Renewed NCI funding supports bedside-to-bench research driven by the needs of patients
BY BOB HECKER
Thyroid cancer incidence in the United States is rising at the fastest rate of all solid tumors, producing an increasingly important public health problem. Researchers at The Ohio State University are working to understand why this is happening and how to better treat and prevent the disease.
In 2013, a team of researchers led by Matthew Ringel, MD, co-director of the Thyroid Cancer Unit at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James), received an $11.3 million, five-year renewal of a Program Project Grant first awarded in 2008 at $11.9 million by the National Cancer Institute (NCI) to study “Genetic and Signaling Pathways in Epithelial Thyroid Cancer” (grant number CA124570-06).
OSUCCC Director and James CEO Michael A. Caligiuri, MD, has called the grants “a landmark achievement in NCI funding for Ohio State’s thyroid cancer program that represents the best in translational science.”
“To our knowledge, this is the only Program Project Grant currently funded by the NCI that focuses entirely on thyroid cancer,” says Ringel, the Ralph W. Kurtz Professor of Medicine, director of the Division of Endocrinology, Diabetes and Metabolism at Ohio State, and a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program (MBCG).
The grant has four interacting research projects that share four core services. This design reflects the multidisciplinary nature of the OSUCCC – James’ Thyroid Cancer Unit, which addresses all aspects of care, including determining genetic predisposition, improving diagnosis and treatment, and managing side effects.
“We also offer therapeutic clinical trials for patients with non-responsive or progressive disease,” Ringel says. “I’d describe our translational-research program as ‘bedside to bench’ rather than ‘bench to bedside,’ because it’s so much driven by the clinical needs of our patients.”
The American Cancer Society expected 60,220 new cases of thyroid cancer and 1,850 deaths from the disease in the United States in 2013. Three out of four of the new cases and more than half the deaths occurred in women. The chance of being diagnosed with this disease is now more than twice what it was in 1990.
Why the incidence is rising is unknown, Ringel says, but one factor may be better detection using technologies such as thyroid ultrasound and fine-needle aspiration.
“There are only a few known environment risk factors, such as radiation exposure for papillary thyroid cancer — the most common form in the United States — and iodine deficiency for follicular thyroid cancer. Some rare genetic syndromes also predispose to follicular thyroid cancer, he says.
The primary goals of the PPG’s translational studies are to:
- Better predict who is at risk for the disease, enable earlier diagnosis and predict tumor behavior by identifying genes that predispose to thyroid cancer;
- Identify cell pathways that influence thyroid cancer development and progression for potential drug targeting;
- Identify why patients stop responding to standard therapy, then develop strategies that improve response rates.
“Thyroid cancer typically takes an indolent course when patients are diagnosed early, so with increasing incidence there is a growing population of long-term survivors,” Ringel says. “For patients with more aggressive disease, we need better treatment options.”
The renewal funding will enable Ringel and his colleagues to further the most promising earlier findings, those with the greatest potential to improve care or advance thyroid cancer research.
Here is a summary of the renewal grant’s four projects and cores.
Project I: Genes in the Predisposition to Papillary Thyroid Carcinoma (PTC)
In the first grant period, the investigators identified 125 families that have at least three members with PTC, enabling them to apply a “clan genomics” approach and learn whether it can improve identification of inherited gene variations that contribute to PTC development.
“Numerous studies done mainly by others show that the heritability of thyroid cancer is very high, so we set out to find predisposing genes that explain this,” says Project Director Albert de la Chapelle, MD, PhD, professor of Medicine and the Leonard J. Immke Jr. and Charlotte L. Immke Chair in Cancer Research.
“But even with many large families to study, we found very little. This we interpret to mean that high-penetrance genes probably are rare or do not exist,” de la Chapelle says.
“We are now concentrating on finding rare, high-penetrance genes that may occur mostly in single patients or families,” he adds. “We are doing this using next-generation sequencing of individuals from families in which the inheritance resembles that of high-penetrance genes. We have so far identified at least three promising genes.” One of those, for example, was polymorphism rs944289, described in a 2012 paper in the Proceedings of the National Academy of Sciences (PNAS).
De la Chapelle and his colleagues now hope to confirm the involvement of these genes in PTC.
Project II: Genetic Alterations That Initiate Follicular Thyroid Carcinogenesis
This study investigates the genetic causes of inherited follicular thyroid carcinoma (FTC) and sporadic FTC in humans and in a mouse model. The project is directed by Charis Eng, MD, PhD, chair and founding director of the Genomic Medicine Institute of the Cleveland Clinic Foundation, and co-led by Lawrence Kirschner, MD, PhD, professor of Medicine in the Division of Endocrinology, Diabetes and Metabolism, and a researcher with the OSUCCC – James MBCG Program.
The human genetic model used in the study is an inherited cancer syndrome called Cowden syndrome (CS), which is caused by germline mutations in the PTEN tumor-suppressor gene and is characterized by high risk for FTC.
“CS presents a unique opportunity to examine the events that are the earliest indicator of FTC,” Eng says.
In the first grant period, the researchers accrued more than 3,000 human subjects who met CS or CS-like criteria. “We then created a Web-based PTEN risk calculator based on the presence or absence of PTEN mutations and clinical characteristics,” Kirschner says. Key findings during the first grant period included:
- PTEN mutation carriers have a 32-percent lifetime risk of thyroid cancer, much higher than previously estimated;
- Germline mutations of PTEN account for 25 percent of CS cases, instead of the widely believed 85 percent from a previous series of accruals, indicating that other predisposition genes must exist. The research team has identified two new CS susceptibility genes so far;
- Thyroid cancer prevalence is higher in patients with SDHx gene variants versus those with PTEN mutations alone, and SDHx variants modify cancer risk in those with PTEN mutations.
During the second grant period, Eng, Kirschner and their team will work to identify the earliest events in FTC initiation and predisposing genetic factors useful for predictive testing to risk assessment.
“Based on data from our first grant period, we hypothesize that interactions of PTEN, SDHx and PRKAR1A play an important role in thyroid neoplasia initiation by modulating mitochondria-associated energetics,” Eng says. To investigate this question, the researchers will:
- Analyze the role of SDHx and PRKAR1A germline variations in modifying risk and the molecular signaling of thyroid cancer in patients with PTEN mutations;
- Analyze PTEN and SDHx interactions;
- Study mitochondrial function in mouse models of thyroid neoplasia.
Project III: Selective Modulation of Thyroidal Radioiodine Accumulation
The ability of thyroid follicular cells to concentrate iodine allows the use of radioiodine to target residual and metastatic thyroid cancer after tumor removal.
“Radioiodine therapy (RAI) can decrease recurrence and improve overall survival in several thyroid cancer patient populations,” says Project Director Sissy Jhiang, PhD, professor of Medicine and a member of the OSUCCC – James MBCG Program. “But about 20 percent of patients with differentiated thyroid carcinomas, and most patients with poorly differentiated thyroid cancer, do not respond to RAI therapy because their ability to accumulate radioiodine is reduced or absent.”
Jhiang’s project seeks to improve RAI therapy in these patients by identifying molecular candidates that restore or enhance radioiodine accumulation in thyroid tumors.
During the first grant period, Jhiang’s team confirmed that inhibitors for MEK, BRAF, and PI3K genes could increase radioiodine accumulation in thyroid cells; they learned that Hsp90 inhibition and Akt inhibition selectively increased radioiodine accumulation; and they used small-animal imaging to quantify radioiodine accumulation in thyroid cancer models.
“Several small-molecule inhibitors that target MEK, BRAF, Akt, PI3K or Hsp90 are in clinical trials to treat other types of cancer, and these could be applied to thyroid cancer patients as well,” Jhiang says. “We hypothesize that these inhibitors might halt thyroid tumor progression and also sensitize surviving tumor cells to radioiodine ablation.”
Project IV: P21-Activated Kinase in Thyroid Cancer
During the first grant period, Ringel’s lab discovered a new link between the BRAF oncogene, which causes about 40 percent of papillary thyroid cancers and is associated with aggressive disease, and the signaling molecule p21-activated kinase (PAK). This pathway regulates the migration of thyroid cancer cells, and it is independent of the classic BRAF target known as MEK. In addition, laboratory studies suggested it is sensitive to RAF-kinase inhibitors that are already in clinical testing.
“Activating mutations in BRAF are the most common identifiable genetic mutations in thyroid cancer so far and are associated with poor prognosis,” says Project Director Ringel. His team worked with Ching-Shih Chen, PhD, a professor of Medicinal Chemistry and Pharmacognosy at Ohio State and member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Program, to develop PAK inhibitors.
“We believe PAK is critical for BRAF signaling, that it is involved in thyroid cancer progression, and that it is a novel therapeutic target to inhibit PTC progression,” Ringel says.
“Now, we’re trying to understand how PAK works at the molecular level, and we’re evaluating tumor samples that have shown invasion and metastasis so we can develop inhibitors to treat that kinase.”
Research Cores
The grant also funds four shared-resource cores that support the research:
- Integrated Clinicopathology and Biorepository Core: Oversees the biospecimens collected for research and the databases that integrate pathology and laboratory samples with clinical information. The team is led by John Phay, MD, of the Division of Surgical Oncology, and Rebecca Nagy, CGC, of the Division of Human Genetics, and includes Paul Wakely Jr., MD, in the Department of Pathology.
- Mouse Imaging and Pathology Core: Provides expertise in mouse thyroid pathology. The team is directed by Kirschner, co-leader of Project II, who has extensive experience in mouse models of endocrine cancer. The researchers use CT/SPECT (computed tomography and single photon emission computed tomography) with ultrasound to quantify iodine uptake in mouse models. The core includes Krista LaPerle, DVM, PhD, a mouse veterinary pathologist at Ohio State.
- Biostatistics Core: Directed by Soledad Fernandez, PhD, of the Department of Biomedical Informatics at Ohio State, this core provides biostatistical support for PPG investigators at all levels of research, from study design to final analyses.
- Administrative Core: “This core is structured to analyze and monitor progress in all aspects so we can foster collaborations to enable more rapid progress,” says Ringel, the core’s director.
Optimistic Outlook
Ringel notes many reasons why the group’s work stands an excellent chance of helping patients. They include support for team science and collaboration by the OSUCCC – James, and the integration of research with longstanding clinical expertise.
“At the same time, we couldn’t do this research without the help of our patients,” he adds. He cites the leadership of Manisha Shah, MD, who directs Ohio State’s Neuroendocrine Tumor Program and is principal investigator for several clinical trials, including some that focus on thyroid cancer. Shah has research and clinical interests in adrenal, neuroendocrine and thyroid cancers.
Ringel also notes other Ohio State faculty who are crucial to the program’s success:
- Jennifer Sipos, MD, and Fadi Nabhan, MD, Division of Endocrinology, Diabetes and Metabolism, experts in thyroid nodules and thyroid cancer and national leaders in thyroid cancer diagnosis and management;
- Nathan Hall, MD, PhD, and his team in Nuclear Medicine;
- Paul Wakely, MD, Rulong Shen, MD, and others in the Department of Pathology;
- Surgeons in Surgical Oncology and Head and Neck Surgery;
“We also have the support of a terrific group of nurses and administrators in multiple divisions who support our joint commitment to a true multidisciplinary approach to this work,” Ringel says.“Also important to patients is our ability to minimize many treatment side effects to improve quality of life,” he adds. “Today, so many patients are doing well and surviving longer that we need to be cognizant of side effects, particularly in those with early-stage disease.”
Yet, much work lies ahead. “The main benefit from our studies might come from the clues they provide to pathways that predisposing genes act through, and from drugs that can be conceived to act on those pathways,” adds de la Chapelle, director of Project I. “This might make it possible to halt or cure the disease. Such studies are now beginning.”
SPORE Grant Brings Added Support for Thyroid Cancer Research
In addition to receiving five years of renewal funding for an NCI Program Project Grant, Matthew Ringel, MD, co-director of the Thyroid Cancer Unit at the OSUCCC – James, has been awarded a five-year, $11.3 million Specialized Program of Research Excellence (SPORE) grant (CA168505-01A1). The SPORE is a collaborative grant with investigators at MD Anderson Cancer Center and centered at Ohio State with Ringel as principal investigator. Its primary goal is to improve the outcomes and lives of patients with thyroid cancer.