The VEGF Inhibitor Axitinib Has Limited Effectiveness as a Therapy for Adrenocortical Cancer

O’Sullivan, Ciara C.; Edgerly, Maureen; Velarde, Margarita; Wilkerson, Julia; Venkatesan, Aradhana M.; Pittaluga, Stefania; Yang, Sherry X.; Nguyen, Dat; Balasubramaniam, Sanjeeve; Fojo, Tito

doi:10.1210/jc.2013-2298

Cited by 80 publications

(52 citation statements)

References 30 publications

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“…Two phase 2 trials analyzed the antitumor response to sunitinib or axitinib and reported no PR and median PFS of 83 days or 5 months in 35 or 13 pretreated patients with ACC, respectively. 90,115 In 2 additional phase 2 trials, combination of antiangiogenic agents with chemotherapy was investigated. In 1 study, bevacizumab plus capecitabine in 10 pretreated patients with ACC produced no PR and median PFS was 59 days.…”

Section: Molecular Targeted Therapiesmentioning

confidence: 99%

Adrenocortical Carcinoma

Baudin

2015

Endocrinology and Metabolism Clinics of North America

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Recent developments in the treatment of adrenocortical carcinoma (ACC) include diagnostic and prognostic risk stratification algorithms, increasing evidence of the impact of historical therapies on overall survival, and emerging targets from integrated epigenomic and genomic analyses. Advances include proper clinical and molecular characterization of all patients with ACC, standardization of proliferative index analyses, referral of these patients to large cancer referral centers at the time of first surgery, and development of new trials in patients with well-characterized ACC. Networking and progress in the molecular characterization of ACC constitute the basis for significant future therapeutic breakthroughs.

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Section: Molecular Targeted Therapiesmentioning

confidence: 99%

Adrenocortical Carcinoma

Baudin

2015

Endocrinology and Metabolism Clinics of North America

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“…Several studies have been undertaken with VEGFR inhibitors in patients with ACC (Table 5). Three phase II studies evaluated sorafenib in combination with paclitaxel, sunitinib or axitinib respectively , Kroiss et al 2012, O'Sullivan et al 2014). Sorafenib did not show an anti-tumor effect in patients, whereas sunitinib and axitinib showed a partial response in 14 and 62% of the patients respectively (Table 5).…”

Section: Future Directions and Pathway Driven Therapiesmentioning

confidence: 99%

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Creemers¹,

Hofland²,

Korpershoek³

et al. 2015

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

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“…Targeting of tumor vasculature has also attracted attention in ACC treatment as we and others have detected high expression of vascular endothelial growth factor (VEGF (VEGFA)) and its receptor VEGFR2 (KDR) in many ACC specimens (43,70,71,72). Among the VEGFtargeting drugs (58,73,74,75), the multi-TKI sunitinib has demonstrated modest anti-tumor effects in a phase II clinical trial. Of the 35 patients analyzed per protocol, five patients (14%) experienced stable disease, but no objective tumor response was observed (58).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

EJE PRIZE 2014: Current and evolving treatment options in adrenocortical carcinoma: where do we stand and where do we want to go?

Ronchi

Kroiß

Sbiera

et al. 2014

European Journal of Endocrinology

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Adrenocortical carcinoma (ACC) is not only a rare and heterogeneous disease but also one of the most aggressive endocrine tumors. Despite significant advances in the last decade, its pathogenesis is still only incompletely understood and overall therapeutic means are unsatisfactory. Herein, we provide our personal view of the currently available treatment options and suggest the following research efforts that we consider timely and necessary to improve therapy: i) for better outcome in localized ACCs, surgery should be restricted to experienced centers, which should then collaborate closely to address the key surgical questions (e.g. best approach and extent of surgery) in a multicenter manner. ii) For the development of better systemic therapies, it is crucial to elucidate the exact molecular mechanisms of action of mitotane. iii) A prospective trial is needed to address the role of cytotoxic drugs in the adjuvant setting in aggressive ACCs (e.g. mitotane vs mitotaneC cisplatin). iv) For metastatic ACCs, new regimens should be investigated as first-line therapy. v) Several other issues (e.g. the role of radiotherapy and salvage therapies) might be answered -at least in a first step -by large retrospective multicenter studies. In conclusion, although it is unrealistic to expect that the majority of ACCs can be cured within the next decade, international collaborative efforts (including multiple translational and clinical studies) should allow significant improvement of clinical outcome of this disease. To this end, it might be reasonable to expand the European Network for the Study of Adrenal Tumors (ENSAT) to a truly worldwide international network -INSAT.

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The VEGF Inhibitor Axitinib Has Limited Effectiveness as a Therapy for Adrenocortical Cancer

Cited by 80 publications

References 30 publications

Adrenocortical Carcinoma

Adrenocortical Carcinoma

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

EJE PRIZE 2014: Current and evolving treatment options in adrenocortical carcinoma: where do we stand and where do we want to go?

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