M. Sue O’Dorisio, MD, PhD
Professor of Pediatrics
Stead Family Department of Pediatrics
UI Children’s Hospital
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.
Theranostics in NETs
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.
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.
Molecular Mechanisms and Biomarkers of 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.