Endocrine Neoplasia Research Group

The Endocrine Neoplasia Research Group is dedicated to advancing our knowledge of endocrine tumor biology.

Our translational and collaborative research seeks to improve patient outcomes and discover new treatment opportunities for patients affected by endocrine tumors and cancers.

Over its 20-year history, the endocrine neoplasia research program has been well-funded by the NIH (3 R01s, 1 R21, 2 K awards, a T32), society and industry support, and junior investigator grants.

We have published over 50 peer-reviewed manuscripts in leading, high impact journals, and we have trained many junior scientists.

Parathyroid research

Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia in ambulatory patients. Untreated PHPT causes bone loss, fractures, kidney stones, cardiovascular disease, and neurocognitive impairment. Our team of scientists investigates how G-protein coupled receptor signaling and parathyroid tumor clonal structure affects parathyroid tumor biology and treatment outcomes for patients treated with surgery.

Thyroid research

Thyroid cancer is the 12th most common cancer with 2200 projected deaths in 2021. The incidence of advanced-stage thyroid cancers is also increasing and it was predicted that thyroid cancer costs were $18 to $21 billion in 2019. Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer, is highly lethal, and accounts for half of all thyroid cancer deaths. Improvements in treatment options is urgently needed. Our research is investigating how tumor clonal architecture affects responses to molecular therapies and how DNA repair pathways can be targeted in ATC to improve survival.

Principal investigator

The Endocrine Neoplasia Research Group is led by John A. Olson Jr., MD, PhD, chair of the Department of Surgery, who achieved recognition for his groundbreaking basic science and clinical research on endocrine tumor formation.

His work has led to a greater understanding of how excessive hormone and calcium levels can contribute to hyperparathyroidism. His research team reported the first isolation and functional characterization of parathyroid cell subtypes from parathyroid tumors, findings that have enabled the field to home in on the disease’s development and trajectory. Further, his clinical research has focused on novel endocrine therapies aimed at shrinking breast cancer tumors and determining biomarkers related to breast cancer outcomes.

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Current research

Parathyroid investigations

Tumor clonal status as a biomarker in primary hyperparathyroidism

Since the first description of PHPT and its surgical treatment in the 1920’s, the pathogenesis of PHPT has been viewed simply: A parathyroid tumor develops from a single transformed clone (i.e. monoclonal) that expands and secretes excessive PTH resulting in hypercalcemia that causes the symptoms and sequalae of PHPT. This paradigm predicts that PHPT develops from a single tumor (single gland disease, SGD) and that removal of this single tumor by parathyroidectomy (PTX) cures the disease. Although conceptually attractive, this simple model does not explain several observations including: 1. The presence of multiple gland disease (MGD) in up to 20% of PHPT patients; 2. The observation that PTH remains elevated following PTX in up to 30% of patients; 3. The reality that symptoms and sequellae of PHPT often do not improve following PTX; and 4. The development of recurrent PHPT in up to 15% of patients. These observations, combined with data from our laboratory describing the molecular heterogeneity of parathyroid tumors have led us to suspect that PHPT may represent several different diseases are reflected in characteristics of the parathyroid tumor. The foundation for the proposed work has been published by our group in two studies. Our first study characterized individual oxyphil and chief cells isolated from parathyroid tumors from patients with PHPT showing that while many tumors are monoclonal by X-inactivation (monoclonal-X), a significant proportion (36%, 5/14) of tumors were comprised of multiple clones (i.e. polyclonal-X). Our second study patients confirmed that up to 46% of PHPT patients have polyclonal tumors and that the clonal status (i.e. monoclonal-X versus polyclonal-X) of the tumor predicts MGD that is often missed at surgery. This study also suggested clinically relevant differences between the two tumor types. These findings support the premise that parathyroid tumor clonal status reflects different types of PHPT with different etiologies, disease presentation and treatment outcomes.

• Specific aim 1. To determine the clinicopathologic features of monoclonal-X versus polyclonal-X parathyroid tumors in a prospective multi-center cohort of patients with PHPT referred for PTX.
• Specific aim 2. To perform a prospective study of outcomes of PTX in PHPT patients with monoclonal X and polyclonal-X tumors
• Specific aim 3. To investigate mechanism(s) of monoclonal-X and polyclonal-X parathyroid tumorigenesis using functional and genomic approaches.

G-protein coupled-receptor signaling in hyperparathyroidism

Parathyroid tumors are insensitive to calcium feedback to PTH secretion. We previously reported that RGS5, a GTPase activating protein (GAP) that targets Gαq, is expressed in parathyroid tissue and is selectively upregulated in parathyroid tumors relative to normal glands. RGS5 inhibits calcium signaling through CASR. We created a RGS5-null mice that display significantly reduced levels of circulating plasma PTH with preserved responses to changes in calcium, consistent with a constitutively elevated baseline of CASR signaling activity. These data suggested that opposing CASR signaling through increased expression of RGS5 in the parathyroid could result in inappropriate PTH secretion and afford a unique opportunity to test whether RGS5 can contribute to parathyroid neoplasia. To determine whether RGS5 overexpression in the parathyroid gland can lead to PHPT, we generated a strain of mice overexpressing RGS5 specifically in the parathyroid gland (PTG-RGS5) using a Cre-lox strategy. Characterization of this strain revealed that overexpression of RGS5 in the murine parathyroid gland results in elevated PTH secretion and parathyroid neoplasia as well as a bone phenotype reflecting abnormally elevated production of PTH. Additionally, overexpression of RGS5 increased PTH secretion by normal human parathyroid cells and reduced calcium signaling in a HEK-CASR stable cell line and in human normal parathyroid cells, mechanistically supporting our in vivo observations. The mouse model described here provides direct experimental support for the involvement of RGS5 in CASR signaling, PTH secretion, and neoplasia in parathyroid tissue. Further analysis of this model could reveal a novel mechanistic basis for hyperparathyroidism caused by inhibition of CASR signaling in the parathyroid gland.

Thyroid cancer investigations

Mapping of tumor heterogeneity and treatment resistance in anaplastic thyroid cancer

Anaplastic thyroid cancers (ATCs) are rare, deadly, and respond poorly to current treatment regimens. Single-agent, phase II clinical trials in ATC patients have shown encouraging responses. Most responses, however, were temporary and patients succumbed to disease progression. This limited response is likely attributable to intratumoral heterogeneity (ITH), which allows for clonal expansion and disease progression of untargeted, tumor sub-clones during therapeutic intervention. In contrast, multi-agent regimens that possibly target different tumor regions with unique mutation profiles may provide a therapeutic advantage. We and others have identified driver mutations associated with anaplastic conversion and many of these mutations are also druggable. However, these studies have relied predominantly on single sample genetic analysis and it remains uncertain how and to what extent these targetable mutations are represented and/or vary across the entire ATC intratumoral landscape. While specific data is lacking, anaplastic conversion and ITH likely results in formation of multiple druggable targets per tumor. This research project utilizes innovative approaches of characterizing tumor heterogeneity and druggable target distribution in ATC tumors using multi-regional next generation sequencing technology. The research is supported by a grant American Association of Endocrine Surgeons.

Credentialling human polymerase theta (POLQ) as a therapeutic target in ATC

Anaplastic thyroid cancer (ATC) is a highly aggressive thyroid cancer with an extremely poor prognosis and limited treatment options. In this project we are credentially human DNA polymerase theta (POLQ) as a therapeutic target. In ATCs that are DNA repair deficient, POLQ inhibition has the potential to cause synthetic lethality or sickness when used in combination with established thyroid cancer therapies that target DNA replication and repair, including chemotherapies (doxorubicin and carboplatin) and external beam radiation (EBRT). POLQ inhibitors are currently under development by several biotechnology companies and novobiocin (NVB) was recently identified as a potent and specific inhibitor of POLQ, highlighting the translational relevance of this research project. The results of this project will also have significant translational implications for other aggressive and treatment-resistant types of thyroid cancers. The research is supported by a grant from the American Association of Endocrine Surgeons.

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