Searchable abstracts of presentations at key conferences in endocrinology
Previous issue | Volume 98 | NANETS2023



Basic Science

ea0098b1 | Basic Science | NANETS2023

Spatial profiling of neuro-immune interactions in gastroenteropancreatic NETs

Duan Suzann , Sawyer Travis W. , Witten Brandon L. , Song Heyu , Merchant Juanita L.

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Until recently, the absence of reliable methods to unmix tumor- and stroma-derived signals has precluded a comprehensive understanding of how GEP-NETs arise in different tissues. Here, we sought to decipher tumor-derived signals from the surrounding microenvironment by applying Nanostring Digital Sp...

ea0098b2 | Basic Science | NANETS2023

TMEM127 exerts a tumor suppressive role in pheochromocytoma by mediating RET ubiquitin-dependent degradation

Gonzalez-Cantu Hector , Guo Qianjin , Cheng Zi-Ming , Rotondi Matthew , Huelgas-Morales Gabriela , Lefkowitz Jonathan , Ethiraj Purushoth , Qiu Zhijun , Song Wan , Landry Bethany N. , Lopez Hector , Estrada-Zuniga Cynthia M. , Goyal Shivi , Aasif Khan Mohammad , Walker Timothy J. , Wang Exing , Li Fagian , Ding Yanli , Aguiar Ricardo C. T. , Mulligan Lois M. , Dahia Patricia L. M.

Background: TMEM127 encodes for a ubiquitously expressed transmembrane protein with limited knowledge into its role. TMEM127 germline loss-of-function is a driver of pheochromocytoma and paraganglioma (PPGLs), tumors derived from the adrenal medulla and extra-adrenal paraganglia, respectively. Molecularly, TMEM127 mutant PPGLs belong to the kinase cluster, characterized by kinase signaling transcriptional programs. Receptor tyrosine kinase RET, a driver of PPGLs via germline o...

ea0098b3 | Basic Science | NANETS2023

Translational biomarkers in G2-3 NENs: Analysis from NET-001 and NET-002 trials

Nunez Jose E. , Bruce Jeffrey , Danesh Arnavaz , Chan David L. , Rodriguez-Freixinos Victor , Hallet Julie , Myrehaug Sten , Law Calvin , Pugh Trevor , Singh Simron

Background: The treatment of neuroendocrine neoplasms (NENs) of higher grade remains a dilemma. In these patients the role of immunotherapy is still unclear and predictive biomarkers are an unmet need. Herein, we present a revised translational analysis of the NET001 and NET002 (NCT03278405, NCT03278379) clinical trials.Methods: Patients with advanced WHO G2-3 NENs who had a gastroenteropancreatic (GEP) or a bronchial primary (excluding typical carcinoid...

ea0098b4 | Basic Science | NANETS2023

Cardiac autonomic dysfunction in a mouse model of carcinoid disease

Kuehn, BS Sydney , Penrose, BS Sofia , Pommier, MD Rodney F. , McCully, PhD Belinda H.

Background: Patients with metastatic carcinoid disease confer a risk for carcinoid syndrome, characterized by hemodynamic instability and syncope. While the physiologic mechanisms linking carcinoid tumor metastases to impaired blood pressure regulation are not well understood, this may be attributed to changes in autonomic function, which is a key regulator of blood pressure. We hypothesize that metastatic carcinoid disease induces autonomic dysfunction. To test this, we longi...

ea0098b5 | Basic Science | NANETS2023

Unveiling pancreatic neuroendocrine tumors through plasma-derived small extracellular vesicles

Kumari Gorai Priya , Rastogi Simran , Singh Seema , Agarwal Shipra , Pal Sujoy , Chandra Nag Tapas , Dhingra Renu , Chand Sharma Mehar , Kumar Rakesh , Kumar Saroj , Rani Neerja

Background: The global incidence of pancreatic neuroendocrine tumors (PanNETs) has witnessed a steady rise in the past three decades. Unfortunately, the survival rates remain low primarily due to late-stage diagnoses and a lack of specific and sensitive diagnostic markers. Therefore, there is an urgent need for improved and efficient early diagnostic biomarkers. Small extracellular vesicles (sEVs) have gained significant attention in the field of tumor growth and cancer metast...

ea0098b6 | Basic Science | NANETS2023

Prevalence of cardiac arrhythmias in a mouse model of carcinoid disease

Penrose, BS Sofia , Kuehn, BS Sydney , Pommier, MD Rodney F. , McCully, PhD Belinda H.

Background: Neuroendocrine tumors that release prostaglandins and biogenic amines that can impact cardiac function. In consequence, patients with carcinoid liver metastases are at risk for carcinoid heart disease. This is primarily characterized by fibrosis in the heart that leads to plaques on the valvular cusps, leaflets and walls of the atrium and ventricles leading to a thickened right heart with regurgitation. Interestingly, 50-80% of patients with carcinoid heart disease...

ea0098b7 | Basic Science | NANETS2023

Genomic analyses of multifocal ileal neuroendocrine tumors

Makinen Netta , Zhou Meng , Zhang Zhouwei , Kasai Yosuke , Kim Grace E. , Thirlwell Chrissie , Nakakura Eric , Meyerson Matthew

Background: Small intestinal neuroendocrine tumor (SI-NET) is one of the major cancer subtypes of the small bowel. Most SI-NETs locate in the terminal ileum with a high incidence of multiple synchronous primary tumors. The only essentially curative treatment of SI-NETs is complete surgical resection; however, most SI-NET patients cannot undergo surgery as they typically present with an extensive metastatic disease. Several high-throughput sequencing studies have reported low s...

ea0098b8 | Basic Science | NANETS2023

ATRX: a novel predictive biomarker for peptide receptor radionuclide therapy in neuroendocrine tumors

Hammad M. , Lee Z. , Asa S.L. , Aboody K. , Mahipal A. , Bajor D. , Chakrabarti S. , Selfridge J.E. , Ocuin L.M. , Hoehn R.S. , Winter J. , Ammori J. , Hardacre J. , Tirumani S.H. , Henke L.E. , Mohamed A.

Background: Peptide receptor radionuclide therapy (PRRT) including Lutetium177 (Lu177) has changed the treatment landscape of metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). There is a subgroup of patients who are resistant or develop resistance after initial success to PRRT, indicating that accurate predictive markers are urgently needed to identify who will benefit from PRRT. We hypothesize that expression of ATRX (Alpha Thalassemia and Mental Retardation...

ea0098b9 | Basic Science | NANETS2023

Machine learning algorithm to classify multiphoton microscopy images of pancreatic neuroendocrine tumors

Daigle Noelle , Duan Suzann , Merchant Juanita L. , Sawyer Travis W.

Background: Surgery is the preferred method of treatment for most pancreatic neuroendocrine tumors (PNETs), particularly functional PNETs or those greater than 2 cm in largest dimension. Existing techniques include intraoperative ultrasound and manual palpation, both of which have inherent disadvantages such as poor resolution and low contrast against normal pancreatic tissue. This results in surgeons performing more demolitive resections, such as the Whipple procedure, when t...

ea0098b10 | Basic Science | NANETS2023

Notch1 and Notch3 signaling interplay regulates pancreatic neuroendocrine cell proliferation

Guenter Rachael , Chen Weisheng , Golivi Yuvasri , Robledo Mario , Jaskula-Sztul Renata , Chen Herbert , Rose Bart

Background: The 5-year survival rate for patients with advanced pancreatic neuroendocrine tumors (pNETs) is less than 30%. Notch signaling is a transmembrane receptor pathway with four distinct isoforms, activation of which is linked to cellular differentiation, cell fate, and viability. Both Notch1 and Notch3 signaling have been shown to be dysregulated in pNETs. Notch3 activation has been shown to repress Notch1 activity in other cancers. We hypothesize that activation of No...

ea0098b11 | Basic Science | NANETS2023

The Notch1 pathway is a critical regulator of SSTR2 expression in neuroendocrine tumors

Guenter Rachael , Whitt Jason , Chen Weisheng , Houson Hailey , Bart Rose J. , Chen Herbert , Lapi Suzanne , Jaskula-Sztul Renata

Background: Patients with neuroendocrine tumors (NETs) have a 5-year survival rate of 30-60%. Surgery, and newly approved ‘tar-geted radionuclide therapy (TRT)’ with [177Lu]DOTATATE, are the only curative options for patients with NETs. TRT is limited to pa--tients that have high levels of somatostatin receptor subtype 2 (SSTR2) and can im-prove the survival of patients with low-grade tumors, but has little effect on high-grade NETs that express low SSTR2 ...

ea0098b12 | Basic Science | NANETS2023

Notch1 receptor-mediated metabolic flexibility promotes a survival advantage in pancreatic neuroendocrine neoplasms

Chen Weisheng , Guenter Rachael , Herring Brendon , Golivi Yuvasri , Whitt Jason , Sammy Melissa , Adams Cole , Jaskula-Sztul Renata , Chen Herbert , Rose Bart

Background: Cancer cells utilize both oxidative phosphorylation (OXPHOS) and glycolysis to generate energy. Switching between OXPHOS and glycolysis can promote tumor progression. The mechanisms governing oncogenic metabolic flexibility are largely unknown, but recent data has suggested that Notch1 dysregulation in cancer cells can contribute to altered metabolic phenotypes. We hypothesized that Notch1 signaling supports metabolic flexibility in pancreatic neuroendocrine tumor ...

ea0098b13 | Basic Science | NANETS2023

Dissecting the role of neuronal mimicry in pancreatic neuroendocrine tumours

Wang Zoey , Qureshi Areeba , Kulathunga Nilakshi , Schuurmans Carol , Hansen He Housheng , Michael Iacovos

Background: Pancreatic neuroendocrine tumours (PanNETs) are an understudied cancer type characterised by frequent metastasis, clinical recurrence, and high mortality rate. PanNETs originate from pancreatic islets, primarily β cells, and comprise two molecular subtypes: poorly invasive, relatively benign islet tumour (IT) and highly aggressive metastasis-like primary (MLP) tumour. The MLP subtype arises from IT through a switch in cell fate involving the acquisition of neu...

ea0098b14 | Basic Science | NANETS2023

Scandium-43-DOTATATE, a Novel Positron Emission Tomography (PET) Tracer for Neuroendocrine Tumor Imaging

Zhang Hannah J. , Pusateri Antonino J. , Meier Jason P. , Lakiza Olga , Bhuiyan Mohammed , Tsai Hsiu-Ming , Leoni Lara , Ghosh Kaustab , Freifelder Richard , Andy Liao Chih-Yi , Pu Yonglin , Appelbaum Daniel , Weichselbaum Ralph , Nolen Jerry , Kao Chien-Min , Rotsch David , Chen Chin-Tu , Keutgen Xavier M.

Background: Neuroendocrine tumors (NETs) represent a heterogenous group of neoplasms and their diagnosis can be challenging. In 2019, FDA approved 68Gallium labeled DOTATATE PET tracer for SSTR2 overexpressing NETs, which has been widely adopted since. However, limitations of 68Ga-DOTATATE have led to the development of additional radiotracers for the diagnosis of NETs. Herein we report on a novel PET tracer using 43Sc for DOTATATE labeling. <s...

ea0098b15 | Basic Science | NANETS2023

Investigating serotonin metabolism in neuroendocrine cancers

Tow Dane H. , Ridder Maclain , Tran Catherine G. , Borbon Luis C. , Li Guiying , Kaemmer Courtney A. , Abusada Ellen , Harish Mahalingam Aswanth , Sadanandam Anguraj , Chandrasekharan Chandrikha , Dillon Joseph , Spitz Douglas R. , Quelle Dawn E. , H.F. Chan Carlos , Bellizzi Andrew , Howe James R. , Po Hien Ear and

Background: Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. Other NETs and other cancers may also produce serotonin but do not store them in vesicles. The rate limiting enzyme of serotonin biosynthesis is tryptophan hydroxylase 1 (Tph1). Patients with high serotonin level could develop carcinoid syndrome, which can be treated with somatostatin analogues and the Tph1 inhibitor telotristat ...

ea0098b16 | Basic Science | NANETS2023

Chemotherapy-mediated upregulation of SSTR2 in NET tumors in mice and in tumor biopsies from lung- and gastroenteropancreatic-NET patients

Merlin Marine A. , Deshaies Isabelle , Joubert Philippe , Beauregard Jean-Mathieu , Shah Girish M.

Background: The peptide receptor radionuclide therapy (PRRT) is recommended for somatostatin receptors (SSTR) positive neuroendocrine tumors (NET). However, complete remissions with PRRT remain anecdotal and NET patients with low SSTR-positivity are excluded from this treatment. Hence, any approach to increase SSTR2 expression can improve therapeutic efficacy of PRRT. Based on previous in vitro studies with NET cell lines, we hypothesize that a treatm...

ea0098b17 | Basic Science | NANETS2023

YAP and TEAD form a transcriptional complex regulating neuroendocrine differentiation and tumorigenesis through a modular mechanism

Nanayakkara Jina , Imtiaz Tashifa , Yang Xiaojing , Hafner Markus , Yang Xiaolong , Renwick Neil

Background: Neuroendocrine tumors (NETs) are unusual tumors with neural and secretory morphology and loss of Yes-associated protein (YAP). YAP is a transcriptional co-activator of the Hippo pathway and canonical oncogene in numerous cancers, except NETs. Although YAP typically binds TEAD transcription factors to drive gene expression, we demonstrate that YAP-TEAD complex formation represses NET differentiation and tumorigenesis through targeted gene dysregulation.<p class=...

ea0098b18 | Basic Science | NANETS2023

Identifying the relationship between neuroendocrine tumors (NET) and glutamic acid decarboxylase 65 (GAD65) antibody

Watkins Claudia , James Tanner , Thomas MD Katharine

Background: Glutamic acid decarboxylase 65-kilodalton isoform (GAD65) antibody is a known to be present in inhibitory interneurons and pancreatic islet β-cells. Arino et al suggests that high levels of GAD65 present with neurological symptoms should prompt physicians to screen patients for occult cancer. The literature also suggests high GAD65 antibodies have been associated with various malignancies; although large studies are lacking. This research focuses on i...

ea0098b19 | Basic Science | NANETS2023

Label-free phenotyping of duodenal neuroendocrine tumors using tissue autofluorescence microscopy and digital spatial profiling

Knapp Thomas , Duan Suzann , Merchant Juanita , Sawyer Travis

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are an extremely heterogenous group of diseases with complicated treatment and management decisions. For example, patients with Multiple Endocrine Neoplasia Type 1 (MEN1)-associated gastrinomas present with more aggressive tumors and poorer outcomes. Recent work has shown that sequencing (transcriptomic, proteomic) can phenotype GEP-NETs to accurately reflect important clinical parameters such as tumor aggress...

ea0098b20 | Basic Science | NANETS2023

Establishment of novel PDXovo models for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs)

Kulathunga Nilakshi , Mar Sara , Wang Zoey , Qureshi Areeba , Tsui Hubert , Hallet Julie , Law Calvin , Leong Hon S. , Michael Iacovos P.

Background: Neuroendocrine cancers arise in the endocrine cells localized throughout the body. Most are found in the Gastroenteropancreatic (GEP) system pancreas, stomach, and small and large intestines. They are heterogenous in their etiology, morphology, and phenotypes. Due to late diagnosis and low prevalence, clinical specimens are limited for research. Thus, preclinical models are pivotal for the understanding of this disease. This study focuses on establishing a novel pa...

ea0098b21 | Basic Science | NANETS2023

Transcriptomic profiling of the BCL-2 pathway in Neuroendocrine Neoplasms (NENs)

Sukrithan Vineeth , Ahmed Uzair , Krause Harris , Gandhi Nishant , Walker Phillip , Lou Emil , Soares Heloisa , Vanderwalde Ari , Konda Bhavana

Background: BCL-2 is an anti-apoptotic protein associated with resistance to tumor cell death and is a histopathologic marker of neuroendocrine differentiation. We characterized the transcriptomic profile of BCL2 expression in NENs and its association with site, immune infiltration, and overall survival (OS).Methods: Next-generation sequencing of both DNA (592-gene panel or whole exome) and RNA (whole transcriptome) was performed on NENs of pancreatic (P...

ea0098b22 | Basic Science | NANETS2023

Germline whole-exome sequencing of patients with neuroendocrine neoplasms (NENs) reveals pathogenic or likely pathogenic variants in a large subset of patients

Sukrithan Vineeth , Boateng Isaiah , Liyanarachchi Sandya , Jain Prachi , Buss Jill , Parwani Anil , Shah Manisha H. , Das Komal , Yearsely Martha , Konda Bhavana , Brock Pamela , Eisfeld Ann-Kathrin

Background: We conducted whole-exome sequencing (WES) of germline(g) and somatic(s) DNA from a prospective cohort of patients with NENs (n =151) to study the genetic predisposition to NENs.Methods: Variants obtained from gWES were filtered using a standard bio-informatics pipeline. Variant Effect Predictor (Release 107) was applied to obtain population allele frequencies. Variants were restricted to those among 974 genes obtained by combining pu...

ea0098b23 | Basic Science | NANETS2023

Calreticulin is associated with clinical characteristics in pancreatic neuroendocrine tumors

Herring Brendon , Macvicar Caroline , Guenter Rachael , Chen Weisheng , Elhussin Isra , Yates Clayton , Dhall Deepti , Chen Herbert , Lee Goo , Bart Rose J.

Background: Following IHC of CALR, H-scoring was performed by a pathologist. H-scoring was validated by MIF of the same tissue, wherein random-forest machine learning (ML) classifiers were employed to classify cells. ML classifiers were trained to distinguish between pNET cells and tumor stroma using approximately 30% of cells for the respective cell population of interest in each TMA core. Pearson’s correlations were used to evaluate the relationship between H-scoring an...

ea0098b24 | Basic Science | NANETS2023

PARP inhibitors potentiate chemotherapy of NET cells and tumors and PAPR1-knockdown suppresses growth of NET tumors in mice#

Montoni Alicia , Shah Rashmi G. , Decobert Marc , Rajawat Jyotika , Richard Veronique , Merlin Marine A. , Girish M. Shah and

Background: In mammalian cells, poly(ADP-ribose) polymerase-1 (PARP1) is among the earliest proteins to reach the site of DNA damage and play key roles in different cellular responses ranging from DNA repair to cell death. PARP-inhibitors are recommended in mono or combination therapy for a subset of breast and ovarian cancers with BRCAness type of DNA repair deficiency. In addition, current clinical trials are examining whether PARP-inhibitors can potentiate the efficacy of c...

ea0098b25 | Basic Science | NANETS2023

A STING Operation in neuroendocrine neoplasms

Eagal Erika , Lou Emil , Gandhi Nishant , Elliott Andrew , Sukrithan Vineeth , Vijayvergia Namrata , Puri Sonam , Chauhan Aman , Hadfield Matthew , Florou Vaia , Affolter Kajsa , Vanderwalde Ari , Soares Heloisa P.

Background: Significant advances have been made in the treatment of gastrointestinal (GI-) and pancreatic (P-) NENs. However, the use of immunotherapy is still limited, with most tumors considered immune “cold”. The cGAS-STING signaling pathway has emerged as a critical mediator of inflammation and immune-mediated responses, with pathway agonists under development for enhancing immunotherapy. In this study, we evaluated associations between cGAS-STING pathway activit...

ea0098b26 | Basic Science | NANETS2023

Cancer testis antigen and interleukin expression correlates with survival in small bowel neuroendocrine tumors

David Seo MD Y. , Witt MD, MAS Russell G. , Lazcano MD Rossana , MD Samuel Cass , Hudgens Courtney , Wani Khalida , Chelvanambi PhD Manoj , Johnson MS Sarah , Hernandez MD Sharia D. , Halperin MD Daniel M. , Lazar MD, PhD Alexander J. , Wargo MD, MMSc Jennifer A. , Estrella MD Jeannelyn S. , Maxwell MD, MBA Jessica E.

Background: Patients with small bowel neuroendocrine tumors (SBNETs) frequently present with metastatic disease, and unfortunately, the range and efficacy of available therapies is limited. Immunotherapeutic checkpoint inhibitors have demonstrated benefit in other malignancies and may also play a role in SBNETs, although relatively little is known about the immune infiltrate in these tumors. Toward a goal of developing novel immunomodulatory strategies, we sought to evaluate t...

ea0098b27 | Basic Science | NANETS2023

Development of GEP-NEN patient derived organoids for therapy screening

Forsythe Steven D. , Madigan James P. , Andrews Stephen , del Rivero Jaydira , Hernandez Jonathan M. , Nilubol Naris , Sadowski Samira M.

Background: Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) are a rare subset of cancers which nevertheless are a rising health burden. Development of new therapies suffers from several bottlenecks, including low patient accrual and poor understanding of tumor characteristics. Patient tumor organoids (PTOs) are a novel model capable of improving screening of patient tissue in an accurate, standardized, and high-throughput capacity. In this study, we utilized patient...

ea0098b28 | Basic Science | NANETS2023

Therapies targeting CDK4/6 cause regression, immune cell activation, and sensitization to PD-L1 immunotherapy in pancreatic neuroendocrine tumors

Kaemmer Courtney , Umesalma Shaikamjad , Maharjan Chandra , Kohlmeyer Jordan , Lingo Joshua , Wilkerson Emily , Sheehy Ryan , Leidinger Mariah , Meyerholz David , Bell Sarah , Zamba Gideon , Breheny Patrick , Lattime Edmund , Chandrasekharan Chandrikha , Bellizzi Andrew , Herring Laura , Graves Lee , Darbro Benjamin , Yuan Ziqiang , Libutti Steven , Quelle Dawn

Background: New effective therapies are needed to improve the survival of patients with metastatic pancreatic NETs (pNETs). RABL6A is a novel oncogenic driver of pNET pathogenesis. Kinome and phosphoproteome analyses of proliferating (RABL6A-positive) pNET cells, vs arrested (RABL6A-knockdown) controls, demonstrated that cyclin-dependent kinase 4 and 6 (CDK4/6) and MEK kinases are actionable drug targets in growing pNET cells. In agreement, published studies of patient pNETs b...