Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma

Abou‐Alfa, Ghassan K.; Mayer, Robert J.; Venook, Alan P.; O’Neill, Allison F.; Beg, Muhammad Shaalan; LaQuaglia, Michael P.; Kingham, Peter; Kobos, Rachel; Baştürk, Olca; Brennan, Cameron; Yopp, Adam C.; Harding, James J.; Leong, Stephen; Crown, John; Hoti, Emir; Leonard, Gregory D.; Ly, Michele; Bradley, Mikaela; Valentino, Emily; Markowitz, David; Zukiwski, Alexander; Ren, Ken; Gordan, John D.

doi:10.1634/theoncologist.2020-0093

Cited by 31 publications

(22 citation statements)

References 15 publications

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“…ENMD-2076 shows antitumor activity in colorectal cancer [154], multiple myeloma [156] and triple-negative breast cancer [157,158] both in vitro and in vivo. Due to the potent inhibitory effects of ENMD-2076 on cancer cells and xenografts, several phase I/II clinical trials on this compound have been conducted in solid tumors and hematologic malignancies [113][114][115][116][117][118][119] (Table 4). Table 1 and Table 2.…”

Section: Specific Akismentioning

confidence: 99%

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

et al. 2021

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Aurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

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Section: Specific Akismentioning

confidence: 99%

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

et al. 2021

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“…29 Targeting AURKA currently is underway in a recent study evaluating ENMD-2076 with selective activities against Aurora kinases 30 that recently was reported, disappointingly, as negative. 31 Riehle et al examined mTOR pathway activation in 23 samples of FLC. Phosphorylated S6 ribosomal protein (P-S6), a downstream target of mTORC1, and fibroblast growth factor receptor 1 (FGFR1) demonstrated strong staining activity on the tissue microarray.…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver

Dika

Bowman

Berger

et al. 2020

Cancer

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Background Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in‐frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets. Methods Archival fresh, formalin‐fixed, paraffin‐embedded samples from patients with FLC who prospectively consented to an institutional review board–approved protocol were analyzed using Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT), a next‐generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA‐Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations. Results A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1‐PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK‐IMPACT did not detect the fusion, its presence was confirmed by targeted RNA‐Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6‐153 months). The 3‐year overall survival rate was 84% (95% CI, 61%‐93%). Conclusions The DNAJB1‐PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1‐PRKACA fusion transcript or any therapeutic target identified from next‐generation sequencing in patients with FLC.

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“… 102 Moreover, aurora kinase A inhibitors had a limited antitumour effect in a phase II clinical trial. 103 Shutdown of the PRKCA pathway and targeting the DNABJ1-PRKACA fusion is an appealing therapeutic avenue. While several therapeutic options have been proposed in FLC, such as inhibitors of the kinase pocket of the fusion protein or the combination of Hsp70 and MEK inhibitor, 104 , 105 currently no efficient targeted therapy has been validated.…”

Section: Combined Hepatocholangiocarcinomamentioning

confidence: 99%

New insights into the pathophysiology and clinical care of rare primary liver cancers

et al. 2021

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Summary Hepatocholangiocarcinoma, fibrolamellar carcinoma, hepatic haemangioendothelioma and hepatic angiosarcoma represent less than 5% of primary liver cancers. Fibrolamellar carcinoma and hepatic haemangioendothelioma are driven by unique somatic genetic alterations ( DNAJB1-PRKCA and CAMTA1-WWTR1 fusions, respectively), while the pathogenesis of hepatocholangiocarcinoma remains more complex, as suggested by its histological diversity. Histology is the gold standard for diagnosis, which remains challenging even in an expert centre because of the low incidences of these liver cancers. Resection, when feasible, is the cornerstone of treatment, together with liver transplantation for hepatic haemangioendothelioma. The role of locoregional therapies and systemic treatments remains poorly studied. In this review, we aim to describe the recent advances in terms of diagnosis and clinical management of these rare primary liver cancers.

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Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma

Cited by 31 publications

References 15 publications

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver

New insights into the pathophysiology and clinical care of rare primary liver cancers

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