The vault complex in endocrine tumors

• Applicant: Dr. Constanze Hantel
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 369159814

Malignant endocrine cancers are rare and heterogenous tumors with an overall poor prognosis. Many patients are diagnosed at an advanced stage of the disease and often highly resistant to commonly used systemic treatments. In recent years, studies involving the Tumor-Vascular-Disrupting Agent ASA404 have indicated anti-tumor efficacy in preclinical models of different types of solid tumors, provided promising results in initial trials, but performed poorly in further clinical studies. In an attempt to gather insights into specific drug response and resistance mechanisms we compared one ASA-responsive and one unresponsive tumor model for endocrine tumors in a preclinical setting. Our analyses identified vault RNAs 1 to 3 as highly therapy-induced transcripts in endocrine tumor models showing therapeutic responsiveness upon ASA404 as well as cytostatic drugs in vivo. Although recently the vault complex was believed to be involved in multidrug resistance, the exact function of this large ribonucleoprotein complex has remained uncertain. Our novel findings indicate that investigation and modulation of vault particles might have therapeutic potential in endocrine tumors. Thus, we propose the treatment-dependent trafficking of the vault complex, the functional role and mechanistic insights of vault RNAs as well as their putative exosomal release upon tumor cell damage. Finally, these findings will be translated in therapeutic experiments with direct clinical relevance.

• DFG Programme: Research Grants