Introduction:Recruitment for rare disease studies is challenging due to small eligible populations. Traditional clinical research management systems often lack tools to track recruitment contacts prior to enrollment. The NET-PRO study, focused on neuroendocrine tumors (NETs), implemented a participation monitoring system to enhance recruitment efficiency and representativeness. Methods:NET-PRO is a multicenter cohort study of 2538 adults diagnosed with gastroenteropancreatic (GEP) or lung NETs between January 2018 and September 2024. Recruitment occurred from January 2022 to February 2025 across 14 U.S. medical centers. Sites used flexible recruitment methods (email, mail, phone, in-clinic) and tracked contacts using REDCap-based tools. Participant characteristics were analyzed by enrollment mode (online or mail) and recruitment difficulty (number of contacts required prior to enrollment) using standardized mean differences, chi-square tests, and ANOVA. Results:Of 9279 contacted patients, 2675 consented (28.8%) and 2538 enrolled (27.4%). Most enrolled online (83.2%), while 16.8% enrolled by mail. Mail respondents were older, had lower education and income, and more comorbidities. Among those enrolled, recruitment difficulty was associated with older age, lower education and income, but not comorbidity. Over half of the most difficult-to-recruit participants enrolled online. Contact methods varied by attempt, with email dominating early contacts and phone/mail used more in later attempts. Conclusions:A participation monitoring tool supported flexible, multimodal recruitment and improved sample representativeness in a rare cancer study. Tracking recruitment contacts enabled adaptive strategies and may reduce bias in observational research by enabling better outreach to harder-to-reach populations.

BACKGROUND:Neuroendocrine tumors (NETs) are rare, heterogeneous neoplasms associated with prolonged survival and substantial symptom burden. However, patient-reported outcomes across NET subtypes remain poorly characterized, particularly in real-world settings. This study describes baseline health-related quality of life (HRQoL) and care experiences among patients with gastroenteropancreatic and lung NETs, examining differences by tumor site and time since diagnosis. METHODS:The Neuroendocrine Tumors-Patient Reported Outcomes study is a prospective, multi-institutional US cohort of adults (aged 18 years and older) with incident small intestinal, pancreatic, gastroenteropancreatic, or lung NETs diagnosed from January 2018 through September 2024, identified via a validated electronic medical record-based computable phenotype. Baseline surveys assessed HRQoL, symptoms, care experiences, and clinical characteristics using validated instruments. Descriptive statistics and standardized mean differences compared responses by NET site and time since diagnosis. RESULTS:Among 2367 participants (mean age = 57.8 years; 57.3% female), 1974 had gastroenteropancreatic NETs (659 small intestinal NET, 555 pancreatic NET) and 393 had lung NETs. Fatigue (mean = 33.0), insomnia (mean = 32.5), and diarrhea (mean = 25.7) were the most burdensome symptoms. Lung NET patients reported worse dyspnea (standardized mean difference = 0.58, P < .001) and lower physical, role, and global QoL scores than those with gastroenteropancreatic NETs, while pancreatic NET patients reported better functioning. Diarrhea worsened over time, especially in small intestinal NETs. Most rated care highly (75.3%) but cited concerns about treatment side effects (80.4%), costs (60.7%), and travel burden (58.8%). CONCLUSIONS:This large US cohort reveals persistent symptom burden and HRQoL variation by tumor site and disease duration, underscoring the need for longitudinal HRQoL assessment in NET care.

632 Background: Paltusotine is an oral, nonpeptide, selective somatostatin receptor 2 agonist. In a phase 2 study, treatment with once-daily paltusotine reduced the frequency and severity of carcinoid syndrome (CS) symptoms and was well tolerated. The effect of paltusotine on biomarkers of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was further explored. Methods: This exploratory study, without formal power calculations, included an 8-week randomized treatment phase (completed) and a 102-week open-label extension phase (currently ongoing). The purpose was to evaluate safety, pharmacokinetics, and exploratory efficacy endpoints, including changes in biomarkers of paltusotine treatment. Enrolled patients were adults with a stable, documented grade 1 or 2 neuroendocrine tumor (NET) and CS. These patients were actively symptomatic and either untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day in ≥2 days over a 2-week period) or washed out of SRL therapy (symptoms previously controlled on SRL), with demonstrated symptom worsening after washout. Patients were randomized to once-daily paltusotine 40 mg or 80 mg; one optional uptitration (from 40 mg to 80 mg or 80 mg to 120 mg) was permitted. Blood samples for assessment of biomarkers (serum serotonin and plasma 5-HIAA) were collected longitudinally from screening to end of treatment. Upper limit of normal was prespecified as 541 ng/mL for serotonin and 22 ng/mL for 5-HIAA. This analysis focuses on changes in biomarker from baseline to the end of 8-week randomized treatment phase and after approximately one year (48 weeks). Results: Thirty-six patients (n=9 untreated; n=27 SRL washout) were randomized. Mean age was 60.8 years (range 35-83), and 52.8% were female. Nineteen patients had grade 1 NETs, and 17 had grade 2 NETs. As reported previously, treatment with once-daily, oral paltusotine was well tolerated and reduced the frequency and severity of CS symptoms, justifying further clinical development of the 80 mg dose. Mean serum serotonin decreased from 1553.0 ng/mL at baseline to 643.9 ng/mL at Week 8, and mean plasma 5-HIAA decreased from 245.1 ng/mL to 159.7 ng/mL. There was a trend of untreated patients achieving a greater reduction in comparison to washout patients. At 48-week follow-up, mean serum serotonin was stabilized at 791.50 ng/mL (n=20), and mean plasma 5-HIAA was stabilized at 190.45 ng/mL (n=20). Conclusions: Paltusotine significantly reduced serotonin and 5-HIAA levels, with effects maintained at 48 weeks. Biomarker reductions paralleled reductions in BM and flushing frequency. These findings support further investigation in the ongoing phase 3 study (CAREFNDR, NCT07087054). Clinical trial information: NCT05361668 .

644 Background: Serum pancreastatin, a cleave product of chromogranin A, has shown promise as a prognostic and predictive biomarker in neuroendocrine tumors (NETs) undergoing surgical cytoreduction or liver-directed therapies. However, its role as a predictive biomarker among patients undergoing Peptide Receptor Radionuclide Therapy (PRRT) has not been investigated. We sought to retrospectively analyze the role of pancreastatin as a biomarker for outcomes among patients with advanced NETs who received treatment with PRRT at our institution. Methods: An IRB-approved prospective institutional NET registry (2018-2024) was used to identify and include patients who received at least 3 cycles of Lu177-DOTATATE and had serum pancreastatin levels measured within 100 days before and after PRRT. Patient demographics, tumor grade and site of origin, pancreastatin levels and therapies received before and after PRRT and outcomes were abstracted. Cox regression was used to evaluate the ability of the post-treatment change in pancreastatin to predict progression-free survival (PFS). Predictive performance was estimated using Uno’s C-statistic and statistically compared to a null value of 0.50. Standard errors were computed using 100 perturbation samples. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Results: 162 patients received PRRT, of which 49 patients met criteria for inclusion. The majority of patients had small bowel (n=29, 61.7%) and pancreatic NETs (n=14, 29.8%). Median PFS for the entire cohort was 30.2 months. The mean and median change in serum pancreastatin before and after PRRT was 196.8 pg/ml and -103 pg/ml, respectively. On univariate analysis, the post-treatment change in serum pancreastatin was not found to have a C-index significantly greater than 0.50 (Concordance=0.52, p=0.66). Results were consistent when dichotomizing according to the first quartile (p=0.38), median (p=0.91), and third quartile (p=0.97), indicating that the post-treatment change in serum pancreastatin was not found to be predictive of the risk of progression or death. The predictive effect of serum pancreastatin did not significantly differ according to site of origin in an interaction analysis (p=0.77). Conclusions: In this single-institution analysis, changes in serum pancreastatin before and after treatment were not predictive of progression-free survival across analytic thresholds or sites of origin. Although prospective data are needed to validate these findings, our findings do not support the routine use of pancreastatin among patients undergoing treatment with PRRT.

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RA) and dual incretin agonists, are increasingly used for the management of diabetes, obesity, and cardiometabolic disease. Although their systemic benefits are well established, uncertainty remains regarding their safety in patients with neuroendocrine neoplasms (NENs), a biologically heterogeneous group of tumors with diverse molecular profiles. Preclinical studies suggest that GLP-1 receptor activation may promote tumor growth in select receptor-expressing models, although receptor expression varies widely across NEN subtypes and is often absent in common tumors such as ileal neuroendocrine tumors. Population-level and retrospective clinical data have not demonstrated a consistent increase in oncologic risk but are limited by methodological constraints. In this expert consensus statement, the authors synthesize current evidence and provide a practical framework for the use of incretin mimetics in patients with NENs. The authors emphasize individualized risk assessment, shared decision-making, and multi-disciplinary collaboration, balancing potential but unquantified oncologic risks against substantial cardiometabolic benefits. Until prospective data are available, careful patient selection, dose optimization, and close clinical and radiologic surveillance remain essential to guide safe and effective use of these agents in this population.

OBJECTIVES:The incidence of early-onset gastrointestinal malignancies is increasing globally; however, early-onset small bowel neuroendocrine tumors (EO-SBNETs) remain poorly characterized. We evaluated clinical characteristics, treatment patterns, incidence trends, and survival outcomes of EO-SBNETs compared with average-onset SBNETs (AO-SBNETs). METHODS:We conducted a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database (2004 to 2021). Patients with SBNETs were identified using ICD-O-3 histology codes and categorized as early-onset (30 to 49 y) or average-onset (≥50 y). Baseline characteristics were compared using χ2 tests. Overall survival (OS) was estimated using the Kaplan-Meier method and evaluated with multivariable Cox regression models that adjusted for demographic, socioeconomic, clinical, and treatment-related factors. Temporal incidence trends were assessed using linear regression. RESULTS:Among 3713 patients with SBNETs, 925 (25.0%) had EO-SBNETs. EO-SBNETs were more frequently observed in females and racial and ethnic minority populations, including non-Hispanic Black and Hispanic patients (all P<0.05). Stage at diagnosis and treatment patterns, including rates of surgery, lymphadenectomy, chemotherapy, and radiation therapy, were comparable between the groups. Incidence increased significantly over time in both EO-SBNETs and AO-SBNETs (annual increase 14.9% vs. 14.8%, P<0.001), without differences in temporal trends. The median OS was not reached for AO-SBNETs and was 188 months for EO-SBNETs. On multivariable analysis, early-onset disease was independently associated with improved survival (HR=0.50, 95% CI: 0.41-0.60, P<0.001). CONCLUSIONS:EO-SBNETs represent a rising and clinically distinct subgroup characterized by similar presentation and treatment but relatively favorable long-term outcomes compared with AO-SBNETs, suggesting potential biological differences warranting further investigation.

Background: Carcinoid syndrome (CS) is a common paraneoplastic syndrome in patients with neuroendocrine tumours and can be debilitating. Here, we describe results of the first clinical trial of paltusotine, a new oral, once-daily, nonpeptide, selective somatostatin 2 receptor agonist, in patients with CS. Methods: This phase 2, randomised, open-label study (18 sites; 5 countries) enrolled adults with stable grade 1 or 2 neuroendocrine tumours and symptomatic CS. Patients were treatment naive or currently untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day on ≥2 days over a 2-week period) or washed out of SRLs (demonstrated control on SRL with symptom worsening after washout). Patients were randomised to once-daily paltusotine 40 mg or 80 mg for 8 weeks; one optional up-titration (to 80 mg or 120 mg) was permitted. This trial is registered with ClinicalTrials.gov, NCT05361668. Findings: Between March 27, 2023 and December 11, 2023, 36 patients (untreated, n=9; SRL washout, n=27) were randomly assigned to treatment (18 to paltusotine 40 mg/day, 18 to 80 mg/day). Nine patients had a paltusotine dose increase during randomised treatment. In patients completing 8 weeks of treatment (n=30), mean (SE) change in daily flushing frequency was a reduction of 1·7 (0·3) episodes per day and in daily BM frequency was a reduction of 1·1 (0·3) episodes per day. The most commonly reported adverse events (AEs) were diarrhoea (n=15 [42%]), abdominal pain (n=9 [25%]), and headache (n=8 [22%]). No severe or serious AEs were considered treatment related, and no treatment-related AEs led to study discontinuation. Interpretation: In this phase 2 study, treatment with once-daily, oral paltusotine reduced the frequency and severity of CS symptoms and was well-tolerated. These findings support further development of paltusotine for the treatment of CS.

643 Background: The incidence of neuroendocrine tumors (NETs) has increased over the past few decades, especially among younger patients. While data from other gastrointestinal malignancies suggest early-onset may be associated with biological differences, this is yet to be investigated in NETs. We sought to characterize the molecular and immune landscape of early (EO)- versus average-onset (AO) pancreatic (pNETs) and small intestinal NETs (siNETs). Methods: Cases with metastatic pNETs and siNETs sequenced using the Tempus xT assay were included. DNA sequencing was performed to identify somatic alterations and whole transcriptome RNA-seq data were normalized to log2(TPM+1) with assay correction. Immune profiling analysis included tumor mutational burden (TMB), microsatellite instability (MSI), PD-L1 status, and immune infiltration estimated via quanTIseq. Differential expression between EO (<50 years of age at diagnosis) and AO-NETs (>50 years) was assessed using Wilcoxon rank sum tests with Benjamini–Hochberg correction, and pathway enrichment was assessed via GSEA (Gene Set Enrichment Analysis). Statistical significance was defined as p<0.05 and q<0.10 for GSEA. Results: A total of 502 patients were included, of which, 134 had EO-NETs (EO-pNETs=94, EO-siNETs=40). Compared to AO, EO-pNETs had a significantly lower prevalence of KRAS (2.1% vs 14%, p=0.001), TP53 (14% vs 25%, p=0.004), SMAD4 (3.2% vs 12%, p=0.01) and RB1 (6.4% vs 14%, p=0.04) and a higher prevalence of LRP1B (8.5% vs 1.3%, p=0.003) alterations. Among siNETs, EO cohort had a significantly higher prevalence of PAX5 (5% vs 0%, p=0.04) and HDAC2 (5% vs 0%, p=0.04) alterations. On GSEA, EO-pNETs had a significantly higher expression in the VEGF, apical junction, hedgehog signaling, and myogenesis pathways while AO-pNETs had higher expression in MYC, E2F, DNA repair and G2M checkpoint pathways. No significant differences in transcriptomic expression were noted between EO- and AO-siNETs. On immune profiling, EO-pNETs cases were enriched for M2 macrophages (p=0.004) while siNETs displayed no significant age-based differences. TMB-H, MSI-H, and PD-L1 expression did not differ by age in either group. Conclusions: This is the largest molecular analysis comparing EO and AO-enteropancreatic NETs. More age-based differences were seen in pNETs with some changes in EO cases predicting better response to immunotherapy while AO cases attained more alterations found in grade 3 NETs or NECs. Our results suggest that age at diagnosis may be an important determinant of tumor biology and clinical management options.

We compared demographic and clinical characteristics of patients with gastroenteropancreatic (GEP) and lung neuroendocrine tumors (NETs) enrolled in the NET-PRO study to those in the U.S. Surveillance Epidemiology and End Results (SEER) program to evaluate the comparability of NET-PRO as a resource for real-world evidence generation and patient reported outcomes (PROs). NET-PRO enrolled adults with GEP or lung NETs from 14 health systems between 2018 and 2024. SEER data included patients diagnosed with NETs from 2018 to 2021 across 22 U.S. cancer registries. We compared age, sex, race/ethnicity, tumor site, stage, and surgery between cohorts using standardized mean differences (SMDs), with values ≥ 0.2 interpreted as meaningful. We analyzed 1,974 GEP-NET and 394 lung NET patients in NET-PRO versus 38,942 and 11,265, respectively, in SEER. Most demographic and clinical characteristics were broadly similar between cohorts, with trivial differences by sex (SMDs 0.16–0.22) and moderate differences in mean age (SMD = 0.47 for lung NETs). Race/ethnicity differences were larger, with Non-Hispanic White patients overrepresented in NET-PRO (SMDs 0.53–0.84). Tumor site and stage distributions differed modestly. Surgery rates were comparable for GEP-NETs but higher among NET-PRO lung NET patients (SMD = 0.47). NET-PRO demonstrates broadly comparable demographic characteristics to SEER across factors such as age and sex. While race/ethnicity differences highlight areas for improved inclusion, other areas of variation suggest important future research covariates. These findings support the contextual comparability of NET-PRO with the broader NET population and its value as a resource for real-world evidence generation. NCT05064150 (Start Date: 2022-05-10).

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

BACKGROUND:The incidence of neuroendocrine tumors (NET), which arise primarily in lung and gastroenteropancreatic (GEP) tissues, has increased dramatically in the past 50 years. However, the etiology of NETs remains inconclusive. METHODS:We conducted a nested case-control study using data from the All of Us Research Program (version 7; index dates: 2000-2022) to compare the odds of diagnosed GEP or lung NET in the presence or absence of various potential risk factors. One case was matched to five controls without cancer diagnoses by age at consent and sex. We used piecewise structural equation modeling to generate effect estimates. RESULTS:Of 2,180 individuals (including 366 with NETs), most were non-Hispanic White (62.8%) and female (61.0%). Individuals with a family history of any cancer [OR, 1.43; 95% confidence interval (CI), 1.06-1.95; P = 0.021], a past diagnosis of type 2 diabetes (OR, 1.46; 95% CI, 1.09-1.96; P = 0.012), and any immune-mediated disease (OR, 1.40; 95% CI, 1.11-1.76; P = 0.004) had higher odds of developing GEP or lung NETs. CONCLUSIONS:This study confirms prior evidence in less diverse cohorts that the risk of developing GEP or lung NETs is significantly associated with having a first-degree relative with any cancer or previous diagnosis of type 2 diabetes. IMPACT:Our findings are the first to demonstrate that a preexisting diagnosis of any immune-mediated disease is a risk factor for developing NETs. Together, our findings suggest that NET development may be influenced by unmodifiable factors as well as modifiable conditions.

670 Background: The global incidence of early-onset gastrointestinal cancers (GI) is increasing. Although patients with more common early-onset GI cancers, e.g. colorectal cancer, often present with more advanced disease and experience relatively worse outcomes; the characteristics and treatment outcomes for less common early-onset small bowel neuroendocrine tumors (SBNETs) have yet to be explored. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with SBNETs (2004-2021), using ICD-0-3 SEER histology codes (8240/3, 8241/3, 8243/3, 8244/3, 8249/3, 8246/3). Patients with poorly differentiated histology were excluded. We used the chi-square test to compare categorical variables between early-onset SBNETs (EO-SBNETs, aged 30-49 years) and average-onset SBNETs (AO-SBNETs, aged ≥ 50 years) patients. Overall survival was estimated using the Kaplan-Meier method followed by application of the log-rank test to assess for differences in survival. A multivariable Cox regression analysis included early onset of disease, sex, race/ethnicity, marital status, urban/rural residence, prior treatments, and disease extent as covariates. All tests were conducted with a significance threshold of p < 0.05 using RStudio. Results: A total of 3,713 patients were included, of which, 925 (25%) were EO-SBNETs. Compared to AO-SBNETs, EO-SBNETs patients were more likely to be females (51.1% vs 46.7%, p=0.02), non-Hispanic Black (20.8% vs 17.6%, p=0.04), Hispanic (13.6% vs 8.8%, p<0.0001) and less likely to be non-Hispanic White 60.8% vs 69.9%, p<0.0001). There were no differences in stage at diagnosis between the EO-SBNETs and AO-SBNETs, i.e,, localized disease (33.5% vs 31.0%, p=0.15), regional spread (41.9% vs 42.8%, p=0.64) and distant metastatic disease (20.9% vs 21.9%, p=0.50). There were no differences in receipt of surgical resection (90.5% vs 89.1%, p=0.25) or chemotherapy (5% vs 6.3%, p=0.15) comparing EO-SBNETs and AO-SBNETs respectively. In a multivariate cox regression analysis, early onset was associated with a significantly better overall survival (HR=0.49, 95% CI 0.41-0.59, p<0.0001). Conclusions: With this first of its kind analysis, significantly superior overall outcomes among EO-SBNETs despite no differences in stage and receipt of surgery establishes age at diagnosis as a significant prognostic factor for SBNETs. Further studies investigating the role of factors such as differences in tumor biology and patient preferences in receipt of other therapies besides surgery are needed.

Neuroendocrine neoplasms (NENs) are rare cancers originating from neuroendocrine cells that are found throughout the body. NENs are subdivided into 2 categories: Well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Both NET and NEC are highly metastatic and difficult to treat. NEN cases are on the rise and yet the etiology remains unclear. Commonly used drugs such as proton pump inhibitors can promote NET growth and result in poor prognosis for NET patients. Nowadays, the diabetes and weight loss drug semaglutide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, has gain extensive popularity and are currently being taken by over 15 million people in the USA. Semaglutide is contraindicated for NET patients with medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2) since some of these cancers express the GLP-1R. However, this area of research remains understudied. Little is known about the expression levels of GLP-1R in NEN from different anatomical locations and their response to semaglutide since these are rare cancers and few NET models are available for drug testing. We recently identified 2 human NET cell lines (GOT1 and NT-3) that express the GLP-1R and showed that semaglutide promotes tumor cell growth both in vitro and in vivo. In this study, we aim to investigate the levels of GLP-1R expression in a large collection of NEN tissue microarrays and determine the effects of semaglutide in novel GLP-1R positive NET patient-derived spheroid cultures. We stained for GLP-1R expression by immunohistochemistry in 357 NET tissue microarrays covering 7 classes of NEN: 78 pancreas NET, 62 duodenum NET, 33 ileal NET, 42 lung NET, 10 small cell lung NEC, 12 extrapulmonary visceral NEC, 29 thyroid NET, 12 gastric NET, 6 appendix NET, 6 rectum NET, 22 pheochromocytoma, 22 paraganglioma, and 23 Merkel cell carcinoma. Furthermore, we generated GLP-1R positive pancreas, ileal, and duodenal NET spheroids for drug testing. Our data showed 45% of duodenum NET, 17% of gastric NET, and 14% of pancreas NET stained positive for GLP-1R expression. Less than 2% of other classes NET or NEC stained positive for GLP-1R expression. Using newly established NET patient-derived spheroid models, we demonstrated that 100 nM of semaglutide accelerates tumor cell growth by 1.4 to 2-fold. Surprisingly, duodenum NET is the class of NET that frequently express GLP-1R and should be highly cautioned for the semaglutide usage. Sophia A. Hueser, Reese E. Townsend, Casandro J. Chan, Leona Rupp, Leopaul J. Chan, Dawn E. Quelle, Joseph S. Dillon, Andrew M. Bellizzi, James R. Howe, Po Hien H. Ear. The significance of GLP-1R and its agonist in neuroendocrine neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4000.

Supplementary Table 7 reports risk factors associated with GEP or lung NETs in incident cases and corresponding controls.

Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. SBNETs express high levels of tryptophan hydroxylase 1 (Tph1), a key enzyme in serotonin biosynthesis. Patients with high serotonin level may develop carcinoid syndrome, which can be treated with somatostatin analogues and the Tph1 inhibitor telotristat ethyl (TE) in severe cases. Although the active drug TE can efficiently reduce serotonin levels, its effect on tumor growth is unclear. This study determined the effect of serotonin inhibition on tumor growth in vitro and in vivo. The levels of Tph1 in various neuroendocrine neoplasms (NENs) were determined and the biological effects of Tph1 inhibition using genetic and pharmacologic approaches was tested. Gene and protein expression analyses were performed on patient tumors and cancer cell lines. shRNAs targeting TPH1 were used to create stable knockdown in BON cells. Control and knockdown lines were assessed for their growth rates in vitro and in vivo, angiogenesis potential, serotonin levels, endothelial cell tube formation, tumor weight, and tumor vascularity. TPH1 is highly expressed in SBNETs and many cancer types. TPH1 knockdown cells and TE treated cells showed similar growth rates as control cells in vitro. However, TPH1 knockdown cells formed smaller tumors in vivo and tumors were less vascularized. Although Tph1 inhibition with TE showed no effect on tumor cell growth in vitro, Tph1 inhibition reduced tumor formation in vivo. The combination of TE andcabozantinib, an effective tyrosine kinase inhibitor for NET, showed further improvement of tumor inhibition. Serotonin inhibition in combination with other therapies is a promising new avenue for targeting metabolic vulnerabilities in NENs. Dane H. Tow, Maclain Ridder, Catherine G. Tran, Guiying Li, Courtney A. Kaemmer, Aswanth H. Mahalingam, Anguraj Sadanandam, Douglas R. Spitz, Chandrikha Chandrasekaran, Carlos H.F. Chan, Joseph S. Dillon, Dawn E. Quelle, Andrew M. Bellizzi, James R. Howe, Po H. Ear. Inhibition of serotonin biosynthesis and tyrosine kinases suppresses tumor growth of neuroendocrine neoplasm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB465.