Neuroendocrine tumors (NETs) are considered an orphan disease with a low incidence in the United States. Consequently, government funding agencies and pharmaceutical companies have been reluctant to provide financial support to advance research on the causes of NETs or to sponsor clinical trials to bring newer treatments to the clinical arena.

With the FDA emphasis on personalized medicine for patients with orphan diseases, the National Cancer Institute has recently awarded a Neuroendocrine Tumor Specialized Program of Research Excellence (SPORE) to the Holden Comprehensive Cancer Center at the University of Iowa to fund both basic and clinical research on NETs.

Over the past 16 years, our UI team has built a nationally recognized Neuroendocrine Tumor Clinic, established a NET registry and tumor bank, launched clinical trials to test emerging treatments, and enlisted a broad cross section of research collaborators including nuclear physicists, peptide chemists, genetics experts, epidemiologists, and bioinformatics specialists to be able to successfully compete for this unique SPORE grant.

This first-of-its-kind NET SPORE grant will help accelerate the pace of discovery by enabling us to focus on four major projects that will explore the genetics of these tumors, their molecular makeup, and how this information can be used to develop new approaches for diagnosis and treatment.

The incidence and prevalence of NETs is rising in the United States, yet there is very little research on NETs and no effective treatment for patients with metastatic disease, many of whom die within 5 years of diagnosis, according to the latest Surveillance, Epidemiology, and End Results (SEER) data. NETs do not respond to conventional chemotherapy or external beam radiation, making development of new diagnostic and therapeutic options imperative.

We hypothesize that theranostics, use of a single compound as both a therapeutic and a diagnostic agent, will meet this critical need for children and adults with NETs.

Through genetic analysis we have identified several receptors that are expressed on the surface of NETs and may have potential as theranostic targets. We will design and synthesize peptides that can bind to these prime new targets, which include oxytocin, melanocortin, and glucose-dependent insulinotropic peptide receptors. Peptide ligands that demonstrate high affinity and stability in vitro will then be tested as diagnostic PET imaging agents in preclinical models of bronchial, small bowel, and pancreatic NETs.

Molecular Mechanisms and Biomarkers of NETs

We will apply to the FDA for an investigational new drug (IND) designation to conduct first-inhuman PET imaging studies using the best of these preclinical agents. Successful completion of these preclinical and first-in-human imaging trials will pave the way for development of new therapeutic radioactive drugs with the ultimate goal of providing new imaging and therapy options for patients with NETs.

Mechanisms underlying NET development are only partly understood, and biomarkers that could help diagnose the disease or predict patient prognosis are lacking. While progress in managing pancreatic NETs (pNETs) over the past several decades has been slow, some new targeted therapies have emerged as we’ve learned more about molecular mechanisms of pNET pathogenesis.

Mounting evidence suggests that drug combinations targeting multiple steps of the tumor-promoting PI3K/Akt/mTOR pathway will reduce NET resistance to therapy and improve patient outcome. However, better understanding is needed of PI3K/Akt/mTOR regulation and identification of pNET biomarkers that stratify patients into subgroups of those who will (or will not) respond to particular therapies.

We aim to define clinically relevant therapeutic targets that control pNET proliferation and survival. This work builds upon our discovery that RABL6A (a novel oncoprotein) is essential for pNET cell survival and proliferation via the PI3K/Akt/mTOR pathway.

Our initial studies have identified several genetic changes capable of distinguishing pancreatic from ileal NETs (including RABL6A gene amplification). Extending these results, we plan to identify genetic and proteomic biomarkers that distinguish four different types of NETs (pancreatic, ileal, bronchial, and cervical), and provide prognostic information on NETs.

We are now investigating novel relationships between the status of pNET proliferation pathways (RABL6A-Akt/mTOR, RABL6A-Rb1) and genetic alterations that discriminate between NETs that arise in the bronchi versus the intestine, pancreas or cervix in order to identify molecular alterations that are common or unique to various types of NETs, as well as genetic alteration in primary versus metastatic tumors.

The most immediate clinical outcome of this translational project will be the development of fast and inexpensive genetic (FISH-based) and proteomic (IHC-based) tests for differentiating various types of NETs in patients. This should markedly improve NET diagnosis, classification, prognosis, and treatment.

Very little is currently known about the genetic and molecular mechanisms that cause NETs to arise and progress. This is particularly true of small bowel tumors where no genetic cause for inherited or sporadic disease has been identified.

Analysis of exome sequences and gene expression profiles of these tumors will allow us to determine the tumor site of origin in patients presenting with liver metastases and unknown primary tumors, which will lead to more directed surgical exploration and resection. Knowledge of cell surface receptors or other genes significantly overexpressed in NETs relative to normal tissues will also facilitate the development of new targets for detection, imaging, and medical management. Novel targets for therapy will also be suggested by the identification of frequently mutated or deleted genes in these tumors or in the germline of patients with familial NETs.

We have identified 13 families with multiple members affected by small bowel tumors. Identifying predisposing genes in these cases of familial NETs would be expected to yield valuable new clues into the pathogenesis and management of these tumors.

Although several effective therapies have emerged for metastatic pNETs, small bowel NETs do not respond to these same therapies. By understanding the molecular basis of both forms of metastatic tumors we hope to develop new treatment strategies.

Radionuclide Targeted Treatments in NETs Although slow to progress in the early stages, once NETs metastasize, the current 5-year survival rate is less than 50%. Newer, more effective forms of therapy are urgently needed.

Targeted radionuclide therapies using single agents such as 131I-metaiodobenzylguanidine (131I MIBG) and 90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) have shown promise for therapy of small bowel NETs with response rates of 20% to 40%. Unfortunately, complete responses are notably uncommon, occurring in less than 10% of patients and response duration is often disappointing as well.

Our overarching hypothesis is that multiple targeting approaches conducted simultaneously can lead to increased delivery of radiation dose to NET relative to normal tissues and provide improved durable benefit to patients. We propose a phase I clinical trial combining 90Y-DOTATOC and 131I MIBG that should provide an increase in the radiation dose delivered to tumors without exceeding safe limits for normal kidney and bone marrow. This trial design, based on strong preliminary imaging data and radiation dose modeling, has the potential to provide durable therapeutic benefit for patients with small bowel NETs where other therapeutic strategies fall short.

In further basic science studies, we propose an innovative strategy targeting unique hybrid G-protein coupled receptors such as somatostatin receptor/dopamine receptor conjugates that we have identified in NETs. Preliminary data demonstrate that these new targeting agents have high affinity binding to tumor cells; they are predicted to be highly specific for tumor cells as the heterodimeric receptors are rarely expressed in normal tissues. Successful development of these unique radionuclide therapies will provide a new paradigm for molecular targeting and image-guided radionuclide therapy that will likely be translated to other malignancies.

One of our shared goals at the University of Iowa Holden Comprehensive Cancer Center and the National Cancer Institute is to pioneer new genetic tests, new imaging agents, and new therapies so that patients all over the United States with orphan neuroendocrine tumors can enjoy a longer, high-quality life.

Articles

With the FDA emphasis on personalized medicine for patients with orphan diseases, the National Cancer Institute has recently awarded a Neuroendocrine Tumor Specialized Program of Research Excellence to the Holden Comprehensive Cancer Center at the University of Iowa to fund both basic and clinical research on neuroendocrine tumors.

M. Sue O'Dorisio, MD, PhD

Articles

SPORE Grant Fuels New Research Projects on Neuroendocrine Tumors