Making Progress: Breakthroughs in Adrenocortical Carcinoma

With a brutal five-year survival rate below 40%, adrenocortical carcinoma is not only rare, it is also somewhat misunderstood. New research may shed light on this condition and even provide a path to future treatment options.

Adrenocortical carcinoma (ACC) is an aggressive orphan malignancy that confers a less than 35% survival rate at five years. In addition to its aggressiveness, up to 60% of ACC is associated with hormonal access, with patients presenting with Cushing syndrome (hypercortisolism), Conn syndrome (hyperaldosteronism), or virilization in women (androgen excess). Many patients present late and with metastatic disease, which contributes to poor survival. Surgical resection is first-line therapy, but many tumors are unresectable or recur. Other treatments for ACC have been shown to have minimal benefit, ACC being a devastating diagnosis.

Although it is rare (with an incidence of 0.7–2.0 cases/million habitants/year), in 2013, four patients with ACC were seen at the University of Colorado Hospital’s CU Cancer Center in Denver, providing clinicians and researchers with an unusual opportunity to gain insight into the disease. They were seeking treatment by a multidisciplinary team led by Margaret E. Wierman, MD, and Stephen Leong, MD, co-directors of an Adrenal Neoplasm Program forging new territory in the field. Katja Kiseljak-Vassiliades, DO, had joined Wierman’s lab as a fellow, to explore mechanisms of endocrine tumorigenesis, which has been her interest since early in medical training. “The mechanisms of endocrine tumorigenesis seem to be different than those of classic human malignancies,” she explains. “In pituitary tumors, for example, some of the molecular mechanisms that we see even in advanced malignancy are present, such as epithelial mesenchymal transition, although these tumors never metastasize. So, I think we can learn from these indolent tumors and inform common human malignancies by understanding what the differences are and, with the most aggressive tumors, such as adrenocortical carcinoma and anaplastic thyroid carcinoma, how the molecular signature affects cancer growth and prognosis.”

Preclinical Models Move the Field Forward

When the four patients with ACC presented to the clinic, Kiseljak-Vassiliades says, “we quickly realized that there were no good treatments for these patients. Our team examined what kind of preclinical models and research were available in adrenal cancer. However, progress was slow because preclinical models were scarce, with no animal models available.” The team at CU started treating the patients with mitotane, an insecticide-based adrenolytic and currently the only FDA-approved drug for adrenal cancer, and communicated with other adrenal cancer experts around the country, including Gary Hammer, MD, at the University of Michigan Rogel Cancer Center in Ann Arbor and Mouhammed Habra, MD, FACP, FACE, from the MD Anderson Cancer Center, in Houston, Texas, to establish an effective clinical protocol.

“I think we can learn from these indolent tumors and inform common human malignancies by understanding what the differences are and, with the most aggressive tumors, such as adrenocortical carcinoma and anaplastic thyroid carcinoma, how the molecular signature affects cancer growth and prognosis.” – Katja Kiseljak-Vassiliades, DO, University of Colorado Hospital, CU Cancer Center, Denver

The real breakthrough came when the team collaborated with the gastrointestinal (GI) tumor group including Stephen Leong, MD, and Todd Pitts, MD at University of Colorado, who had developed patient-derived xenografts (PDXs) in colorectal cancer and advised the endocrine team to develop similar models for adrenal cancer. The CU adrenal tumor team’s two 2018 studies, “Development of new preclinical models to advance adrenocortical carcinoma research,” published in Endocrine-Related Cancer, and “Elucidating the Role of the Maternal Embryonic Leucine Zipper Kinase in Adrenocortical Carcinoma,” published in Endocrinology, show how the first two ACC cell lines (CU-ACC1 and CU-ACC2) and two corresponding mouse models of the disease can be used to identify and target potential tumorigenic pathways underlying ACC.

Although attempts at preclinical models had been made before, they were unsuccessful, largely because the animals could not survive the accompanying steroid hormone production when tumors were implanted. Kiseljak-Vassiliades and Adwitiya Kar, PhD, a postdoctoral fellow in the lab, in collaboration with their endocrine surgeons, Christopher Raeburn, MD, and Maria Albuja-Cruz, MD, have been able to implant a variety of ACC tumors “This is a big step for the field,” Kiseljak-Vassiliades says. “One of the things that we have really championed here is the technique to create PDXs, which the GI colorectal group has refined.”

Got MELK?

Now that the models are available, novel therapies can be sought. “One of the biggest deficiencies in the field right now is lack of targeted therapy. All the therapies used in other cancers that have been tried in ACC have not been very successful in patients, and so our focus has been to find new druggable targets,” Kiseljak-Vassiliades says. The team started with identifying the kinases in ACC that have previously shown to have moderate success on other human malignancies. Because most ACC are not associated with targetable genetic mutations, they reasoned that pinpointing problems in the DNA damage response pathway could lead to effective ACC treatment. Analyzing publicly available expression data sets, they found that maternal embryonic leucine zipper kinase (MELK) was one of the most upregulated kinases in adrenal cancer compared to normal tissue. Then, using their newly developed ACC tumor cell lines, they demonstrated that the MELK inhibitor OTSSP167 suppressed tumor growth. Though exciting, still to be tested is what additional therapy should be used along with a MELK inhibitor, as most kinase inhibitors develop resistance eventually, according to Kiseljak-Vassiliades. The team has studies underway to evaluate OTSSP167 more closely and determine what off-target effects it might have along with what other kinases it inhibits. “A single arm kinase inhibitor is probably not going to be the answer,” Kiseljak-Vassiliades says, “but it might be something that is going to prolong the patient’s life as we are currently trying to find new and better targets.”

“The field is getting excited about these new preclinical models because, for the first time, we can test new drugs and new compounds in preclinical models before going to phase I studies in humans.” – Katja Kiseljak-Vassiliades, DO, University of Colorado Hospital, CU Cancer Center, Denver

OTSSP167 is now in phase I studies in solid tumors (mostly breast), and, on the basis of preclinical in vivo data not yet published, the team hopes to move the drug into phase II studies in patients with adrenal cancer once the phase I studies are completed. “Whether giving patients MELK inhibitor would potentially change their outcome or decrease the tumor burden to get them to surgery, is a question we hope to address,” Kiseljak-Vassiliades says. “When we studied OTSSP167 in mice, it showed a very modest decrease in tumor size and seemed rather to prevent tumors from progressing.”

Humanized Mouse Model

There’s more. A third study the team presented at ENDO 2018 and soon to be submitted for publication details the development of another novel preclinical model in a mouse that has a human immune system derived from cord blood–derived hematopoietic stem cells. The team treated the mouse with either control or immunotherapy with the PD-1 blocking antibody pembrolizumab. The mice receiving the treatment showed significantly lower tumor volume than the control group. The researchers simultaneously treated the ACC patient that the PDX was derived from with immunotherapy, and the patient has had a lasting response with 79% tumor reduction — many metastases disappeared, most of them shrank significantly, and the patient has had no progression or new metastases in the last 18 months.

Call to Arms

“The field is getting excited about these new preclinical models because, for the first time, we can test new drugs and new compounds in preclinical models before going to phase I studies in humans,” Kiseljak-Vassiliades says. “It is important to test a drug — even mitotane, that has been approved for patients, should be retested in preclinical models to study its mechanism further and identify which tumor types it would be most efficacious against. Although these studies are moving the field along, the field itself is very behind those of some of the common human malignancies. To make progress, it takes effort and multisite collaboration as well as additional research funding for this orphan endocrine cancer.”

-Horvath is a freelance writer in Baltimore, Md., and a frequent Endocrine News contributor. She wrote about the link between obesity and breastfeeding in the October issue.

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