Abstract 1209: Istiratumab (MM-141), a bispecific antibody targeting IGF-1R and ErbB3, inhibits pro-survival signaling in vitro and potentiates the activity of standard of care chemotherapy in vivo in ovarian cancer models

In human ovarian carcinoma, the endothelin-1 (ET-1) / endothelin A receptor (ETAR) axis is overexpressed, correlating with tumor grade. Moreover, ETAR activation by ET-1 affects cell proliferation, survival, angiogenesis, and invasion. ETAR blockade with zibotentan (ZD4054), a specific ETAR antagonist, significantly inhibits ovarian cancer growth in vitro and in vivo, underscoring the relevance of this pathway as a target for cancer therapy. Since clinical trial results have defined the combination of platinum and taxane as the standard of care in the management of ovarian cancer, here we explored the therapeutic efficacy of the integration of zibotentan with cytotoxic drugs having different modes of action. We found that the combination of zibotentan with cisplatinum as well as zibotentan with paclitaxel was more effective at inhibiting ovarian cancer HEY cell proliferation induced by endogenous ET-1 than were the single agents alone. However, a significantly enhanced efficacy was observed when we combined zibotentan, cisplatinum, and paclitaxel. Accordingly, in HEY xenografts the coadministration of zibotentan with cisplatinum enhanced the efficacy of the cytotoxic drug alone in controlling tumor growth, associated with reduction in proliferation index and microvessel density. Remarkably, the combination of zibotentan with both cisplatinum and paclitaxel was very effective in inhibiting tumor growth, neovascularization, and cell proliferation, representing a preclinical endpoint to guide combination therapy in clinical trials.

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Src Inhibition with Saracatinib Reverses Fulvestrant Resistance in ER-Positive Ovarian Cancer Models In Vitro and In Vivo

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-12-1257 ◽

2012 ◽

Vol 18 (21) ◽

pp. 5911-5923 ◽

Cited By ~ 40

Author(s):

Fiona Simpkins ◽

Pedro Hevia-Paez ◽

Jun Sun ◽

Wendy Ullmer ◽

Candace A. Gilbert ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Models ◽

Er Positive

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Efficacy of a Covalent Microtubule Stabilizer in Taxane-Resistant Ovarian Cancer Models

Molecules ◽

10.3390/molecules26134077 ◽

2021 ◽

Vol 26 (13) ◽

pp. 4077

Author(s):

Samantha S. Yee ◽

April L. Risinger

Keyword(s):

Ovarian Cancer ◽

Acquired Resistance ◽

Disease Model ◽

Intraperitoneal Administration ◽

Metastatic Progression ◽

Clinical Prognosis ◽

Microtubule Stabilization ◽

Cancer Models

Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22,23-epoxytaccalonolides, for their efficacy against taxane-resistant ovarian cancer models in vitro and in vivo. Taccalonolide AF, which covalently binds β-tubulin through its C-22,23-epoxide moiety, demonstrates efficacy against taxane-resistant models and shows superior persistence in clonogenic assays after drug washout due to irreversible target engagement. In vivo, intraperitoneal administration of taccalonolide AF demonstrated efficacy against the taxane-resistant NCI/ADR-RES ovarian cancer model both as a flank xenograft, as well as in a disseminated orthotopic disease model representing localized metastasis. Taccalonolide-treated animals had a significant decrease in micrometastasis of NCI/ADR-RES cells to the spleen, as detected by quantitative RT-PCR, without any evidence of systemic toxicity. Together, these findings demonstrate that taccalonolide AF retains efficacy in taxane-resistant ovarian cancer models in vitro and in vivo and that its irreversible mechanism of microtubule stabilization has the unique potential for intraperitoneal treatment of locally disseminated taxane-resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients.

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