Comprehensive Profiling of OTSSP167 Action in Adrenocortical Carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Adrenocortical carcinoma (ACC) is a rare and aggressive cancer with limited treatment options.
• There is an unmet need for effective targeted therapies in ACC, which is associated with poor patient outcomes.

Purpose of the Study:

• To investigate the efficacy of the multikinase inhibitor OTSSP167 as a potential treatment for adrenocortical carcinoma (ACC).
• To elucidate the mechanisms of action of OTSSP167 in ACC models, including its effects on cell cycle, apoptosis, and DNA damage.
• To explore combination strategies involving OTSSP167 and other targeted agents, such as WEE1 inhibitors.

Main Methods:

• Utilized patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models of ACC, including a novel PDX model (CUACC9).
• Administered OTSSP167 to in vivo tumor models with varying TP53 statuses (wild type and mutant).
• Conducted immunohistochemical (IHC) analysis, RNA sequencing (RNA-seq), and Reverse Phase Protein Arrays (RPPA) to assess molecular changes and identify drug targets.

Main Results:

• OTSSP167 demonstrated significant tumor growth reduction in both wild type and TP53 mutant ACC models.
• OTSSP167 induced apoptosis via caspase activation and caused G2/M cell cycle arrest, independent of TP53 status.
• In TP53 mutant ACC, OTSSP167 enhanced DNA damage and inhibited protein synthesis; RSK1 was identified as a direct target.
• Combination therapy with OTSSP167 and a WEE1 inhibitor (AZD1775) enhanced cytotoxicity and reduced tumor growth in TP53 mutant models.

Conclusions:

• OTSSP167 is a feasible therapeutic agent for ACC, particularly for TP53 mutant subtypes.
• Targeting adaptive responses, such as WEE1 activation, following OTSSP167 treatment presents a novel therapeutic strategy.
• These findings provide a strong rationale for initiating a Phase I clinical trial of OTSSP167 in ACC patients.