022, we performed 23 SPKs and 21 PAKs at the Pusan National University Yangsan Hospital in Korea. We compared the findings of PAK and SPK conducted within the same time period. RESULTS: The waiting time for pancreatic graft was significantly shorter in the PAK than SPK group (345 days vs 1350 days, P ≤ .001). Throughout the monitoring period, just 1 pancreatic graft was lost in patients who underwent PAK, and the 7-year graft survival was 95%, with no statistically significant difference compared to SPK (90.3%, P = .600). Moreover, the graft survival of SPK or PAK was superior to that of pancreatic transplant alone (63.7%, P = .016). Only 1 pancreatic graft loss was a case of mortality with a functioning graft. No additional kidney transplant loss was observed in PAK recipients. There was no variation in creatinine levels between the pretransplant and posttransplant periods. There were 2 incidents of pancreatic graft and kidney graft rejection, respectively, but the grafts entirely recovered following rejection treatment. CONCLUSION: According to our experiences, PAK could be another best choice for individuals with diabetic end-stage renal disease, especially in cases where deceased donors were severely deficient but living donor kidney transplants were actively performed in countries like Korea.
ABSTRACT
INTRODUCTION: This study examined associations between the graft-to-recipient weight ratio (GRWR) for adult-to-adult living donor liver transplantation (LDLT) and hepatocellular carcinoma (HCC) outcomes. MATERIALS AND METHODS: Data from patients in the Korean Organ Transplantation Registry who underwent LDLT for HCC from 2014 to 2021 were retrospectively reviewed. Patients were categorized using the cutoff GRWR for HCC recurrence determined by an adjusted cubic spline (GRWR <0.7% vs. GRWR ≥0.7%). Recurrence-free survival (RFS) and HCC recurrence were analyzed in the entire and a 1:5 propensity-matched cohort. RESULTS: The eligible cohort consisted of 2005 LDLT recipients [GRWR <0.7 ( n =59) vs. GRWR ≥0.7 ( n =1946)]. In the entire cohort, 5-year RFS was significantly lower in the GRWR <0.7 than in the GRWR ≥0.7 group (66.7% vs. 76.7%, P =0.019), although HCC recurrence was not different between groups (77.1% vs. 80.7%, P =0.234). This trend was similar in the matched cohort ( P =0.014 for RFS and P =0.096 for HCC recurrence). In multivariable analyses, GRWR <0.7 was an independent risk factor for RFS [adjusted hazard ratio (aHR) 1.89, P =0.012], but the result was marginal for HCC recurrence (aHR 1.61, P =0.066). In the pretransplant tumor burden subgroup analysis, GRWR <0.7 was a significant risk factor for both RFS and HCC recurrence only for tumors exceeding the Milan criteria (aHR 3.10, P <0.001 for RFS; aHR 2.92, P =0.003 for HCC recurrence) or with MoRAL scores in the fourth quartile (aHR 3.33, P <0.001 for RFS; aHR 2.61, P =0.019 for HCC recurrence). CONCLUSIONS: A GRWR <0.7 potentially leads to lower RFS and higher HCC recurrence after LDLT when the pretransplant tumor burden is high.