Molecule-targeted agents in endometrial cancer

Delmonte, Angelo; Sessa, Cristiana

doi:10.1097/cco.0b013e32830b0deb

Cited by 20 publications

(6 citation statements)

References 46 publications

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“…mTOR inhibitors (temsirolimus, everolimus, and ridaforolimus) have been tested in phase I and II clinical trials for advanced and recurrent endometrial carcinomas with some promising clinical outcomes; however, response rates are not robust. In general, responses are partial and vary from 8%–26% with an additional 20%–63% of patients achieving stable disease for at least four months [15]. Some patients achieve no benefit from therapy (primary resistance), whereas in others, stable disease or an initial response occurs.…”

Section: Introductionmentioning

confidence: 99%

A Mechanism for Synergy with Combined mTOR and PI3 Kinase Inhibitors

et al. 2011

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Dysregulation of the mammalian target of rapamycin (mTOR) signaling has been found in many human cancers, particularly those with loss of the tumor suppressor PTEN. However, mTORC1 inhibitors such as temsirolimus have only modest activity when used alone and may induce acquired resistance by activating upstream mTORC2 and Akt. Other tumors that do not depend upon PI3K/Akt/mTOR signaling for survival are primarily resistant. This study tested the hypothesis that the limited clinical efficacy of temsirolimus is due to a compensatory increase in survival signaling pathways downstream of Akt as well as an incomplete block of 4E-BP1-controlled proliferative processes downstream of mTOR. We explored the addition of a PI3K inhibitor to temsirolimus and identified the mechanism of combinatorial synergy. Proliferation assays revealed that BEZ235 (dual PI3K/mTOR inhibitor) or ZSTK474 (pan PI3K inhibitor) combined with temsirolimus synergistically inhibited cell growth compared to cells treated with any of the agents alone. Co-treatment resulted in G0/G1 cell cycle arrest and up-regulation of p27. Cell death occurred through massive autophagy and subsequent apoptosis. While molecular profiling revealed that, in most cases, sensitivity to temsirolimus alone was most marked in cells with high basal phospho-Akt resulting from PTEN inactivation, combining a PI3K inhibitor with temsirolimus prevented compensatory Akt phosphorylation and synergistically enhanced cell death regardless of PTEN status. Another molecular correlate of synergy was the finding that temsirolimus treatment alone blocks downstream S6 kinase signaling, but not 4E-BP1. Adding BEZ235 completely abrogated 4E-BP1 phosphorylation. We conclude that the addition of a PI3K inhibitor overcomes cellular resistance to mTORC1 inhibitors regardless of PTEN status, and thus substantially expands the molecular phenotype of tumors likely to respond.

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Section: Introductionmentioning

confidence: 99%

A Mechanism for Synergy with Combined mTOR and PI3 Kinase Inhibitors

et al. 2011

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“…There are two major types (I and II) of endometrial cancer with specific features and different changes in a genetic setting (21). HDAC inhibitors are an emerging class of targeted cancer therapeutics, and may have an important impact on the treatment of both types I and II endometrial carcinoma (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor effect of apicidin on Ishikawa human endometrial cancer cells both in vitro and in vivo by blocking histone deacetylase 3 and 4

Kim

2009

Int J Oncol

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Abstract. Histone deacetylase (HDAC) inhibitors are a new class of anticancer agents that act by inhibiting cancer cell proliferation and inducing apoptosis both in vitro and in vivo. This study examined the anti-tumor effect of apicidin on human endometrial cancer Ishikawa cells in an animal model by inhibiting specific HDAC expression. Nude mice were injected subcutaneously (s.c.) with Ishikawa cells, and the levels of cell proliferation and apoptosis were measured in the tumor tissues after an apicidin treatment. The expression patterns of a specific HDAC class by apicidin were measured in Ishikawa endometrial cancer both in vitro and in vivo. The tumor volume and weight were measured after the apicidin treatment. Apicidin significantly increased the acetylated histone H3 levels in an Ishikawa cells in vitro culture but the levels of HDAC3 and HDAC4 expression were significantly decreased. Apicidin suppressed the tumor growth of transplanted Ishikawa cells, the expression of proliferative cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) in tumor xenograft model, respectively. The inhibitory effect of apicidin on tumor growth was mediated in part through the down-regulation of HDAC3 and HDAC4. We suggest that apicidin is an effective anti-tumor agent on human endometrial cancer cells, and acts by regulating cell proliferation and apoptosis through the down-regulation of HDAC3 and HDAC4.

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“…The pathogenesis of endometrial carcinoma involves the progressive, temporal accumulation of genetic changes resulting in alteration of endometrial cell signaling, proliferation, apoptosis, and angiogenesis [3]. Histopathologically, endometrial cancer is categorized into two subtypes.…”

Section: Introductionmentioning

confidence: 99%

Angiogenesis and its modulation in the pathophysiology and treatment of endometrial carcinoma

et al. 2010

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Endometrial cancer is the most common gynecologic malignancy in women. When detected early, this disease has a relatively good prognosis. However, advanced stage disease is associated with a poor outcome. Current therapies for advanced endometrial cancer include surgery, chemotherapy, radiotherapy, and hormonal therapy. Responses to these modalities are variable, but rarely exceed 20%. Angiogenesis plays a critical role in both the normal and the pathologic physiology of the human endometrium. Like a wide array of other tumors, the formation of new blood vessels to feed an enlarging tumor mass occurs in endometrial cancer. This review focuses on the role of angiogenesis and its inhibition in the pathophysiology and treatment of endometrial cancer.

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Molecule-targeted agents in endometrial cancer

Cited by 20 publications

References 46 publications

A Mechanism for Synergy with Combined mTOR and PI3 Kinase Inhibitors

A Mechanism for Synergy with Combined mTOR and PI3 Kinase Inhibitors

Anti-tumor effect of apicidin on Ishikawa human endometrial cancer cells both in vitro and in vivo by blocking histone deacetylase 3 and 4

Angiogenesis and its modulation in the pathophysiology and treatment of endometrial carcinoma

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