Project title: Enhancing somatostatin agonist radionuclide therapy in GEP-NETs

Jeffrey Frost, PhD The University of Texas Health Science Center at Houston

Jeffrey Frost, PhD
  • Status: Completed
  • Year(s): 2020
  • Grant Type: Investigator
  • Research Type: Basic, Translational
  • Primary Tumor Site: Multiple
  • Area of Inquiry: Experimental Therapeutics
  • Article/Video: Click Here
  • Also seen in January 2022 eUpdate


Frost will explore the idea of inhibiting a class of molecules, called Wnts, to boost somatostatin receptor 2 (SSTR2) expression in gastroenteropancreatic (GET) NETs to enhance the effectiveness of peptide receptor radionuclide therapy (PRRT).

What question will you try to answer through your research?

We have found that proteins within the Wnt pathway can regulate the levels of SSTR2 in NETs, and that inhibiting this pathway significantly elevates receptor expression in NET cell lines. My team and I will investigate how this process happens and will use mouse models of NET tumors to determine whether inhibiting the Wnt pathway can increase the effectiveness of SSTR-targeted PRRT.

Why is this important?

Because SSTR2 expression is a common feature of GEP-NET tumor cells, PRRT targets and binds to this receptor to kill growing or metastatic GEP-NETs. Unfortunately, this therapy is limited by the variable expression of SSTR2, especially among patients with advanced disease. Strategies to boost SSTR2 expression would significantly enhance this therapeutic approach.

What will you do as part of this research project?

We will explore how the Wnt pathway targets and degrades SSTR2 and identify drugs that interfere with this process. My team and I will then show that treating animal tumor models with Wnt pathway inhibitors improves detection and treatment of GEP-NET tumors. 

How might your research improve the treatment of NETs?

Increasing SSTR2 expression would widen the patient population that is eligible for PRRT and may increase the treatment’s efficacy in patients whose tumors express the SSTR2 receptor.

What is your next step?

If this project is successful, we will extend the study to preclinical NET models to determine how the approach may be successfully translated into patient care. 


Somatostatin analogs are the primary treatment modality for symptomatic relief in patients with gastro-entero-pancreatic neuroendocrine tumors (GEP NETs). Moreover, labeled somatostatins are used as clinical imaging agents in GEP NET patients, and recently radioactively-labeled somatostatins have been approved as therapeutics for GEP NET patients. Unfortunately, all of these agents are limited by the availability of somatostatin receptors on the surface of GEP NET cancer cells.

In this project, we have found that a class of hormones, called Wnts, target somatostatin receptors for degradation, thereby potentially limiting receptor levels in GEP NETs. We demonstrated that Wnts drive the association of a protein called Dvl1 with somatostatin receptors, thereby targeting somatostatin receptors for lysososmal degradation. Moreover, we showed that inhibition of the Wnt-Dvl1 pathway promotes receptor accumulation in neuroendocrine tumor cells. Lastly, we found that phosphorylation of somatostatin receptors on a key amino acid allows the Wnt pathway to target somatostatin receptors for degradation, and we identified kinases that can drive this phosphorylation. Identification of these kinases provides additional possible avenues for inhibition of this receptor degradation pathway.

In summary, these studies have uncovered a novel regulatory mechanism controlling the expression of somatostatin receptors in neuroendocrine tumor cells, which may serve as future therapeutic targets to significantly expand the clinical efficacy of somatostatin-based therapies in GEP NET patients.

Additional Details

  • City: Houston
  • State: Texas
  • Country: United States
  • Grant Duration: 2 years
  • Awards: Investigator
  • Sponsor: Goldhirsh-Yellin Foundation


NETRF funds laboratory research to understand the development of neuroendocrine tumors and translational research to explore new concepts in treatment. Research grant descriptions and research updates from NETRF are not intended to serve as medical advice. It can take years for research discoveries to be fully validated and approved for patient care. Always consult your health care providers about your treatment options.

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