Rare and relentless

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Fluorescent oxytocin peptides bind to cell membranes of a small bowel neuroendocrine tumor, which is known to have the oxytocin receptor that could become a target for therapeutic and diagnostic agents.

Diligent pursuit of neuroendocrine tumors earns UI team a first-of-its-kind grant

By Jennifer Brown

When they arrived at the University of Iowa 16 years ago, M. Sue O’Dorisio, MD, PhD, and Thomas O’Dorisio, MD, already were recognized experts in the study and treatment of neuroendocrine tumors.

As a pediatric oncologist and an endocrinologist, respectively, at Ohio State University, they had pioneered therapies for neuroendocrine tumors, which originate primarily in the small bowel, pancreas, and lungs. The incidence of these insidious cancers—6.3 per 100,000—has increased significantly in the past 30 years.

The O’Dorisios’ approach focused on a receptor on the tumor’s surface that had been identified as a useful target for diagnosing and treating the cancer. Researchers in Europe continued to expand on this approach, creating more effective therapies, but tight U.S. regulations made these newer options as rare as the cancer they were intended to treat.

The O’Dorisios did not give up. As the incidence of neuroendocrine tumors climbed, partly through improved diagnoses, these UI physician-scientists expanded their data and their investigative team. They built a tissue bank of tumor samples to study; enlisted a broad cross section of research collaborators, including nuclear physicists, peptide chemists, genetics experts, epidemiologists, and bioinformatics specialists; and launched clinical trials to test emerging treatments.

“There is an urgency to bring new therapies to the U.S.,” says Tom O’Dorisio. “If you go back 12 to 14 years, we were aware of peptide receptor radionuclide therapy, and people of means were able to go to Basel, Switzerland, where that therapy was being used. But for me, that is an ethical dilemma, because I could tell a patient exactly what they needed, but for most patients, a trip to Europe and a treatment that costs about $11,000 per single therapy is unattainable.”

The O’Dorisios’ intense focus on providing U.S. patients with access to promising new treatments through clinical trials has drawn patients to the UI from across the country. Today, the Iowa Neuroendocrine Tumor Clinic that Tom O’Dorisio helped create—and now runs with fellow endooncologist Joe Dillon, MD, and surgeon James Howe, MD—is one of the largest in the U.S. The clinic has more than 1,100 patient visits per year, and more than 1,400 people nationwide have joined the patient registry that banks tissue samples along with information about patients’ demographics, treatment course, and outcomes over time. In an era of personalized medicine, this registry has become an invaluable resource that is a cornerstone of the latest chapter in the story: a National Cancer Institute (NCI) Specialized Programs of Research Excellence (SPORE) grant awarded to the UI Holden Comprehensive Cancer Center, with Sue O’Dorisio as principal investigator. It is the first SPORE grant focusing on neuroendocrine tumors.

After nearly 20 years studying these rare but deadly tumors, collecting colleagues from diverse disciplines and knowledge to advance the research, and overcoming regulatory hurdles to bring promising therapies to their patients, the UI team headed by the O’Dorisios is positioned as a leader in accelerating the pace of discovery to improve treatments for neuroendocrine tumors.

Slow to develop, tough to diagnose

Sometimes described as cancer in slow motion, neuroendocrine tumors are no less deadly. These rare—fewer than 250,000 people in the U.S. are affected at any one time—and unusual cancers occur in tissues that secrete or respond to hormones. They’re most common in the small bowel, pancreas, and lungs. They grow relentlessly but very slowly, a characteristic that makes them particularly challenging to diagnose and treat.

Slow-to-Develop
Neuroendocrine tumors of the adrenal glands and colon

Removing a localized, early-stage tumor with surgery can be curative, but the tumor’s slow growth often masks its presence, causing only vague symptoms such as abdominal pain, flushing, or diarrhea. This means that diagnosis can be delayed by up to eight or nine years, at which point the cancer has spread to the liver or lymph nodes in more than 40 percent of patients. The five-year survival rate for patients with advanced disease is less than 50 percent.

Their slow growth also means that neuroendocrine tumors don’t respond well to traditional chemotherapies that target fast-growing, highly proliferative cells. Of the four therapies approved by the Food and Drug Administration for neuroendocrine tumors, none is an effective cure. And given that the incidence of neuroendocrine tumors has risen by 500 percent since 1989, there is critical need for new and better diagnostic and treatment options.

A standard treatment for neuroendocrine tumors that won’t respond to surgery is based on the discovery, some 30 years ago, that many neuroendocrine tumors express receptors for the peptide hormone somatostatin on their surface. Drugs based on somatostatin bind to the receptor, slowing tumor growth and reducing symptoms. Yet this therapy, which was approved in the U.S. in 1989, does not eliminate the tumor.

Researchers, especially in Europe, continue to explore and exploit the therapeutic potential of attacking tumors through the somatostatin receptor. So-called peptide receptor radionuclide therapy (PRRT), in which a somatostatin analogue carries cell-killing radioactivity to the tumor cells, has been widely available in Europe for more than a decade, and evidence increasingly suggests that PRRT is superior to non-radioactive somatostatin analogues for treating neuroendocrine tumors. However, approval of these radiopharmaceuticals has been slow in the U.S. Hence, the O’Dorisios and their team have had to work creatively within the American system to help patients at home by obtaining permission in the form of Investigational New Drug (IND) applications to use these radiopharmaceuticals in clinical trials.

The first U.S. trial of PRRT using the radiopharmaceutical Yttrium-90 (90Y)-DOTATOC was conducted by Tom O’Dorisio and UI nuclear medicine expert David Bushnell, MD. Sue O’Dorisio used the same therapy in the world’s only phase 1 study in children. And the UI was one of 52 sites in a large international clinical trial that recently announced interim results showing that patients with advanced small bowel tumors had dramatically longer progression-free survival times (40 months vs. 8.4 months) with another radiopharmaceutical agent, Lutetium-177 (177Lu)-DOTATATE, compared to the standard somatostatin therapy.

“Over the years, Tom and Sue O’Dorisio have brought all sorts of clinical trials that aren’t available anywhere else in the U.S.,” says Howe. “They have been very effective at developing new approaches here at Iowa that nobody else can offer.”

First, find the tumor

Diagnosing, locating, and staging neuroendocrine tumors, plus monitoring their response to therapy, frequently uses the current standard imaging test called octreoscan. Unfortunately, octreoscan, which was developed in the 1980s and uses somatostatin tagged with a single photonemitting nuclide Indium-111, produces images that are not always able to identify the primary tumor, detect metastases, or effectively measure response to treatment.

The O’Dorisios introduced a better option: a Gallium-68 (68Ga) isotope that emits two photons used in a combination PET/CT (positron emission tomography-computed tomography) scan. This molecularly targeted PET imaging agent uses less radiation than octreoscan, is less expensive, and produces a much better image more likely to reveal the location of primary tumors, which are unknown in 10 to 25 percent of cases. The O’Dorisios were so convinced of the 68Ga scan’s potential that they used their own money to purchase the UI’s first 68Ga “generator” to ensure its availability for testing and clinical use.

A recent UI study, led by nuclear medicine physician Yusuf Menda, MD (’00 R), showed that the 68Ga-DOTATOC PET/CT scan could identify the primary tumor of unknown origin in two-thirds of cases. This is important because some surgeons, including the UI’s Howe, have demonstrated that neuroendocrine tumors, unlike most cancers, might be treatable with surgery even after the cancer has spread. Their experience suggests that finding and removing primary tumors can stave off future metastases and extend a patient’s life.

Sue O’Dorisio and Menda are also combining the precise, functional imaging obtained with 68Ga-DOTATOC PET/CT with the powerful cancer-killing effects of the radiopharmaceutical drug 90Y-DOTATOC in a clinical trial. This so-called theranostic approach—where a single tumortargeting compound is the basis of both a therapeutic and a diagnostic agent—is one area that will benefit from the research being done under the SPORE grant.

By sharing their IND for the 68Ga-DOTATOC PET imaging agent with the Society for Nuclear Medicine Clinical Trials Network, the O’Dorisios are leading the effort to make this state-of-the-art, molecularly targeted PET imaging available throughout the U.S. for use in clinical trials. Their hope is that 68Ga-DOTATOC PET/CT will replace octreoscan as the standard of care.

Turning tissue bank into gold mine

While still at Ohio State, Tom O’Dorisio started a registry of neuroendocrine tumor patients. One of the first things he did on arriving at the UI was to team up with Howe to establish the multidisciplinary Iowa Neuroendocrine Tumor Clinic and obtain university Institutional Review Board approval to allow the registry to continue to grow at Iowa. His foresight has created a unique biobank where tissue from patients’ tumors (both primary and metastatic), as well as normal tissue, can be banked.

“This neuroendocrine clinic and registry was absolutely necessary for the SPORE grant because these specialized program of excellence grants require every project to have both a basic science and a clinical component. If we didn’t have the patients, we couldn’t have the clinical component,” says Sue O’Dorisio.

Tom O'Dorisio
Tom O’Dorisio

Realizing that neuroendocrine tissue samples are a potential gold mine of information to improve understanding of these rare tumors, the O’Dorisios partnered with Chuck Lynch (’79 MS, ’79 MD, ’84 PhD, ’86 R), who runs the Iowa SEER (Surveillance, Epidemiology, and End Results) program and manages a virtual database of residual tumor tissue. Through Lynch’s connections to similar repositories at the University of Hawaii and the University of Southern California, the SPORE researchers gained access to a large and diverse collection of nearly 25,000 neuroendocrine tumor samples.

This sizable biospecimen repository represents an incredibly rich resource that will be used by all the SPORE research projects to search for genetic and molecular causes of neuroendocrine tumors as well as new extra- and intra-cellular targets that might improve diagnosis, prognosis, and treatment of these cancers.

Using whole exome sequencing of tumor tissue samples from the registry, Sue O’Dorisio and Howe— a cancer genetics researcher who discovered two genes that cause the rare form of inherited colon cancer known as juvenile polyposis—have identified several new G-coupled protein receptors expressed on the surface of both pancreatic and small bowel neuroendocrine tumors.

O’Dorisio and Menda are eager to target these newly discovered receptors in the same way that somatostatin analogues target somatostatin receptors in existing therapies.

Peptide chemists F. Christopher Pigge, PhD, Molly Martin (’07 PhD), and Michael Schultz, PhD, will design and synthesize peptide molecules that target the individual receptors as well as hybrid combinations, or dimers, of the receptors, which appear to be unique to the cancer cells. Initially, the peptides will be tagged with 68Ga and tested as PET/CT imaging agents in animal models to determine how well the novel radiopeptides target the tumors.

“The PET/CT scan confirms that the tumor is targeted and identifies which healthy tissue also takes up the tracer so you can anticipate any potential toxicity issues,” says Sue O’Dorisio. “But you give so little, and this imaging agent doesn’t kill cells, so you haven’t done any harm. It is an ideal way to be the first test in humans for any drug. We hope in the next three to five years we will have at least two of these new PET targeting agents ready to use as PET imaging agents in patients with neuroendocrine tumors.”

The Lego-like chemistry developed by the UI researchers means that successful candidates can easily be transformed from imaging agents into therapeutic molecules of the theranostic pairings by simply swapping the harmless 68Ga for the cell-killing payload of 90Y or 177Lu.

Deciphering tumor genetics

Armed with tumor samples from the registry as well as tissue from the SEER residual tissue repositories, researchers funded by the SPORE grant will analyze the DNA, RNA, and proteins of these tumors with the goal of identifying biomarkers— the presence, absence, or alteration of particular proteins or genes that can help facilitate early and accurate diagnosis, predict survival, guide therapy, and even suggest new therapeutic targets.

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

James Howe
James Howe

Through the registry, Howe identified 13 families with multiple members affected by small bowel tumors. Using exome sequencing to analyze DNA from these families, he hopes to identify genes that predispose people to develop small bowel tumors. Finding such genes might open up new avenues for treatment.

Howe’s genetic analysis also has shown that differences in RNA expression patterns in metastatic tumor tissue from the liver can predict the origin (in the pancreas or small bowel) of the tumor. He and his team continue to refine this biomarker test for possible clinical use.

UI pharmacologist Dawn Quelle, PhD, also will focus on identifying biomarkers that can be developed into geneand protein-based tumor assays. Quelle’s addition to the SPORE team hinged on Sue O’Dorisio’s natural inclination toward collaboration and finely tuned attentiveness to anything related to neuroendocrine tumors.

“At a cancer center meeting, I showed a tissue microarray stained for an oncogenic protein that I study, RABL6A, to demonstrate RABL6A is highly expressed in pancreatic ductal adenocarcinoma,” Quelle says. “And then I happened to show a couple of neuroendocrine tumor stains where RABL6A levels were ‘whopping,’ and Sue said, ‘Oh, you should study NETs!’”

That friendly imperative led to Quelle, along with pediatrician and cytogenetics expert Ben Darbro (’07 MD/ PhD), directing one of the SPORE projects examining the role of RABL6A in neuroendocrine tumors and developing biomarker tests to improve diagnosis, prognosis, and treatment decision-making for patients and physicians.

Quelle recently discovered that RABL6A is highly expressed in pancreatic neuroendocrine tumors and is required for their proliferation. The protein promotes tumor cell growth, at least in part, by inactivating the retinoblastoma tumor suppressor protein. These findings suggest RABL6A might be a new biomarker for pancreatic neuroendocrine tumors and possible target for anticancer therapy.

While Quelle’s research will focus on understanding the RABL6A-related mechanisms and pathways that drive tumor progression and resistance to chemotherapy, Darbro’s work will complement this approach by looking more globally at chromosomal deletions, amplifications, or changes in RNA expression in tumor tissue. Through their genomic and molecular analysis of the tumors, Quelle and Darbro aim to identify genetic and protein biomarkers that can distinguish the site of origin of the tumor and predict whether tumors are likely to respond to particular therapies.

“Ultimately, the more we know (about these tumors) the more targets we have,” Darbro says.

Within the five-year timeframe of the SPORE grant, they hope to develop two clinical test kits—one genetic-based using fluorescence in situ hybridization and one proteinbased using immunohistochemistry—to improve the diagnosis, prognosis, and medical management of patients with neuroendocrine cancer.

“By developing a test that uses traditional techniques but directing them based on what we now know about the pathways and mechanisms and how patients are already treated, hopefully we can make strides and advances that are relevant to the patients,” Darbro says.

Personalized radiation therapy

One final project funded by the SPORE grant could advance a different kind of personalized therapy pioneered at the UI.

In 2003, nuclear medicine expert Bushnell, who was Tom O’Dorisio’s partner on the first U.S. trial for the radiopharmaceutical 90Y-DOTATOC, recognized that some small bowel tumors were targeted by two different radioactive drugs: the 90Y-DOTATOC and metaiodobenzylguanidine (MIBG) labeled with iodine-131. Although both drugs latch onto these tumors, each is toxic to a different normal tissue— kidneys in the case of the 90Y-DOTATOC and bone marrow for the 131I-MIBG.

Bushnell reasoned that combining the two radiopharmaceuticals had the potential to significantly increase the amount of radiation that could be delivered to the tumors without increasing radiation exposure to either the kidneys or bone marrow.

He enlisted nuclear physicist Mark Madsen, PhD, who derived a mathematical construct to implement Bushnell’s idea using information from diagnostic scans obtained with each drug to calculate the optimal treatment doses of both radiopharmaceuticals.

Subsequent clinical research using this approach, performed at the Iowa City Veterans Affairs Medical Center, showed that data from diagnostic imaging scans can accurately predict how much radiation energy will be deposited at the various sites—either organ or tumor—for every unit of radiation that is injected. This dosimetrybased approach is essentially nuclear medicine’s answer to precision medicine.

“That is one of the important features of this approach. It’s very personalized,” Bushnell says. “Now we are ready to move forward with a clinical trial where we will use these mathematical calculations to treat patients with precise, patient-specific amounts of the radiopharmaceuticals.”

Dosimetry calculations also will allow the researchers to escalate radiation of the tumor based on the tolerance dose of the kidney. Sue O’Dorisio and Menda also will incorporate patient-specific dosimetry into their ongoing theranostic trial.

“The big payoff will be that we will be able to bring both earlier diagnosis to patients and better therapy to patients with neuroendocrine tumors all over the U.S.,” says Sue O’Dorisio. “One of our shared goals at the University of Iowa and the NCI is to pioneer these new genetic tests, new imaging agents, and new therapies so that patients all over the U.S. can benefit.”

Another SPORE grant for UI cancer research

A multidisciplinary team of scientists and clinicians at the University of Iowa Holden Comprehensive Cancer Center led by M. Sue O’Dorisio, MD, PhD, professor of pediatrics-hematology/ oncology in the Stead Family Department of Pediatrics and the UI Children’s Hospital, received the first-ever Specialized Programs of Research Excellence (SPORE) grant to study neuroendocrine tumors.

Neuroendocrine tumors of the stomach and small intestine.
Neuroendocrine tumors of the stomach and small intestine.

Funded through the National Cancer Institute (NCI), SPORE grants are key mechanism for the NCI to support collaborative, interdisciplinary translational cancer research with the specific aim of reducing cancer incidence and mortality and improving survival and quality of life for cancer patients.

There are currently 52 funded SPOREs at academic centers in 21 states. Holden Comprehensive Cancer Center at the UI is also home to a SPORE grant for lymphoma, which is a collaborative project with Mayo Clinic.

The five-year, $10.67 million neuroendocrine SPORE grant will support four core functions (administration, biospecimens, clinical research, and biostatistics and bioinformatics) and research projects in:
• Theranostics in Neuroendocrine Tumors
• Molecular Mechanisms and Biomarkers of Neuroendocrine Tumors
• Genetic Studies of IIeal (small bowel) Neuroendocrine Tumors
• New Approaches to Improving the Effectiveness of Radionuclide Targeted Treatments in Neuroendocrine Tumors

O’Dorisio honored for mentorship

M. Sue O'Dorisio
M. Sue O’Dorisio

M. Sue O’Dorisio’s goal as a mentor is to help each person under her tutelage develop skills to attain a personal and career transition to new heights in science, medicine, and life.

It’s an approach that earned O’Dorisio, MD, PhD, professor of pediatrics-hematology/oncology, the 2015 University of Iowa Carver College of Medicine Distinguished Mentor Award.

“Anyone who worked with her, at all levels of training, was encouraged to evaluate where they were and find ways to improve themselves,” says Jeffrey Sall (’02 MD/PhD), a graduate of the Medical Scientist Training Program, which O’Dorisio has faithfully served since coming to the UI in 1999, and earlier at Ohio State University as its director.

Upon arriving at the UI, she set out to reactivate the pediatric hematology-oncology fellowship by obtaining a National Institutes of Health (NIH) training grant. Her record of continuous NIH funding since 1976 has enabled her to mentor a steady stream of research trainees, who leave her lab with a pay-it-forward mentality.

“As I begin training residents and postdocs in my own lab, I find myself modeling my teaching and interactions after her direct communication, engaged style, and openness to letting people try experiments and test ideas that were likely wrong,” says Sall, associate professor of anesthesia at the University of California, San Francisco. “Small failures and rejection are an important part of learning to succeed in science.”

Kelsey Olerich (’15 MD/PhD) best describes the effect O’Dorisio has had on so many.

“She has fostered a questioning drive and critical mindset in me. I consider Dr. O’Dorisio to be a lifelong mentor. She exemplifies that type of person that I hope to become,” says Olerich, an OB-GYN resident at Barnes-Jewish Hospital, St. Louis.

The mentorship award and corresponding lecture by a leading scientist are supported by UI alumni Nancy Granner and Daryl Granner (’62 MS, ’62 MD), professor emeritus of internal medicine and physiology, as well as founding director emeritus of the Fraternal Order of Eagles Diabetes Research Center at the UI.