Phase 2 Study Update of Selumetinib for Ovarian Cancer - MPR

Blogger's Note: more info req'd eg. side effects....

Phase 2 Study Update of Selumetinib for Ovarian Cancer - MPR

Array BioPharma announced results of a Phase 2 trial of selumetinib in women with recurrent low-grade serous ovarian or peritoneal cancer.

In the trial, 52 women each received 100mg doses of selumetinib orally twice daily in four-week cycles until disease progression or toxicity. The median number of cycles received was 4.5; 33% underwent ≥12 cycles. Prior to the trial, 58% of the patients in the trial had received three or more rounds of chemotherapy.

A disease control rate, defined as either complete or partial response or progression-free survival or progression-free survival of greater than 6 months, occurred in 81% of patients. Eight patients had complete (1) or partial (7) responses, and 34 (63%) had progression-free survival of >6 months. The median survival rate without cancer progression was 11 months.

Selumetinib is an anti-cancer drug in Phase 2 development in a range of tumors. It is a small molecule MEK inhibitor that targets a key position in the Ras-Raf-MEK-ERK signaling pathway. MEK has been shown to be frequently activated in cancer, in particular in tumors that have mutations in the RAS and RAF pathways.

For more information call (877) MED-CHEM or visit www.arraybiopharma.com

AACR: Selumetinib Controlled Recurrent Low-grade Serous Ovarian Cancer

Selumetinib Controlled Recurrent Low-grade Serous Ovarian Cancer:

• Selumetinib controlled the disease in 81 percent of patients.
• Median progression-free survival was 11 months.
• Patients experienced minimal side effects.

CHICAGO — Selumetinib, a small-molecule MEK inhibitor, demonstrated the ability to control low-grade serous ovarian or peritoneal cancer, according to phase II study results presented at the AACR Annual Meeting 2012, held here March 31 – April 4.
The first line of defense against low-grade serous ovarian cancer is surgery, followed by cytotoxic chemotherapy. However, this is a slow-growing cancer and does not respond well to traditional chemotherapies, which target fast-growing cells.
Seeking a more rational treatment approach, Gynecologic Oncology Group (GOG) researchers led by John Farley, M.D., a professor at Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center in Omaha, Neb., used selumetinib to target the MEK-1/2 protein kinase in the MAPK pathway, which is known to mutate in this form of cancer.
GOG researchers assigned 52 women to 100-mg doses of selumetinib orally twice daily in four-week cycles; 33 percent underwent 12 or more cycles. Prior to the study, 58 percent of patients had received three or more rounds of chemotherapy.
Selumetinib controlled the disease in 81 percent of patients. Specifically, eight patients had complete or partial responses to treatment, and 34 had stable disease. The median survival rate without cancer progression was 11 months, and 63 percent of patients had progression-free survival longer than six months. In addition, selumetinib was well tolerated, with three patients experiencing grade 4 adverse events.
“The results were striking,” said Farley. “Many of the patients in the study had received multiple rounds of chemotherapy and were running out of options. By using these tumors’ historical inherent molecular aberrations to select patients for a treatment that in theory could exploit these abnormalities, we took an important step toward individualized cancer therapies.”
In addition to studying the impact of selumetinib on this type of ovarian cancer, investigators were also interested in how patients with RAS/RAF mutations responded to the drug. The team analyzed the tumor DNA from 34 patients, 62 percent of whom had some form of RAS/RAF mutation. Ultimately, they found that RAS/RAF mutations had no impact on patient response.
The study was funded by the National Cancer Institute.

abstract: (in mice) MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model

Blogger's Note: in research (mice)

Abstract

Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is extracellular signal–related kinase (ERK). PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR–ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of 4 CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Furthermore, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to selumetinib sensitivity. Both selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model.  
However, selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss and severe skin peeling) at high doses. Our findings indicate that the MEK–ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that selumetinib and erlotinib are worth exploring as therapeutic agents for CCC. Mol Cancer Ther; 11(2); 360–9. ©2011 AACR