azd-6244 and Endometrial-Neoplasms

Activation of the mitogen activated protein kinase pathway plays a pivotal role in cell proliferation and is frequently activated in endometrial cancer. We sought to evaluate the efficacy/safety of selumetinib, a selective MEK-1/2 inhibitor in women with recurrent endometrial cancer.. This was a phase II, single-arm, open-label study evaluating response and 6-month event-free survival (EFS) as primary endpoints. Eligible patients had measurable disease, 1-2 prior cytotoxic regimens, and performance status 0-2. Selumetinib 75mg PO BID was administered daily until progression or intolerance. One cycle was 28days.. Fifty-four patients were enrolled; 2 were excluded due to improper pre-study treatment (1) and never treated (1), leaving 52 evaluable for efficacy/safety. Median age was 62; histology included endometrioid (58%), serous (17%) and mixed (23%). Seventeen patients (33%) had 2 prior cytotoxic regimens. The median number of cycles administered was 2 (1-34). Three (6%) patients had objective response (1 CR, 2 PR); 13 had SD as best response. The proportion of patients with 6-month EFS was 12%. Median EFS, progression-free and overall survival was 2.1, 2.3, and 8.5months, respectively. Drug-attributed grade 3/4 adverse events were observed (≥5%) were fatigue (15%), anemia (10%), pain (10%), extremity edema (8%), and dyspnea (6%). There was 1 grade 4 infection (renal), 1 grade 4 anemia, and 1 death due to hemorrhage (rectum).. Selumetinib was tolerable in this population but did not meet pre-trial specifications for clinical efficacy.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Benzimidazoles; Drug Administration Schedule; Endometrial Neoplasms; Female; Humans; Kaplan-Meier Estimate; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Neoplasm Recurrence, Local; Protein Kinase Inhibitors

Endometrial carcinoma (EC) is the most common gynecological cancer in the Western World. Treatment options are limited for advanced and recurrent disease. Therefore, new treatment options are necessary. Inhibition of the PI3K/AKT/mTOR and/or the Ras/Raf/MEK pathways is suggested to be clinically relevant. However, the knowledge about the effect of combination targeted therapy in EC is limited. The aim of this study was to investigate the effect of these therapies on primary endometrioid EC cell cultures in vitro and in vivo.. Primary endometrioid EC cell cultures were incubated with Temsirolimus (mTORC1 inhibitor), NVP-BKM120 (pan-PI3K inhibitor), NVP-BEZ235 (pan-PI3K/mTOR inhibitor), or AZD6244 (MEK1/2 inhibitor) as single treatment. In vitro, the effect of NVP-BEZ235 with or without AZD6244 was determined for cell viability, cell cycle arrest, apoptosis induction, and cell signaling. In vivo, the effect of NVP-BEZ35 was investigated for 2 subcutaneous xenograft models of the corresponding primary cultures.. NVP-BEZ235 was the most potent PI3K/AKT/mTOR pathway inhibitor. NVP-BEZ235 and AZD6244 reduced cell viability and induced cell cycle arrest and apoptosis, by reduction of p-AKT, p-S6, and p-ERK levels. Combination treatment showed a synergistic effect. In vivo, NVP-BEZ235 reduced tumor growth and inhibited p-S6 expression. The effects of the compounds were independent of the mutation profile of the cell cultures used.. A synergistic antitumor effect was shown for NVP-BEZ235 and AZD6244 in primary endometrioid EC cells in vitro. In addition, NVP-BEZ235 induced reduction of tumor growth in vivo. Therefore, targeted therapies seem an interesting strategy to further evaluate in clinical trials.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Endometrioid; Drug Synergism; Endometrial Neoplasms; Female; Humans; Imidazoles; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinolines; raf Kinases; ras Proteins; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays