In:
Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 11_Supplement ( 2016-11-01), p. A33-A33
Abstract:
Background: 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 genes mutated in four types of familial MEN syndromes: Menin, RET, and CDNK1B. 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. Our lab has determined that Cdk5 promotes growth in multiple types of NE cancer. Phosphoproteomic studies revealed a selective set of proteins potentially phosphorylated downstream of Cdk5 activation. We hypothesize that these phosphoproteins will serve as biomarkers to identify tumors that will be responsive to anti-Cdk5 therapies. Methods: Phosphorylation state-specific antibodies were generated to novel phosphoprotein sites by inoculation of New Zealand White rabbits with phosphopeptides specific to each site. Antibodies were isolated from rabbit sera by affinity purification using phosphopeptide columns. Human NE cell lines were treated with Cdk5 inhibitors and monitored for effects on phosphoprotein levels. Phosphoprotein levels were examined in growing and arrested medullary thyroid carcinoma tumors isolated from an inducible/arrestable (NSE-tTA; tetO-p25GFP) mouse model and in normal lung versus small cell lung cancer tumors isolated from a triple conditional knockout (p130 f/f; p53 f/f; Rb f/f) mouse model. Phosphoprotein levels were examined in control tissue and human medullary thyroid carcinoma, gastrointestinal NETs, and pancreatic NETs. Results: Phosphorylation state-specific antibodies were successfully generated to 10 novel phosphoproteins. Cdk5 inhibition decreases phosphorylation levels of 5 of these 10 proteins in several types of NE cell lines. Levels of 4 of these phosphoproteins are elevated in human NE tumors. Conclusion: Four novel phosphoproteins downstream of Cdk5 comprise a set of biomarkers for Cdk5-dependent human NE tumors. The combination of these biomarkers with pathway specific therapies currently under development will constitute a coupled diagnostic-therapeutic regimen for personalized treatment of NE cancer patients. Citation Format: Angela M. Carter, Rahul Telange, Sarah Oltmann, Fiemu Nwariaku, Bruce Robinson, Elizabeth Grubbs, James Bibb. Biomarkers of Cdk5 driven neuroendocrine tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A33.
Type of Medium:
Online Resource
ISSN:
1541-7786
,
1557-3125
DOI:
10.1158/1557-3125.CELLCYCLE16-A33
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2097884-4
SSG:
12
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