Pancreatic neuroendocrine tumors (PanNETs) are increasing in incidence, and 40-95% of them are metastatic at the time of initial diagnosis. Despite various complex management strategies for neuroendocrine liver metastases, surgery is the only treatment that offers potential for cure. There is a critical need to develop new therapeutic options to reduce PanNETs progression. We have discovered that PanNETs are deficient in Notch signaling, and reinstitution of this pathway alters the malignant phenotype. Therefore, there is a need for an effective Notch activator as a therapeutic agent against PanNETs. We hypothesize that the induction of Notch signaling with small molecule compounds will provide an effective strategy to treat patients with PanNETs. High- throughput screening for Notch pathway activators identified a natural compound originating from marine sponges (DHN-III-14) capable of inhibiting PanNETs proliferation and altering the neuroendocrine (NE) cancer phenotype. To improve therapeutic efficacy, we propose to conjugate the drug candidate with an antibody that specifically binds to somatostatin receptor (SSTR2) which is overexpressed on the surfaces of PanNETs cells. Such antibody-drug conjugate (ADC) can selectively deliver a lethal agent to tumor cells and minimize side effects to patients. To delineate the antitumor efficacy of the ADC, we will use the in vitro PanNET cell cultures and the in vivo preclinical mouse model of liver metastases. If the anticancer efficacy will be confirmed in the preclinical models, this will be the first ADC toward targeted therapy for PanNETS.
Pancreatic neuroendocrine tumors (PanNETs) are increasing in incidence, and despite various complex management strategies for the primary PanNETs and liver metastases, surgery is the only treatment that offers potential for cure. Treatment with antibody-drug conjugate (ADC), which combines the tumor-targeting specificity of an antibody with the potent cytotoxicity of small- molecule warhead, will enhance antitumor responses and result in increased clinical benefit for PanNET patients.
