Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options

Abstract

In rare diseases such as adrenocortical carcinoma (ACC), in silico analysis can help select promising therapy options. We screened all drugs approved by the FDA and those in current clinical studies to identify drugs that target genomic alterations, also known to be present in patients with ACC. We identified FDA-approved drugs in the My Cancer Genome and National Cancer Institute databases and identified genetic alterations that could predict drug response. In total, 155 FDA-approved drugs and 905 drugs in clinical trials were identified and linked to 375 genes of 89 TCGA patients. The most frequent potentially targetable genetic alterations included TP53 (20%), BRD9 (13%), TERT (13%), CTNNB1 (13%), CDK4 (7%), FLT4 (7%), and MDM2 (7%). We identified TP53-modulating drugs to be possibly effective in 20–26% of patients, followed by the Wnt signaling pathway inhibitors (15%), Telomelysin and INO5401 (13%), FHD-609 (13%), etc. According to our data, 67% of ACC patients exhibited genomic alterations that might be targeted by FDA-approved drugs or drugs being tested in current clinical trials. Although there are not many current therapy options directly targeting reported ACC alterations, this study identifies emerging options that could be tested in clinical trials.

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

“…FHD-609 is a PROTAC BRD9 degrader in clinical trials to treat synovial sarcoma and smarcb1-deficient tumors 27 . By degrading BRD9, FHD-609 prevents the formation of the BAF complex, thus treating synovial sarcoma.…”

“… 25 developed the first EZH2 PROTAC, followed by the discovery of the first HDAC and EZH2 HyT degraders by the Schiedel group in 2020 26 . Notably, in 2021, the first epigenetic degrader FHD-609, which selectively targets BRD9, entered clinical trials for subjects with advanced synovial sarcoma 27 . Additionally, the second BRD9 selective degrader, CFT8634, is currently undergoing clinical trials for the treatment of synovial sarcoma and SMARCB1-Null tumors 28 .…”

Discovery of a Highly Potent and Selective BRD9 PROTAC Degrader Based on E3 Binder Investigation for the Treatment of Hematological Tumors

“…FHD-609 is developed by Foghorn Therapeutics for synovial sarcoma, with its highest development status in clinical phase I. 10 In addition, there are other BRD9-targeting PROTACs, such as VZ-185, 11 which degrades both BRD7 and BRD9, and dBRD9, 12 a selective BRD9 degrader. These molecules indicate that PROTACs have the potential to become an effective means to address the undruggable profiles of BRD9.…”

“…CFT8634 , administered orally in phase I/II clinical trials, achieves a DC 50 value of 3 nM for BRD9 degradation. FHD-609 is developed by Foghorn Therapeutics for synovial sarcoma, with its highest development status in clinical phase I . In addition, there are other BRD9-targeting PROTACs, such as VZ-185 , which degrades both BRD7 and BRD9, and dBRD9 , a selective BRD9 degrader.…”

“…During the design and development of PROTACs, the majority of the structural modifications of the linkers and POI ligands were investigated. − However, researches showed that the modification of the E3 ligands may greatly enhance the activity of PROTACs. Currently, the commonly used E3 ligases in BRD9 PROTACs include CRBN (Cereblon) ,, and VHL (Von-Hippel Lindau) . Most of the degraders are based on the CRBN ligands (thalidomide, pomalidomide, or lenalidomide) due to their advantages of small molecular weight and convenient synthesis.…”