Patel, Mona

144 Background: Kinase inhibitors have been ineffective in prostate cancer and have no known role in androgen biosynthesis. Inheritance of the adrenal-permissive HSD3B1(1245C) allele encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from non-gonadal precursor steroids and confers poor clinical outcomes in castration-resistant prostate cancer (CRPC). About half of all men with prostate cancer inherit the adrenal-permissive HSD3B1 allele. Multiple clinical studies demonstrate that adrenal-permissive HSD3B1 allele inheritance confers more rapid progression on ADT and others also suggest worse CRPC outcomes even after treatment with abiraterone or enzalutamide. However, there is no known method to clinically block 3βHSD1. Furthermore, 3βHSD1 is not known to be phosphorylated. Methods: Mass spectrometry was used to identify protein phosphorylation sites and steroid metabolites, genetic and pharmacologic methods were used to identify the kinase required for 3βHSD1 phosphorylation and mouse xenograft studies were performed with BMX inhibition. The identified mechanism was used to design and launch a multicenter phase 2 study of the BMX inhibitor abivertinib in combination with abiraterone in men with metastatic CRPC. Results: 3βHSD1 enzyme activity requires tyrosine phosphorylation at Y344 by the BMX kinase. Androgen biosynthesis is blocked by a phosphorylation-defective 3βHSD1 344F, or BMX genetic knockdown, or BMX pharmacologic inhibition. BMX inhibition using zanubrutinib suppresses CRPC growth in the C4-2 and VCaP xenograft models by blocking intratumoral androgen synthesis and tumor androgen receptor (AR) signaling. Discovery of this mechanism provides the rationale for the phase 2 Maverick trial of abivertinib, a BMX inhibitor, combined with abiraterone, in men with CRPC with adrenal-permissive HSD3B1 allele inheritance (NCT05361915). Eligibility includes 1) presence of metastatic CRPC, 2) measurable and/or non-measurable disease, and 3) confirmed positivity of adrenal-permissive HSD3B1(1245C) allele inheritance via central testing (cap heterozygosity at 50%). Patients will be enrolled in 2 arms: 1) abiraterone naïve (n=45) and 2) abiraterone progressing (n=55). All patients will receive treatment with abivertinib 200mg twice daily with abiraterone 1000mg daily and prednisone 5mg by mouth twice daily. The primary outcome is 6-month radiographic progression-free survival. On-treatment biopsies will be used to inform mechanisms of response and resistance in patients. Conclusions: BMX is required for 3βHSD1 phosphorylation, androgen biosynthesis and CRPC progression with the adrenal-permissive HSD3B1(1245C) allele. The Maverick trial will test clinical proof-of-concept of BMX inhibition in men with adrenal-permissive HSD3B1(1245C) inheritance. Clinical trial information: NCT05361915 .

Abstract Background Computed tomography enterography (CTE) is frequently used to assess stricturing Crohn’s disease (CD). However, the reliability of CTE items used for assessment has not been established and there is no validated radiologic stricture severity index. Methods We conducted a retrospective study of 43 patients with symptomatic, terminal ileal stricturing CD. Four radiologists assessed a comprehensive list of pre-defined radiologic items potentially associated with stricture severity in 48 CTE scans in two separate rounds in random order. Reliability was quantified using the intraclass correlation coefficient (ICC). Items with at least moderate (ICC≥0.41) inter-rater reliability that were correlated with a visual analogue scale of overall stricture severity were candidate items for the development of a CTE stricture index. Results Inter-rater reliability was almost perfect for assessment of luminal diameter of pre-stenotic dilation (ICC 0.817 [95% confidence interval 0.703, 0.878]), substantial for stricture length (ICC 0.628 [0.419, 0.797]), and moderate for stricture wall thickness (0.482 [0.330, 0.601]). Intra-rater reliability was almost perfect (ICC ≥ 0.850) for all three items. A stricture severity index was derived and was well calibrated (optimism-adjusted calibration slope = 1.009), with scores calculated as the sum of stricture length (cm) + luminal diameter of pre-stenotic dilation (mm) + 5 x stricture wall thickness (mm). Conclusion Stricture length, prestenotic dilation, and stricture wall thickness can be reliably assessed, and are component items for a novel CTE stricture index (CTE-SI) of stricture severity for CD-related terminal ileal strictures. Additional external index validation for clinical and research contexts is required.