Defining Molecular Pathways Across Neuroendocrine Disease States

The Neuroendocrine Tumor Research Foundation (NETRF) continues to catalyze transformative research through its annual grant awards, supporting investigators who are dismantling the traditional boundaries of neuroendocrine tumor (NET) management. A few of this year’s recipients, including Mauro Cives, MD, an associate professor of Medical Oncology in the Department of Interdisciplinary Medicine at University of Bari Aldo Moro; Suzann Duan, PhD, assistant professor in the School of Pharmacy & Pharmaceutical Sciences at UC Irvine; and Lynette Fernandez-Cuesta, PhD, team leader at the International Agency for Research on Cancer (IARC-WHO), spoke with CancerNetwork® about the research that ultimately resulted in the grant awards and how they plan to leverage the funds to advance research in their respective fields.

Together, they are spearheading projects that range from T-cell receptor (TCR)–based immunotherapy to the biological impact of the aging microenvironment and the identification of aggressive “supra-carcinoids.” For the multidisciplinary oncology community, these studies represent a pivotal shift toward highly personalized, biology-driven interception strategies.

Harnessing TCR-Based Immunotherapy for Pancreatic NETs

Although immune checkpoint inhibitors have seen limited success in pancreatic NETs, Cives is exploring a more targeted approach: T-cell receptor (TCR) therapy. Unlike CAR-T cell therapy, which targets surface proteins, TCR-based approaches allow for the recognition of intracellular antigens presented via the human leukocyte antigen (HLA) complex.

His initial research set out to answer a question: “Can we isolate tumor-infiltrating lymphocytes (TILs) from pancreatic NET liver metastases?” Upon affirming this question, his team also deduced that this finding was clinically meaningful, prompting them to characterize TILs emerging from pancreatic NET liver metastases. Thereafter, they discovered memory progenitor stem-like phenotypes, which are double negative for CD39 and CD69. As such, they are known to predict antitumor activity when injected back into the patient.

“[P]ancreatic NETs were once considered immunologically ‘cold’ tumors. Now, we know that this is not completely true, and that there is a lot of heterogeneity, particularly in a subset of pancreatic NETs that exhibit T-cell infiltration. Quite importantly, T cells that infiltrate these tumors are also exhausted. Moreover, we now know that HLA1 is widely expressed by pancreatic NETs, and that there is also expression of the antigen-processing machinery,” Cives noted. His research focuses on cancer-testis antigens, such as MAGE-A3, which are typically absent in healthy tissues but highly expressed in aggressive NETs.

With the support of the NETRF grant, Cives plans to validate the expression of these intracellular targets across a large cohort of patients with pancreatic NETs. The funding will facilitate the engineering of high-affinity TCRs and the testing of these modified T-cells in both in vitro and patient-derived xenograft models. The goal is to move beyond non-specific immunotherapy toward a precise “search and destroy” mission that minimizes adverse effects (AEs) on healthy cells while overcoming the inherent resistance of pancreatic NETs.

“We plan to elucidate the TCR-specificity of TILs and harness this information to design novel TCR-based cellular immunotherapies. We aim to generate an atlas of TCR antigen pairs, functionally validate the predicted TCR antigen interaction, and assess its special relevance... Then, we would like to clone the TCRs with the antitumor activities that were capable of NET antigen recognition,” Cives said.

Uncovering the Role of Age-Related Signals in GEP-NET Development

As the global population ages, the intersection of oncology and geriatrics has become increasingly critical. Contextualized by this trend, Duan was awarded a grant to investigate how aging—specifically the aging microenvironment—drives the development and progression of gastroenteropancreatic (GEP) NETs.¹

Specifically, she highlighted a potential link between senescence-associated secretory phenotype (SASP) and upregulation of cytokines such as IL-17B, TNF-α, and IL-6 in duodenal gastrinomas. Given the ability for these cytokines to induce the expression of neuroendocrine genes and markers, her team generated 3D organoid models from duodenal tissue and validated the potential for these cytokines in activating the neuroendocrine differentiation pathway.

“In terms of bringing in the senescence aspect, we also know that these tumors can express certain senescence markers, like p16 or p21, and they can present as slow-growing, slow-cycling tumors, which is [like] a puzzle,” Duan explained. “We then thought that maybe these cytokine profiles are related to a senescence phenotype, particularly the SASP. We also know that is increased in aging individuals and could potentially be a biological reason for why increased age contributes to potentially higher incidence of these tumors.”

Her research suggests that the SASP—a formulation of pro-inflammatory cytokines and growth factors secreted by aging fibroblasts—may act as a facilitator for neuroendocrine cell transformation.

Duan will apply the NETRF funding to utilize advanced mouse models and human tissue samples to map the cross-talk between aging stroma and GEP-NET cells. By identifying the specific age-related signals that drive tumor growth, her team aims to identify senolytic strategies or targeted inhibitors that could effectively stall tumor progression in older patients, potentially offering a more tolerable alternative to aggressive systemic therapies.

“We know that [NETs] have been historically excluded [and] understudied, and I’m so glad that they are gaining more attention and traction within the medical and research field. I am extremely grateful for organizations like NETRF for supporting research that my lab is doing and advocating for patients and care providers within that space,” Duan concluded.

Targeting “Supra-Carcinoids” in the Lung NET Landscape

In the field of lung neuroendocrine neoplasms, the traditional binary of “typical/atypical carcinoids” vs small cell lung cancer (SCLC) is being challenged by the work of Fernandez-Cuesta. Her decade-long research has led to the discovery of “supra-carcinoids”, tumors that look like indolent carcinoids under a microscope but behave like aggressive SCLCs at the molecular level.

“Investigating these diseases led to the discovery of supra‑carcinoids, a new biological entity with the morphology of carcinoids but the molecular and clinical behavior of the more aggressive SCLC and large cell neuroendocrine carcinomas[LCNEC],” Fernandez-Cuesta stated. “These breakthroughs have opened new avenues for understanding who develops lung NETs, as well as how and why for tumors with aggressive behavior.”

The Petersen Accelerator Grant will allow Fernandez-Cuesta’s team to employ single-cell RNA sequencing and proteomics to characterize the heterogeneity within these tumors.² Because many tumors contain small pockets of aggressive supra-carcinoid cells hidden among less aggressive regions, the grant provides the means to identify the “key players” driving this transformation. The ultimate objective is to translate these high-resolution data into clinically accessible biomarkers—such as targeted IHC or FISH assays—that can guide real-time interception decisions before significant clinical decline occurs.

“Many tumors seem to be heterogeneous, with small pockets of aggressive supra-carcinoid cells among many less aggressive tumor regions,” Fernandez-Cuesta explained. “With the grant, we will have the means to characterize these aggressive cells to understand what makes them unique and thus find ways to detect them earlier and target them.”

The Future of Multidisciplinary NET Care

The research supported by these NETRF grants underscores a broader trend in oncology: the transition from histological classification to molecularly defined treatment pathways. Whether through the engineering of T cells to recognize intracellular mutations, the targeting of age-related systemic signals, or the molecular unmasking of aggressive sub-populations, these investigators are providing the multidisciplinary team with the necessary tools to match the right patient with the right therapy.

As these projects mature, the oncology community can expect a refined understanding of the biological drivers of NETs, leading to therapeutic regimens that maximize efficacy while mitigating long-term AEs.

References

1. NETRF 2025 BTSI awardee spotlight: advancing GEP-NET research with Suzann Duan, PhD. News release. Neuroendocrine Tumor Research Foundation. August 18, 2025. Accessed March 19, 2026. https://tinyurl.com/2s4jynta
2. Characterization of supra-carcinoids cell states to inform interception strategies. Neuroendocrine Tumor Research Foundation. Accessed March 19, 2026. https://tinyurl.com/mrehxemy