A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer

Kelly, Ronan J.; Thomas, Anish; Rajan, Arun; Chun, Guinevere; López-Chávez, Ariel; Szabó, Éva; Spencer, Shawn D.; Carter, C. A.; Guha, Udayan; Khozin, Sean; Poondru, Srinivasu; Sant, Charles Van; Keating, Anne; Steinberg, Seth M.; Figg, William D.; Giaccone, Giuseppe

doi:10.1093/annonc/mdt249

Cited by 134 publications

(123 citation statements)

References 19 publications

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“…Our data demonstrate that YM155 exerts cell growth inhibition effects synergistically with gemcitabine. This is consistent with reports that YM155 enhances the anti-tumor effects of other chemotherapeutic agents including: cisplatin, rituximab and paclitaxel (14, 19, 34, 48, 49). Our study raises the potential prospect of using YM155 and gemcitabine in combination for pancreatic cancer therapy.…”

Section: Discussionsupporting

confidence: 93%

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Small Molecule Inhibitor YM155-Mediated Activation of Death Receptor 5 Is Crucial for Chemotherapy-Induced Apoptosis in Pancreatic Carcinoma

Zhao

Puszyk

et al. 2015

Molecular Cancer Therapeutics

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Despite much effort, pancreatic cancer survival rates are still dismally low. Novel therapeutics may hold the key to improving survival. YM155 is a small molecule inhibitor which has shown anti-tumor activity in a number of cancers by reducing the expression of survivin. The aim of our study is to understand the mechanisms by which YM155 functions in pancreatic cancer cells. We established the anti-tumor effect of YM155 with in vitro studies in the cultured cells, and in vivo studies using a mouse xenograft model. Our data demonstrated that YM155 reduced the expression of survivin; however down-regulation of survivin itself is insufficient to induce apoptosis in pancreatic cancer cells. We showed for the first time that treatment with YM155 increased death receptor 5 (DR5) expression in pancreatic cancer cells. We found that YM155 induced apoptosis by broad-spectrum inhibition of IAP family member proteins (e.g. CIAP1/2 and FLIP) and induced pro-apoptotic Bak protein up-regulation and activation; the anti-tumor effect of YM155 treatment with either the DR5 agonist lexatumumab or gemcitabine on pancreatic cancer cells was synergistic. Our data also revealed that YM155 inhibit tumor growth in vivo, whilst had no apparent toxicity to the non-cancerous human pancreatic ductal epithelial cell line (HPDE). Together, these findings suggest that YM155 could be a novel therapeutic agent for pancreatic cancer.

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Section: Discussionsupporting

confidence: 93%

“…In the present study, we demonstrate YM155 can induce apoptosis in pancreatic cancer cells at clinically relevant doses. The reported plasma concentration is approximately 15 nM (12, 13, 34). Our study suggests that YM155 may have potential use as a systemic therapy for pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Inhibitor YM155-Mediated Activation of Death Receptor 5 Is Crucial for Chemotherapy-Induced Apoptosis in Pancreatic Carcinoma

Zhao

Puszyk

et al. 2015

Molecular Cancer Therapeutics

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“…Several clinical studies of YM155 revealed that it was very well tolerated, but likely would be best utilized in combination chemotherapy due to its limited single-agent efficacy (44)(45)(46)(47)(48). Multiple combination studies with YM155 were conducted with paclitaxel or docetaxel regimens based on the rationale that YM155 may be able to overcome taxane-mediated upregulation of survivin expression, which promotes drug resistance (44,(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple combination studies with YM155 were conducted with paclitaxel or docetaxel regimens based on the rationale that YM155 may be able to overcome taxane-mediated upregulation of survivin expression, which promotes drug resistance (44,(48)(49)(50). However, the lack of efficacy that was observed in these clinical studies may have been due to incomplete suppression of survivin levels in the tumors.…”

Section: Discussionmentioning

confidence: 99%

Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

Carew

Espitia

Zhao

et al. 2015

Molecular Cancer Therapeutics

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Elevated expression of the antiapoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal cell carcinoma (RCC) pathogenesis is not well defined. We investigated the roles of survivin in RCC tumor progression, resistance to mTOR inhibitors, and evaluated the therapeutic activity of the survivin suppressant YM155 in RCC models. Here, we report that survivin expression levels were significantly higher in RCC cell lines compared with normal renal cells. Stable targeted knockdown of survivin completely abrogated the ability of 786-O RCC tumors to grow in mice, thus demonstrating its importance as a regulator of RCC tumorigenesis. We next explored multiple strategies to therapeutically inhibit survivin function in RCC. Treatment with the mTOR inhibitor temsirolimus partially diminished survivin levels and this effect was augmented by the addition of YM155. Further analyses revealed that, in accordance with their combined anti-survivin effects, YM155 significantly improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in xenograft models in vivo. Similar to pharmacologic inhibition of survivin, shRNA-mediated silencing of survivin expression not only inhibited RCC tumor growth, but also significantly sensitized RCC cells to temsirolimus therapy. Subsequent experiments demonstrated that the effectiveness of this dual survivin/mTOR inhibition strategy was mediated by a potent decrease in survivin levels and corresponding induction of apoptosis. Our findings establish survivin inhibition as a novel approach to improve RCC therapy that warrants further investigation.

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“…Disruption of Survivin causes impaired chromosome movements, spindle checkpoint override and polyploidy [ 190 ], suppressing cell proliferation [ 191 ]. YM155, a drug that interferes with induction of the Survivin promoter, has entered clinical trials, with inconclusive results thus far in non-small-cell lung cancer [ 192 ]. Another drug, S12, that allosterically blocks Survivin interactions with CPC binding partners, shows promise as an inhibitor of tumor growth in vivo [ 193 ].…”

Section: Spindle Protein Inhibitorsmentioning

confidence: 99%

Non-motor Spindle Proteins as Cancer Chemotherapy Targets

Margolis

Mythili

2015

Kinesins and Cancer

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A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer

Abstract: NCT01100931.

Cited by 134 publications

References 19 publications

Small Molecule Inhibitor YM155-Mediated Activation of Death Receptor 5 Is Crucial for Chemotherapy-Induced Apoptosis in Pancreatic Carcinoma

Small Molecule Inhibitor YM155-Mediated Activation of Death Receptor 5 Is Crucial for Chemotherapy-Induced Apoptosis in Pancreatic Carcinoma

Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

Non-motor Spindle Proteins as Cancer Chemotherapy Targets

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