Somatostatin receptor 2 (SSTR2) antibody-drug conjugate for pancreatic neuroendocrine tumor (PanNET) therapy

胰腺神经内分泌肿瘤（PanNETs）的发病率正在增加，其中40-95%的人 在初次诊断时是转移性的。尽管有各种复杂的管理策略， 对于神经内分泌肝转移，手术是唯一有可能治愈的治疗方法。那里 迫切需要开发新的治疗方案来减少PanNET的进展。我们有 发现PanNET缺乏Notch信号传导，而重新建立这一通路会改变 恶性表型因此，需要一种有效的Notch活化剂， 针对PanNET的治疗剂。我们假设Notch信号的诱导与 小分子化合物将提供治疗PanNET患者的有效策略。高- Notch途径激活剂的通量筛选鉴定了一种源自 海洋海绵（DHN-III-14）能够抑制PanNET增殖并改变 神经内分泌（NE）癌表型。为了提高治疗效果，我们建议 将候选药物与特异性结合生长抑素受体的抗体偶联 （SSTR 2），其在PanNETs细胞的表面上过表达。这种抗体药物 偶联物（ADC）可以选择性地将致死剂递送至肿瘤细胞，并使副作用最小化， 患者为了描述ADC的抗肿瘤功效，我们将使用体外PanNET细胞 培养物和肝转移的体内临床前小鼠模型。如果抗癌功效将 在临床前模型中得到证实，这将是第一个用于靶向治疗的ADC， PANNETS。

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.