Neuroendocrine Cancer Research
Neuroendocrine tumors share common characteristics such as abnormal hormone secretion, an indolent course, specific genetic mutations, and poor response to conventional therapy. Medullary thyroid cancer (MTC), the most common neuroendocrine tumor, arises from calcitonin-producing parafollicular or C-cells and metastasizes frequently to regional lymph nodes, and to the lungs, liver, and brain. Although MTC accounts for 3-5% of all thyroid cancer, it accounts for over 14% of thyroid cancer related deaths overall and is the fifth most common form or cancer related deaths in women. Despite conventional therapy, patients with distant metastases have high mortality. Approximately 25% of the cases are hereditary, stemming from activating mutations in the RET proto-oncogene, as a component of the multiple endocrine neoplasia-2 syndrome (MEN-2). RET encodes receptor protein tyrosine kinases and well described RET mutations are responsible for oncogenic transformation and proliferation of MTC. The downstream targets and pathways affected by RET mutations are well characterized. However the majority of MTC cases (>75%) arise spontaneously (sporadic MTC) in the absence of known mutations or abnormalities in RET signaling. The underlying mechanisms of oncogenesis in these patients are poorly understood. Given the poor response to conventional therapy and debilitating symptoms of recurrent and metastatic MTC (airway obstruction, flushing, abdominal pain and diarrhea), a great need exists for knowledge about the molecular signals that regulate oncogenesis in the majority of patients with MTC. Despite the large body of research on MTC, there has been little effect on the poor outcomes associated with this disease and progress has been hindered by the lack of a clinically-relevant, reproducible animal model for MTC.
We are studying the role of cyclin-directed kinases in the oncogenesis of neuroendocrine cancers. We have developed a provocative inducible/arrestalbe animal model of MTC and are using this model together with studies using human tumor tissue to delineate novel oncogenic mechanisms. Importantly many of these mechanisms appear to be shared with neurodegenerative diseases or pathways of neuronal injury. We feel our research into the relationship between oncogenic and neuronal injury pathways provides a unique perspective and bring a fresh approach to the identification and validation of novel oncogenic targets for drug discovery.
See the following publication to learn more about our mood disorder research:
Pozo, K., Castro-Rivera, Tan, C., Plattner, F., Schwach, G., Siegl, V., Meyer, D.A. Guo, A., Gundara, J., Mettlach, G., Richer, E., Guevara, J.A., Ning, L., Gupta, A., Hao, G., Tsai, L-H., Sun, X., Antich, P., Sidhu, S., Robinson, B.G., Chen, H., Nwariaku, F.E., Pfragner, R., Richardson J.A., and Bibb, J.A., (2013) The role of Cdk5 in neuroendocrine cancer, 24:499-511, Cancer Cell, cover article.