Abstract 5389: Exploring potential predictive biomarkers for the responsiveness to CTX-712 by in vivo drug sensitivity analysis on PDX models

Abstract

Abstract Cancer’s remarkable diversity had been understood through a logical framework of six key hallmarks. Additionally, several equally prevalent hallmarks have been identified in recent analyses of cellular phenotypes as the stress phenotypes of cancers. A novel hallmark of cancer RNA deregulation has been newly proposed as another hallmark of cancer within this group of stress phenotypes. However, the development of cancer therapies targeting RNA deregulation has only just begun. Indeed, small molecules that attack the RNA maturation processes and produce aberrant RNA are currently under development. We developed orally available, selective, and a first-in-class pan- CDC-like kinase (CLK) inhibitor, CTX-712, currently in phase 1 clinical trials for advanced, relapsed or refractory malignant cancers. CTX-712 dephosphorylates serine and arginine-rich proteins and induces primarily skipped exon type of splicing changes, resulting in the generation of RNA deregulation stress. In multiple preclinical models, excessive RNA deregulation stress caused cancer cell death and tumor growth inhibition. To explore the patient selection biomarkers for CTX-712, in vivo efficacy survey analysis has been conducted on breast, ovarian, colorectal, pancreatic, gastric and lung cancer models from patient derived xenograft (PDX) library with a detailed clinical information. Besides the efficacy investigation, the preclinical pharmacokinetics (PK) and pharmacodynamics (PD) analysis on tested PDX models were also performed to confirm plasma/tumor PK and PD (target CLK inhibition in xenografted tumors). Importantly, tested PDX models could be divided to sensitive (T/C on the most sensitive model = -71.1) and insensitive (T/C on the least sensitive model = 67.7), and the correlated tendency was observed between the efficacy and the inhibition magnitude of intratumor PD marker, production of exon skipped aberrant mRNA. To clarify the differences of sensitivity among tested PDXs will lead us to identity patient selection biomarkers of CTX-712. Therefore, whole transcriptome RNA sequencing, exome sequencing, and other approaches have been applied to reveal the differences of sensitivity among tested PDXs. Through this study on multiple PDXs, integration of drug responsiveness, and genomic/transcriptomic profiling may provide prediction markers for treatment responsiveness of CTX-712. Citation Format: Daisuke Morishita, Shigehiro Yagishita, Akio Mizutani, Hiroko Yamakawa, Shunsuke Ebara, Akinobu Hamada. Exploring potential predictive biomarkers for the responsiveness to CTX-712 by in vivo drug sensitivity analysis on PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5389.