Abstract 3567: Identification of potential biomarkers and novel therapeutic candidates for neuroendocrine cancer

Abstract

Abstract Neuroendocrine (NE) cancers originate from secretory cells of the body's various endocrine structures. Surgical resection is the primary treatment for these tumors. However, the majority of NE cancers are metastatic at the time of detection and no effective adjuvant therapies exist for primary NE tumors or their metastases. Patients often develop two or more NE cancers, a syndrome termed multiple endocrine neoplasia (MEN). DNA sequencing has lead to breakthroughs in the identification of the causes of familial forms of the four types of MEN syndromes. Mutations in a protein of unknown function, menin, are associated with MEN1. Mutations in the receptor tyrosine kinase RET are linked to MEN2 and MEN3. The cyclin-dependent kinase inhibitor, CDNK1B, is mutated in MEN4. Unfortunately, a large percentage of NE cancers are sporadic, resulting from somatic mutations, and a high percentage of these do not harbor menin, RET, or CDNK1B mutations. Due to the lack of development of successful adjuvant therapies there has been little improvement in survival rates of NE cancer patients in the past several decades. Thus, there is a great need for the elucidation of signaling molecules that promote NE tumorigenesis in order to guide the development of novel and effective treatments for this family of cancers. Our laboratory has found that cyclin-dependent kinase 5 (Cdk5) is an important tumorigenic signaling molecule in sporadic medullary thyroid carcinoma (MTC), a type of NE cancer that originates from calcitonin-producing C cells in the thyroid. New data supports a role for Cdk5 in multiple types of NE cancer and provides a new prospective from which to explore their causes. Cdk5 is expressed in many NE cancers and inhibition of Cdk5 activity blocks growth of NE cancer cell lines. Phosphoproteomic analysis of growing versus arrested MTC tumors, induced by expression of the Cdk5 activator p25 in our transgenic mouse model of MTC, revealed elevation of over 200 phosphorylation sites. We have used short interfering peptides (SIPs) to selectively target a set of these phosphorylation sites and found that 15 of these SIPs blocked growth of NE cancer cell lines. Phosphorylation state specific antibodies were generated to several of these sites and phosphorylation levels were confirmed to be decreased in arrested MTC tumors. In conclusion, 1) multiple types of NE cancer cells are dependent on Cdk5 activity for growth, 2) phosphorylation of multiple signaling proteins is elevated downstream of Cdk5, and 3) select inhibition of these pathways blocks growth of NE cancer cells. Future studies will focus on analysis of these phosphoproteins in human NE tumors to validate of them as biomarkers for targeted cancer therapies as well as exploration of these phosphoproteins as direct targets for developing new therapeutics that are effective against NE cancers. Citation Format: Angela Carter, Karine Pozo, Chun-Feng Tan, Fiemu Nwariaku, James Bibb. Identification of potential biomarkers and novel therapeutic candidates for neuroendocrine cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3567. doi:10.1158/1538-7445.AM2015-3567