Endocrine Abstracts

Background: Pancreatic neuroendocrine tumors (PNETs) are a rare, understudied form of cancer with few curative options, and their occurrence is rising. With approximately 4,000 new cases diagnosed per year in the US, and a 5-year relative survival rate of 54%, it’s imperative to understand the molecular mechanisms governing PNET carcinogenesis. To date, most studies used whole-tumor sequencing to characterize PNETs, which hampers the discovery of their microenvironment, c...

Background: Pancreatic neuroendocrine tumors (P-NETs) are a rare cancer with increasing incidences worldwide. Low-grade P-NETs are unique in that they express high levels of Somatostatin Receptor Type 2 (SSTR2), which represents a target for both tumor imaging and therapeutics. P-NET grade inversely correlates with SSTR2 tumor staining, and higher tumor grade is associated with poor patient prognosis. Unfortunately, application of SSTR2-targeted treatment options is currently ...

Background: Well-differentiated neuroendocrine tumors (NETs) are characterized by the overexpression of somatostatin receptors (SSTRs). To efficiently engage and activate tumor infiltrating lymphocytes against NET cells, we designed a novel bispecific T-cells engager (BiTE) composed of 2 molecules of somatostatin-14 (SST14), the hormone that physiologically binds SSTRs, linked with a single chain variable fragment (scFV)-based anti-CD3.Methods: The optim...

Background: Neuroendocrine tumor (NET) patients with diminished SSTR2 expre-ssion are not eligible for any type of SSTR2-specific imaging or treatment. Herein, we propose to epigenetically enhance and enable somatostatin receptor type 2 (SSTR2)-targeted theranostics for patients with NETs. Specifically, we have found that simultaneous inhibition of DNA methylation and his-tone de-ace-tylation enhanced SSTR2 expression and in vitro binding of [68Ga]DOTATATE....

Background: Oncolytic viruses (OV) hold potential for not only delivering durable anti-tumor responses but also converting immunologically “cold” tumors to “hot” tumors. Seneca Valley Virus (SVV-001) is a naturally occurring oncolytic picornavirus found to have selectivity for tumor cells with neuroendocrine (NE) properties. Because of the paucity of syngeneic murine NE tumor models, we evaluated the efficacy of Seneca Valley Virus (SVV), in combination wit...

Background: Current theragnostic techniques for pancreatic neuroendocrine tumors (pNETs) exploit the overexpression of somatostatin receptors (SSTRs) on the cell surface. However, approximately 25% of low-grade and most high-grade pNETs do not express SSTRs, requiring alternative theranostics. Calreticulin (CALR) is a protein linked to reticular calcium homeostasis and immunogenic cell death. Upon sufficient cellular insult, CALR translocates from the endoplasmic reticulum (ER...

Background: Peptide receptor radionuclide therapy (PRRT) is a promising radiation-based therapy for metastatic neuroendocrine tumors (NETs) but remains palliative. Peptidyl-prolyl cis-trans isomerase (Pin1) is an evolutionally conserved enzyme that catalyzes the cis-trans isomerization of phosphorylated serine/threonine-proline motifs of its substrates and has recently been involved in DNA double strand break (DSB) repair in BRCA-proficient breast cancer cells. Here we study w...

Background: New therapeutics and combinations are needed to improve the survival of patients with advanced, metastatic pancreatic NETs (pNETs). RABL6A is a novel oncogenic driver of pNET pathogenesis that acts through multiple oncogenic pathways. Kinome and phosphoproteome analyses of proliferating (RABL6A-positive) pNET cells, vs arrested (RABL6A-knockdown) controls, demonstrated that druggable cyclin-dependent kinase 4 and 6 (CDK4/6) and MEK kinases are activated in growing ...

Background: The 5-year survival rate for patients with unresectable, metastatic pancreatic neuroendocrine tumors (pNETs) remains less than 30%, emphasizing the need for new and effective treatment options for patients with advanced pNETs. Notch1 signaling is a critical cell-cell communication pathway responsible for regulating differentiation, cell fate determination, and epithelial-mesenchymal transition (EMT). Notch1 plays a critical role in the differentiation state of NE c...

Background: The use of peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs) is increasing, but PRRT remains palliative at this time. Estrogen (E2) has been extensively linked to cellular proliferation and DNA repair in other cancers. Our aim is to determine whether NET cells are similarly affected by estrogen and whether inhibition of estrogen receptor alpha (ESR1) increases radiosensitivity of NET cells, which could improve PRRT response.<p class=...

Background: Neuroendocrine tumors (NETs) are a heterogeneous group of malignant neoplasms arising from neuroendocrine cells distributed throughout the body. The most common sites of NETs are the gastrointestinal tract, pancreas and lungs. The clinical management of NETs is not standardized, with few FDA-approved therapies. Moreover, drug development has been challenging for NETs due to limited pre-clinical models. To address this unmet need, the NCI Natural History Study of Ch...

Background: There are known outcome disparities between Black and White patients with pancreatic neuroendocrine tumors (pNETs). Recently, Black patients were shown to have higher rates of lymph node metastasis in smaller tumors than White patients, indicating possible differences in tumor biology. Numerous prognostic gene expression differences between racial groups have been reported in other cancers, but no such analysis has been conducted in pNETs. This study evaluated pNET...

Background: Genomic structural variants (SVs) encompass a large portion of mutations driving cancer progression, however, there is a paucity of data regarding such drivers in metastatic neuroendocrine tumor (mNET). Existing studies have focused on short-read sequencing of primary NET samples, which can detect single nucleotide variants, but are unable to identify larger SVs. Such studies have demonstrated a low rate of genetic mutations. Optical genome mapping (OGM) represents...

Background: Pancreatic mixed acinar-neuroendocrine carcinomas are a rare distinctive entity with histologic and immunohistochemical features of pancreatic acinar cell carcinoma and pancreatic neuroendocrine tumor and pose diagnostic challenges. Very few cases have been described in the literature. Genomic information about these tumors remains unknown. We identified two cases of mixed acinar- neuroendocrine carcinoma from our database since January 2020 who had full genomic in...

Background: More than 12,000 people in the United States are diagnosed with a NET each year and approximately 175,000 people are living with this diagnosis. Little progress has been made in the therapy of NETs over the last two decades, and identification of new vulnerabilities remains a priority.Methods: We used two libraries of compounds selected for potential repurposing and identified agents with the highest cytotoxic activity in neuroendocrine model...

Background: Peptide-based targeted alpha-particle radiotherapy has emerged as a promising approach to cancer treatment. 203Pb/212Pb is the only elementally identical isotope pair for this application. Tyr3-Octreotide (TOC) peptide ligands targeting SSTR2 have been widely investigated preclinically and clinically. [177Lu]DOTATATE was approved by the US FDA to treat patients with gastroenteropancreatic neuroendocrine tumors. However, t...