A phase II evaluation of temsirolimus in combination with carboplatin and paclitaxel followed by temsirolimus consolidation as first-line therapy in the treatment of stage III-IV clear cell carcinoma of the ovary.

Farley, John H.; Brady, William E.; Nomura, Hiroyuki; Yunokawa, Mayu; Tokunaga, Hideki; Saitou, Motoaki; Gershenson, David M.

doi:10.1200/jco.2016.34.15_suppl.5531

Cited by 33 publications

(18 citation statements)

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“…In the clinic, inhibition of mTORC1 with temsirolimus added to standard chemotherapy did not improve overall survival in newly diagnosed stage 3-4 OCCC patients as compared to historical controls (39). However, by blocking both mTORC1 and mTORC2, re-activation of PI3K and MAPK signaling via mTORC2 can be prevented in OCCC.…”

Section: Discussionmentioning

confidence: 96%

Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Caumanns

Berns

Wisman

et al. 2018

Clinical Cancer Research

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Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor and activating mutations in the PI3K subunit In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models. In a large set of patients with OCCC ( = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines ( = 17) and OCCC patient-derived xenografts ( = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055. We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models. These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. .

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Section: Discussionmentioning

confidence: 96%

Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Caumanns

Berns

Wisman

et al. 2018

Clinical Cancer Research

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“…This regimen did not statistically significantly increase progression-free survival compared with historical control. 117 In a study of nivolumab, an immune checkpoint inhibitor that blocks programmed cell death 1 (PD-1), Review for platinum-resistant ovarian carcinoma, one of two patients with clear cell carcinoma exhibited complete response and, in a study of avelumab for recurrent/refractory ovarian carcinoma, both patients with clear cell carcinoma exhibited partial response. 118 119 Immune checkpoint inhibitors may represent a new treatment option for clear cell carcinoma, and clinical trials using these are ongoing.…”

Section: Radiotherapymentioning

confidence: 99%

Clear cell carcinoma of the ovary: a clinical and molecular perspective

Iida

Okamoto

Hollis

et al. 2020

Int J Gynecol Cancer

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Clear cell carcinoma of the ovary has distinct biology and clinical behavior. There are significant geographical and racial differences in the incidence of clear cell carcinoma compared with other epithelial ovarian tumors. Patients with clear cell carcinoma are younger, tend to present at an early stage, and their tumors are commonly associated with endometriosis, which is widely accepted as a direct precursor of clear cell carcinoma and has been identified pathologically in approximately 50% of clear cell carcinoma cases. The most frequent and important specific gene alterations in clear cell carcinoma are mutations of AT-rich interaction domain 1A (ARID1A) (~50% of cases) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (~50% cases). More broadly, subgroups of clear cell carcinoma have been identified based on C-APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and C-AGE (age-related) mutational signatures. Gene expression profiling shows upregulation of hepatocyte nuclear factor 1-beta (HNF1β) and oxidative stress-related genes, and has identified epithelial-like and mesenchymal-like tumor subgroups. Although the benefit of platinum-based chemotherapy is not clearly defined it remains the mainstay of first-line therapy. Patients with early-stage disease have a favorable clinical outcome but the prognosis of patients with advanced-stage or recurrent disease is poor. Alternative treatment strategies are required to improve patient outcome and the development of targeted therapies based on molecular characteristics is a promising approach. Improved specificity of the histological definition of this tumor type is helping these efforts but, due to the rarity of clear cell carcinoma, international collaboration will be essential to design appropriately powered, large-scale clinical trials.

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“…For the PI3K/AKT/mTOR pathway, the clinical efficacy of the mTOR inhibitor temsirolimus has been evaluated for advanced-stage CCC in a phase II trial (GOG268) in both the US and Japan (45 patients each). However, temsirolimus failed to show a significant survival benefit for advancedstage CCC in combination with TC and in consolidation as first-line chemotherapy (20). Another mTOR inhibitor, everolimus, is expected to be less effective than cabozantinib because a recent phase III trial demonstrated that cabozantinib significantly improved the survival of patients with advanced-stage renal CCC compared to everolimus (21).…”

Section: Discussionmentioning

confidence: 99%

The Anti-tumor Effect of Cabozantinib on Ovarian Clear Cell Carcinoma In Vitro and In Vivo

Nakatani

Watari

Mitamura

et al. 2017

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A phase II evaluation of temsirolimus in combination with carboplatin and paclitaxel followed by temsirolimus consolidation as first-line therapy in the treatment of stage III-IV clear cell carcinoma of the ovary.

Cited by 33 publications

References 0 publications

Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Clear cell carcinoma of the ovary: a clinical and molecular perspective

The Anti-tumor Effect of Cabozantinib on Ovarian Clear Cell Carcinoma In Vitro and In Vivo

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