Contemporary preclinical human models of adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is an uncommon and heterogeneous disease and may present differently in children and adults. Management of ACC is dependent on disease stage and complete surgical resection is the only potentially curative treatment. The first and most extensively used adrenocortical cancer cell line, as model system to examine mechanisms controlling normal and pathologic function of adrenal cortex, was initially isolated in 1980. Although NCI-H295 maintained steroid capabilities and adrenocortical characteristics, the lack of new cell lines and animal models of ACC has hampered the progress and development of new therapies. In this review we provide description of cellular and patient-derived tumor xenograft (PDTX) models of ACC generated for the elucidation of the underlying pathogenic mechanisms and preclinical functional studies for this aggressive disease

Physicians' awareness of gadolinium retention and MRI timing practices in the longitudinal management of pituitary tumors::a "Pituitary Society" survey

PURPOSE: In view of mounting attention related to possible brain retention of gadolinium-based contrast agents (GBCAs) in patients with normal renal function, our purpose was to detail results from a survey of pituitary experts to assess: 1) the timing interval and frequency of pituitary magnetic resonance imaging (MRI) following surgical and/or medical and/or radiation therapy of pituitary tumors, 2) awareness of the types of GBCAs used and their possible safety issues. METHODS: The Pituitary Society Education Committee composed a survey with 12 multiple choice questions, 8 of which specifically addressed the time interval and frequency of MRI in the longitudinal management of pituitary tumors. The survey was distributed at two meetings; the International Pituitary Neurosurgeons Society conference in San Diego, CA, on February 18th, 2018, and the Pituitary Society Membership and Career Development Forum, Chicago, IL on March 18th, 2018. RESULTS: There is consensus among pituitary endocrinologists and neurosurgeons that long-term repeated imaging is recommended in most pituitary tumors, although the precise strategy of timing varied depending on the specialist group and the specific clinical context of the adenoma. The data also suggest that International Pituitary Neurosurgeons Society neurosurgeons, as well as Pituitary Society neuroendocrinologists, are sometimes unaware of which contrast agents are used by their institution, and many are also unaware that evidence of long-term brain retention has been reported with the use of GBCAs in patients with normal function. CONCLUSIONS: International pituitary endocrinologists and pituitary neurosurgeons experts suggest ongoing MRIs for the management of pituitary tumors; strategies vary based on clinical context, but also on individual experience and practice

The Immunotherapy Landscape in Adrenocortical Cancer.

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland that is frequently associated with excess production of adrenal hormones. Although surgical resection may be curative in early-stage disease, few effective therapeutic options exist in the inoperable advanced or metastatic setting. Immunotherapies, inclusive of a broad array of immune-activating and immune-modulating antineoplastic agents, have demonstrated clinical benefit in a wide range of solid and hematologic malignancies. Due to the broad activity across multiple cancer types, there is significant interest in testing these agents in rare tumors, including ACC. Multiple clinical trials evaluating immunotherapies for the treatment of ACC have been conducted, and many more are ongoing or planned. Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies

Preclinical Models of Adrenocortical Cancer.

Adrenocortical cancer is an aggressive endocrine malignancy with an incidence of 0.72 to 1.02 per million people/year, and a very poor prognosis with a five-year survival rate of 22%. As an orphan disease, clinical data are scarce, meaning that drug development and mechanistic research depend especially on preclinical models. While a single human ACC cell line was available for the last three decades, over the last five years, many new in vitro and in vivo preclinical models have been generated. Herein, we review both in vitro (cell lines, spheroids, and organoids) and in vivo (xenograft and genetically engineered mouse) models. Striking leaps have been made in terms of the preclinical models of ACC, and there are now several modern models available publicly and in repositories for research in this area

Targeted genomic analysis of 364 adrenocortical carcinomas.

Despite recent advances in elucidating molecular pathways underlying adrenocortical carcinoma (ACC), this orphan malignancy is associated with poor survival. Identification of targetable genomic alterations is critical to improve outcomes. The objective of this study was to characterize the genomic profile of a large cohort of patient ACC samples to identify actionable genomic alterations. Three hundred sixty-four individual patient ACC tumors were analyzed. The median age of the cohort was 52 years and 60.9% (n = 222) were female. ACC samples had common alterations in epigenetic pathways with 38% of tumors carrying alterations in genes involved in histone modification, 21% in telomere lengthening, and 21% in SWI/SNF complex. Tumor suppressor genes and WNT signaling pathway were each mutated in 51% of tumors. Fifty (13.7%) ACC tumors had a genomic alteration in genes involved in the DNA mismatch repair (MMR) pathway with many tumors also displaying an unusually high number of mutations and a corresponding MMR mutation signature. In addition, genomic alterations in several genes not previously associated with ACC were observed, including IL7R, LRP1B, FRS2 mutated in 6, 8 and 4% of tumors, respectively. In total, 58.5% of ACC (n = 213) had at least one potentially actionable genomic alteration in 46 different genes. As more than half of ACC have one or more potentially actionable genomic alterations, this highlights the value of targeted sequencing for this orphan cancer with a poor prognosis. In addition, significant incidence of MMR gene alterations suggests that immunotherapy is a promising therapeutic for a considerable subset of ACC patients

FSCN1 as a new druggable target in adrenocortical carcinoma

International audienceAdrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high risk of relapse and metastatic spread. The actin‐bundling protein fascin (FSCN1) is overexpressed in aggressive ACC and represents a reliable prognostic indicator. FSCN1 has been shown to synergize with VAV2, a guanine nucleotide exchange factor for the Rho/Rac GTPase family, to enhance the invasion properties of ACC cancer cells. Based on those results, we investigated the effects of FSCN1 inactivation by CRISPR/Cas9 or pharmacological blockade on the invasive properties of ACC cells, both in vitro and in an in vivo metastatic ACC zebrafish model. Here, we showed that FSCN1 is a transcriptional target for β‐catenin in H295R ACC cells and that its inactivation resulted in defects in cell attachment and proliferation. FSCN1 knock‐out modulated the expression of genes involved in cytoskeleton dynamics and cell adhesion. When Steroidogenic Factor‐1 (SF‐1) dosage was upregulated in H295R cells, activating their invasive capacities, FSCN1 knock‐out reduced the number of filopodia, lamellipodia/ruffles and focal adhesions, while decreasing cell invasion in Matrigel. Similar effects were produced by the FSCN1 inhibitor G2‐044, which also diminished the invasion of other ACC cell lines expressing lower levels of FSCN1 than H295R. In the zebrafish model, metastases formation was significantly reduced in FSCN1 knock‐out cells and G2‐044 significantly reduced the number of metastases formed by ACC cells. Our results indicate that FSCN1 is a new druggable target for ACC and provide the rationale for future clinical trials with FSCN1 inhibitors in patients with ACC