A review of mitotane in the management of adrenocortical cancer.

IMPORTANCE: Mitotane (Lysodren, o,p'-DDD [1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane)] is currently the only United States Food and Drug Administration and European Medicines Agency-approved product for the treatment of adrenocortical carcinoma. OBSERVATIONS: Mitotane is challenging to administer; however, its toxicities (specifically adrenal insufficiency) are well known, and the management of adverse consequences has established approaches. While often viewed through the prism of a cytotoxic agent, it can also interfere with hormone production making it a valuable asset in managing functional ACC. A recently completed prospective trial has shed some light on its use in the adjuvant setting, but further clarity is needed. Many think mitotane has a role in the advanced or metastatic setting, although prospective data are lacking and retrospective analyses are often difficult to interpret. CONCLUSIONS AND RELEVANCE: When used carefully and thoughtfully, especially in patients with hormonal excess, mitotane is an important component of the treatment armamentarium for ACC.

FSCN1 as a new druggable target in adrenocortical carcinoma.

Adrenocortical 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 ß-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.

American Association of Clinical Endocrinology Disease State Clinical Review on the Evaluation and Management of Adrenocortical Carcinoma in an Adult: a Practical Approach.

OBJECTIVE: The aim of this Disease State Clinical Review is to provide a practical approach to patients with newly diagnosed adrenocortical carcinoma, as well as to follow-up and management of patients with persistent or recurrent disease. METHODS: This is a case-based clinical review. The provided recommendations are based on evidence available from randomized prospective clinical studies, cohort studies, cross-sectional and case-based studies, and expert opinions. RESULTS: Adrenocortical carcinoma is a rare malignancy, often with poor outcomes. For any patient with an adrenal mass suspicious for adrenocortical carcinoma, the approach should include prompt evaluation with detailed history and physical exam, imaging, and biochemical adrenal hormone assessment. In addition to adrenal-focused imaging, patients should be evaluated with chest-abdomen-pelvis cross-sectional imaging to define the initial therapy plan. Patients with potentially resectable disease limited to the adrenal gland should undergo en bloc open surgery by an expert surgeon. For patients presenting with advanced or recurrent disease, a multidisciplinary approach considering curative repeat surgery, local control with surgery, radiation therapy or radiofrequency ablation, or systemic therapy with mitotane and/or cytotoxic chemotherapy is recommended. CONCLUSION: As most health care providers will rarely encounter a patient with adrenocortical carcinoma, we recommend that patients with suspected adrenocortical carcinoma be evaluated by an expert multidisciplinary team which includes clinicians with expertise in adrenal tumors, including endocrinologists, oncologists, surgeons, radiation oncologists, pathologists, geneticists, and radiologists. We recommend that patients in remote locations be followed by the local health care provider in collaboration with a multidisciplinary team at an expert adrenal tumor program. ABBREVIATIONS: ACC = adrenocortical carcinoma; ACTH = adrenocorticotropic hormone; BRACC = borderline resectable adrenocortical carcinoma; CT = computed tomography; DHEAS = dehydroepiandrosterone sulfate; EDP = etoposide, doxorubicin, cisplatin; FDG = 18F-fluorodeoxyglucose; FNA = fine-needle aspiration; HU = Hounsfield units; IVC = inferior vena cava; LFS = Li-Fraumeni syndrome; MEN1 = multiple endocrine neoplasia type 1; MRI = magnetic resonance imaging; OAC = oncocytic adrenocortical carcinoma; PC = palliative care; PET = positron emission tomography.

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.

Short term effects of intraarticular triamcinolone acetonide injection on serum testosterone, luteinizing hormone, and follicle stimulating hormone levels in male veterans: A prospective pilot study.

BACKGROUND: Despite the common practice of intraarticular corticosteroid injections (ICSIs) for peripheral joint disease, little is known about their systemic effects on the hypothalamic-pituitary-gonadal axis. OBJECTIVE: To assess the short-term effects of ICSIs on serum testosterone (T), luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels together with changes in Shoulder Pain and Disability Index (SPADI) scores in a veteran population. DESIGN: Prospective pilot study. SETTING: Outpatient musculoskeletal clinic. PARTICIPANTS: Thirty male veterans, median age 50 (range 30-69) years. INTERVENTIONS: Ultrasound-guided glenohumeral joint injection using 3 mL of 1% lidocaine HCl and 1 mL of 40 mg triamcinolone acetonide (Kenalog). OUTCOME MEASURE(S): Serum T, FSH, and LH levels, Quantitative Androgen Deficiency in the Aging Male (qADAM), and SPADI questionnaires at baseline, 1, and 4 week(s) post procedure. RESULTS: At 1 week post injection, serum T levels decreased by 56.8 ng/dL (95% confidence interval (CI): 91.8, 21.7, p = .002) compared with baseline. Between 1 and 4 weeks post injection, serum T levels increased by 63.9 ng/dL (95% CI: 26.5, 101.2, p = .001), recovering to near baseline levels. SPADI scores were reduced at 1 week (-18.3, 95% CI: -24.4, -12.1, p < .001) and 4 weeks (-14.5, 95% CI -21.1, -7.9, p < .001). CONCLUSIONS: A single ICSI can temporarily suppress the male gonadal axis. Future studies are needed to evaluate for long-term effects of multiple injections at a single setting and/or higher corticosteroid doses on male reproductive axis function.

Novel repurposing of sulfasalazine for the treatment of adrenocortical carcinomas, probably through the SLC7A11/xCT-hsa-miR-92a-3p-OIP5-AS1 network pathway.

BACKGROUND: Recent multigenomic analysis of adrenocortical carcinomas (ACCs) identified SLC7A11/xCT as a novel biomarker. The Food and Drug Administration-approved anti-inflammatory drug, sulfasalazine (SAS), induces ferroptosis by blocking SLC7A11 expression. We hypothesize that SAS could be repurposed to target ACC cells. METHODS: Expression of SLC7A11 and its association with ACC survival was analyzed using Gene Expression Profiling Interactive Analysis (GEPIA). The validated ACC cell lines NCI-H295R, ACC1, and ACC2 were grown in 2D culture. In vitro studies included the CellTiter-Glo assay to calculate viability, Western blot (WB) analysis for apoptosis and other target protein changes, reverse transcriptase polymerase chain reaction for steroidogenic enzyme changes, C11BODIPY for lipid peroxidation, and mass spectrometry for changes in lipids. RESULTS: The Cancer Genome Atlas Program database analysis in GEPIA showed that SLC7A11 and linked long noncoding RNA OAP5-AS1 are highly expressed in ACC tumors versus normal adrenals (n = 77 vs 128; P < .05). This was associated with poor overall and disease-free survival with hazard ratios of 4.3 and 5.2 for SLC7A11 and 4.8 and 2.7 for OAP5-AS1, respectively. ACC cell line half-inhibitory maximum concentration values after 72-hour SAS treatment ranged from 412 nM (ACC1) to 799 nM (ACC2), and all showed cleavage of poly (ADP-ribose) polymerase, upregulation of p-Akt and p-ERK, and downregulation of GPX4 and SLC7A11 (P < .05) by WB analysis. Sphere formation, migration, and invasion assay showed inhibition, and lipid peroxidation using C11BODIPY, increase in intracellular iron, induction of oxidative stress, and significant upregulation of oxidized polyunsaturated fatty acid phospholipids (P < .05 each) by mass spectrometry suggests induction of ferroptosis. CONCLUSION: SAS downregulates tSLC7A11 in ACCs, targets the Akt/ERK pathway and lipid metabolism, and induces cell death in vitro, warranting additional translational studies to define its therapeutic potential in ACC.

E-cadherin expression and gene expression profiles in corticotroph pituitary neuroendocrine tumor subtypes.

Corticotroph adenomas/pituitary neuroendocrine tumors (PitNETs) are associated with significant morbidity and mortality. Predictors of tumor behavior have not shown high prognostic accuracy. For somatotroph adenomas/PitNETs, E-cadherin expression correlates strongly with prognosis. E-cadherin expression has not been investigated in other PitNETs. A retrospective chart review of adults with corticotroph adenomas/PitNETs was conducted to assess correlation between E-cadherin expression and tumor characteristics. In addition, gene expression microarray was performed in subset of tumors (n = 16). Seventy-seven patients were identified; 71% were female, with median age of cohort 45.2 years. Seventy-five percent had macroadenomas, of which 22% were hormonally active. Ninety-five percent of microadenomas were hormonally active. Adrenocorticotropic hormone granulation pattern by IHC identified 63% as densely granulated (DG) and 34% as sparsely granulated (SG). All microadenomas were DG (p < .001); 50% of macroadenomas were DG associated with increased tumor invasion compared to SG. E-cadherin IHC was positive in 80%, diminished in 17%, and absent in 20% and did not correlate with corticotroph PitNETs subtype, size, or prognosis. In contrast to the distinct transcriptomes of corticotroph PitNETs and normal pituitaries, a comparison of clinically active and silent corticotroph PitNETs demonstrated similar molecular signatures indicating their common origin, but with unique differences related to their secretory status.

PLK1 inhibitors as a new targeted treatment for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. Polo-like kinase 1 (PLK1) is a promising drug target; PLK1 inhibitors (PLK1i) have been investigated in solid cancers and are more effective in TP53-mutated cases. We evaluated PLK1 expression in ACC samples and the efficacy of two PLK1i in ACC cell lines with different genetic backgrounds. PLK1 protein expression was investigated by immunohistochemistry in tissue samples and correlated with clinical data. The efficacy of rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53 wild-type CU-ACC1. Effects on proliferation, apoptosis, and viability were determined. PLK1 immunostaining was stronger in TP53-mutated ACC samples vs wild-type (P = 0.0017). High PLK1 expression together with TP53 mutations correlated with shorter progression-free survival (P= 0.041). NCI-H295R showed a time- and dose-dependent reduction in proliferation with both PLK1i (P< 0.05at 100 nM RGS and 30 µM Pol). In MUC-1, a less pronounced decrease was observed (P< 0.05at 1000 nM RGS and 100 µM Pol). 100 nM RGS increased apoptosis in NCI-H295R (P< 0.001), with no effect on MUC-1. CU-ACC2 apoptosis was induced only at high concentrations (P < 0.05 at 3000 nM RGS and 100 µM Pol), while proliferation decreased at 1000 nM RGS and 30 µM Pol. CU-ACC1 proliferation reduced, and apoptosis increased, only at 100 µM Pol. TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.

A Database Tool Integrating Genomic and Pharmacologic Data from Adrenocortical Carcinoma Cell Lines, PDX, and Patient Samples.

Adrenocortical carcinoma (ACC) is a rare and highly heterogeneous disease with a notably poor prognosis due to significant challenges in diagnosis and treatment. Emphasizing on the importance of precision medicine, there is an increasing need for comprehensive genomic resources alongside well-developed experimental models to devise personalized therapeutic strategies. We present ACC_CellMinerCDB, a substantive genomic and drug sensitivity database (available at https://discover.nci.nih.gov/acc_cellminercdb) comprising ACC cell lines, patient-derived xenografts, surgical samples, and responses to more than 2,400 drugs examined by the NCI and National Center for Advancing Translational Sciences. This database exposes shared genomic pathways among ACC cell lines and surgical samples, thus authenticating the cell lines as research models. It also allows exploration of pertinent treatment markers such as MDR-1, SOAT1, MGMT, MMR, and SLFN11 and introduces the potential to repurpose agents like temozolomide for ACC therapy. ACC_CellMinerCDB provides the foundation for exploring larger preclinical ACC models. SIGNIFICANCE: ACC_CellMinerCDB, a comprehensive database of cell lines, patient-derived xenografts, surgical samples, and drug responses, reveals shared genomic pathways and treatment-relevant markers in ACC. This resource offers insights into potential therapeutic targets and the opportunity to repurpose existing drugs for ACC therapy.

Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma.

Disruption of processes involved in tissue development and homeostatic self-renewal is increasingly implicated in cancer initiation, progression, and recurrence. The adrenal cortex is a dynamic tissue that undergoes life-long turnover. Here, using genetic fate mapping and murine adrenocortical carcinoma (ACC) models, we have identified a population of adrenocortical stem cells that express delta-like non-canonical Notch ligand 1 (DLK1). These cells are active during development, near dormant postnatally but are re-expressed in ACC. In a study of over 200 human ACC samples, we have shown DLK1 expression is ubiquitous and is an independent prognostic marker of recurrence-free survival. Paradoxically, despite its progenitor role, spatial transcriptomic analysis has identified DLK1 expressing cell populations to have increased steroidogenic potential in human ACC, a finding also observed in four human and one murine ACC cell lines. Finally, the cleavable DLK1 ectodomain is measurable in patients' serum and can discriminate between ACC and other adrenal pathologies with high sensitivity and specificity to aid in diagnosis and follow-up of ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, detail its hierarchical expression in homeostasis and oncogenic transformation and propose a role for its use as a biomarker in this malignancy.

In Situ Spatial Reconstruction of Distinct Normal and Pathological Cell Populations Within the Human Adrenal Gland.

The human adrenal gland consists of concentrically organized, functionally distinct regions responsible for hormone production. Dysregulation of adrenocortical cell differentiation alters the proportion and organization of the functional zones of the adrenal cortex leading to disease. Current models of adrenocortical cell differentiation are based on mouse studies, but there are known organizational and functional differences between human and mouse adrenal glands. This study aimed to investigate the centripetal differentiation model in the human adrenal cortex and characterize aldosterone-producing micronodules (APMs) to better understand adrenal diseases such as primary aldosteronism. We applied spatially resolved in situ transcriptomics to human adrenal tissue sections from 2 individuals and identified distinct cell populations and their positional relationships. The results supported the centripetal differentiation model in humans, with cells progressing from the outer capsule to the zona glomerulosa, zona fasciculata, and zona reticularis. Additionally, we characterized 2 APMs in a 72-year-old woman. Comparison with earlier APM transcriptomes indicated a subset of core genes, but also heterogeneity between APMs. The findings contribute to our understanding of normal and pathological cellular differentiation in the human adrenal cortex.

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.

Senescence-induced immune remodeling facilitates metastatic adrenal cancer in a sex-dimorphic manner.

Aging markedly increases cancer risk, yet our mechanistic understanding of how aging influences cancer initiation is limited. Here we demonstrate that the loss of ZNRF3, an inhibitor of Wnt signaling that is frequently mutated in adrenocortical carcinoma, leads to the induction of cellular senescence that remodels the tissue microenvironment and ultimately permits metastatic adrenal cancer in old animals. The effects are sexually dimorphic, with males exhibiting earlier senescence activation and a greater innate immune response, driven in part by androgens, resulting in high myeloid cell accumulation and lower incidence of malignancy. Conversely, females present a dampened immune response and increased susceptibility to metastatic cancer. Senescence-recruited myeloid cells become depleted as tumors progress, which is recapitulated in patients in whom a low myeloid signature is associated with worse outcomes. Our study uncovers a role for myeloid cells in restraining adrenal cancer with substantial prognostic value and provides a model for interrogating pleiotropic effects of cellular senescence in cancer.

Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function.

GnRH neurons follow a carefully orchestrated journey from their birth in the olfactory placode area. Initially, they migrate along with the vomeronasal nerve into the brain at the cribriform plate, then progress caudally to sites within the hypothalamus where they halt and send projections to the median eminence to activate pituitary gonadotropes. Many factors controlling this precise journey have been elucidated by the silencing or over-expression of candidate genes in mouse models. Importantly, a number of these factors may not only play a role in normal physiology of the hypothalamic-pituitary-gonadal axis but also be mis-expressed to cause human disorders of GnRH deficiency, presenting as a failure to undergo normal pubertal development. This review outlines the current cadre of candidates thought to modulate GnRH neuronal migration. The further elucidation and characterization of these factors that impact GnRH neuron development may shed new light on human reproductive disorders and provide potential targets to develop new pro-fertility or contraceptive agents.

Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer.

BACKGROUND: The objective of this study was to document the differences in testosterone (T) levels between crizotinib-treated and noncrizotinib-treated patients with metastatic nonsmall cell lung cancer (NSCLC). METHODS: Testosterone levels were measured in 19 men with metastatic NSCLC who received crizotinib and in 19 men with metastatic NSCLC who did not receive crizotinib. Clinical characteristics of the patients were compared, and additional hormone assays were performed as appropriate. Two patients who began crizotinib and 4 patients who had dose interruptions or who stopped crizotinib therapy had serial hormone measurements, permitting the documentation of dynamic hormone changes on and off crizotinib treatment. RESULTS: Total T levels were low (<241 ng/dL) in 19 of 19 (100%) crizotinib-treated men and in 6 of 19 men (32%) with metastatic NSCLC who did not receive crizotinib (mean T levels, 131 ng/dL and 311 ng/dL, respectively; P = .0002). Only 1 in 5 patients who had anaplastic lymphoma kinase (ALK) gene rearrangements and had not yet received crizotinib had low T. The initiation of crizotinib in 2 patients who had previously normal T levels was associated with a rapid decreases in T and in luteinizing hormone and follicle stimulating hormone levels within 14 to 21 days. Discontinuation of crizotinib led to increases back to normal T levels. CONCLUSIONS: Crizotinib therapy caused rapid suppression of T levels in men. The current results indicated that the site of action must include a central (hypothalamic or pituitary) effect, but additional direct testicular effects could not be excluded. Further work is required to assess the correlation between low T levels and crizotinib side effects as well as the exact molecular mechanism and site of drug toxicity.

Should Dehydroepiandrosterone Be Administered to Women?

CONTEXT: Androgen prohormones such as dehydroepiandrosterone (DHEA) increase in early puberty, peak in the second and third decade, and thereafter decline, independent of menopausal status. Investigators have examined their potential beneficial effects in normal women and those with DHEA-deficient states. EVIDENCE ACQUISITION: A review of the literature from 1985 to 2021 on the potential benefits and risks of androgen prohormones in women. EVIDENCE SYNTHESIS: Studies have examined the potential benefit of DHEA therapy for anti-aging, sexual dysfunction, infertility, metabolic bone health, cognition, and wellbeing in hormone-deficient states such as primary adrenal insufficiency, hypopituitarism, and anorexia as well as administration to normal women across the lifespan. CONCLUSIONS: Data support small benefits in quality of life and mood but not for anxiety or sexual function in women with primary or secondary adrenal insufficiency or anorexia. No consistent beneficial effects of DHEA administration have been observed for menopausal symptoms, sexual function, cognition, or overall wellbeing in normal women. Local administration of DHEA shows benefit in vulvovaginal atrophy. Use of DHEA to improve induction of ovulation response in women with diminished ovarian reserve is not recommended. Risks of high physiologic or pharmacologic use of DHEA include androgenic and estrogenic side effects which are of concern for long-term administration. CLINICAL CASE: A 49-year-old woman with Addison's disease who is on low dose estrogen with cyclic progesterone therapy for menopausal symptoms returns for follow-up. She is on a stable glucocorticoid replacement strategy of hydrocortisone 10 mg in the morning and 5 mg in the early afternoon and fludrocortisone 0.05 mg each morning. She has read on the internet that additional therapy with DHEA may help her overall quality of life and libido. She asks whether she should add this therapy to her regimen and at what dose.

Pathological and Genetic Stratification for Management of Adrenocortical Carcinoma.

CONTEXT: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that affects patients across the age spectrum. Although the overall survival in patients with ACC is poor, there is significant heterogeneity in terms of outcomes, presentation, and underlying genetic drivers. EVIDENCE ACQUISITION: This review is based on the evidence collected from primary research studies, expert reviews, and published guidelines. The studies were identified through PubMed search with key words "adrenocortical carcinoma," "prognosis," "pathology," and "genetics." The PubMed search was complemented by authors' expertise, research, and clinical experience in the field of ACC. EVIDENCE SYNTHESIS: Identification of biomarkers has been critical to gain better insight into tumor behavior and to guide therapeutic approach to patients. Tumor stage, resection status, and Ki67 are pathological tumor characteristics that have been identified as prognosticators in patients with ACC. Cortisol excess also correlates with worse prognosis. Clinical and histopathological characteristics help stratify patient outcomes, yet still up to 25% of patients have a different outcome than predicted. To bridge this gap, comprehensive genomic profiling studies have characterized additional profiles that correlate with clinical outcomes. In addition, studies of clinically applicable molecular markers are under way to further stratify outcomes in patients with ACC tumors. CONCLUSIONS: Clinical predictors in combination with pathological markers play a critical role in the approach to patients with ACC. Recent advances in genetic prognosticators will help extend the stratification of these tumors and contribute to a personalized therapeutic approach to patients with ACC.

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.

Mastermind Like Transcriptional Coactivator 3 (MAML3) Drives Neuroendocrine Tumor Progression.

Metastatic disease in pheochromocytomas and paragangliomas (PCC/PGL) is not well-understood. The Cancer Genome Atlas discovered recurrent MAML3 fusion genes in a subset of tumors that lacked known germline or somatic driver mutations and were associated with aggressive disease. Here, we aimed to investigate the role of MAML3 in tumorigenesis. Human PCC/PGLs were used for IHC and genetic analysis. Three neuroendocrine tumor cell lines, SK-N-SH, QGP-1, and BON-1, were transiently transfected with MAML3 (FL) or exon 1 deleted MAML3 (dEx1; mimicking the fusion), and biologic effects of overexpression were examined in vitro. We found 7% (4/55) of human PCC/PGL have UBTF∼MAML3 fusions and all were sporadic cases with metastatic disease. Fusion-positive tumors had intense MAML3 nuclear staining and increased ß-catenin by IHC and showed increased WNT4 expression. In vitro, overexpression of FL and dEx1 MAML3 increased invasion in SK-N-SH, QGP-1, and BON-1 (all P < 0.05) and increased soft-agar colony formation in QGP-1 and BON-1 (all P < 0.05). Cotransfection with FL or dEx1 MAML3 and ß-catenin increased TCF/LEF promoter activation by luciferase activity and coimmunoprecipitation confirmed interaction between MAML3 and ß-catenin. These data suggest MAML3 is involved in WNT signaling pathway activation. In summary, UBTF∼MAML3 fusions are present in a subset of PCC/PGL and associated with metastatic disease without other known drivers. MAML3 overexpression led to increased tumorigenicity in neuroendocrine tumor cells and the mechanism of action may involve WNT signaling pathways. IMPLICATIONS: MAML3 increases tumorigenicity and invasion in neuroendocrine tumor cells and may be a prognostic marker for aggressive disease.