Phase I Study of YM155, a Novel Survivin Suppressant, in Patients with Advanced Solid Tumors

Satoh, Taroh; Okamoto, Isamu; Miyazaki, Masaki; Morinaga, Ryotaroh; Tsuya, Asuka; Hasegawa, Yoshikazu; Terashima, Masaaki; Ueda, Shinya; Fukuoka, Masahiro; Ariyoshi, Y; Saito, Toshikazu; Masuda, Noriyuki; Watanabe, Hirokazu; Taguchi, Tetsuo; Kakihara, Toru; Aoyama, Yumiko; Hashimoto, Yohko; Nakagawa, Kazuhiko

doi:10.1158/1078-0432.ccr-08-1946

Cited by 158 publications

(130 citation statements)

References 20 publications

Supporting

Mentioning

125

Contrasting

Order By: Relevance

“…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%

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

Carew

Espitia

Zhao

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Moreover, we found that YM155 significantly enhanced the antitumor effect of erlotinib in EGFR mutation-positive NSCLC cells with PTEN loss both in vitro and in vivo. YM155, a small-molecule inhibitor of the expression of the antiapoptotic protein survivin, is currently in clinical development as the first survivin suppressant (18,19,(34)(35)(36). This drug was found to exhibit a favorable safety tolerability profile and moderate single-agent activity in a recent phase II trial with patients with advanced, refractory NSCLC (37).…”

Section: Discussionmentioning

confidence: 99%

Overcoming Erlotinib Resistance in EGFR Mutation–Positive Non–Small Cell Lung Cancer Cells by Targeting Survivin

Okamoto

Hatashita

et al. 2012

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation-positive non-small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR-TKIs contributes to EGFR-TKI-induced apoptosis in EGFR mutationpositive NSCLC cells. We have now investigated the role of survivin expression in EGFR-TKI resistance induced by PTEN loss. The EGFR-TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation-positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation-positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT-survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation-positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR-TKI resistance in EGFR mutation-positive NSCLC.

show abstract

“…Currently, the most intensively investigated survivin antagonist is the small imidazolium-based compound YM155 (Sepantronium bromide). This small molecule survivin inhibitor demonstrated impressive anticancer activity in several preclinical studies using cancer cell lines originating from various types of cancer, including GC cells (30,(48)(49)(50) and was well tolerated in phase I studies (51,52). Concerning the potential efficacy of anti-XIAP treatment strategies in GC initial promising results have been published.…”

Section: Svv (Cyt)-center Svv (Cyt)-invasion ----------------------mentioning

confidence: 99%

Survivin and XIAP expression in distinct tumor compartments of surgically resected gastric cancer: XIAP as a prognostic marker in diffuse and mixed type adenocarcinomas

et al. 2017

View full text Add to dashboard Cite

Abstract. There is considerable evidence that the inhibitor of apoptosis protein (IAP) family serves a role in tumorigenesis. The most studied IAP family members, survivin and X-linked inhibitor of apoptosis (XIAP), have been demonstrated to serve as biomarkers in distinct tumor entities. Thus, the present study aimed to investigate the expression levels of both IAPs in the tumor center, invasion front and lymph node metastases of surgically resected gastric cancer (GC) specimens. Tissue microarrays containing samples from 201 primary GCs were analyzed. IAP expression was detected using immunohistochemistry in different tumor compartments, normal mucosa and lymph node metastases. In addition, the association between the expression levels of these proteins, and clinicopathological parameters and overall survival was investigated. High levels of survivin and XIAP were evident in GC, when compared with normal mucosa, and were correlated with intestinal-type and well-differentiated GC, as well as low International Union Against Cancer stages. Increased XIAP expression was detected in lymph node metastases as compared with corresponding primary tumors. XIAP overexpression was identified to be an independent negative prognostic marker in diffuse and mixed type GC. These results suggest a potential role of survivin and XIAP in the early phase of gastric carcinogenesis. In addition, increased XIAP expression in lymph node metastases supports the observation that IAPs serve an essential role in metastatic tumor disease. Since XIAP expression was identified to be associated with poor survival in diffuse and mixed type GC, XIAP may serve as a novel therapeutic target in these types of GC.

show abstract

Phase I Study of YM155, a Novel Survivin Suppressant, in Patients with Advanced Solid Tumors

Cited by 158 publications

References 20 publications

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

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

Overcoming Erlotinib Resistance in EGFR Mutation–Positive Non–Small Cell Lung Cancer Cells by Targeting Survivin

Survivin and XIAP expression in distinct tumor compartments of surgically resected gastric cancer: XIAP as a prognostic marker in diffuse and mixed type adenocarcinomas

Contact Info

Product

Resources

About