TY - JOUR
T1 - Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer
AU - Bradford, Leslie S.
AU - Rauh-Hain, Alejandro
AU - Clark, Rachel M.
AU - Groeneweg, Jolijn W.
AU - Zhang, Ling
AU - Borger, Darrell
AU - Zukerberg, Lawrence R.
AU - Growdon, Whitfield B.
AU - Foster, Rosemary
AU - Rueda, Bo R.
N1 - Funding Information:
Funding for this project was provided by the Advanced Medical Research Fund (BRR) and Vincent Memorial funds (BRR). We appreciate the efforts of Minji Kim for conducting protein analysis. In addition, we would like to acknowledge the contributions of the clinical research coordinators (Celeste DiGloria and Virginia Byron) who were responsible for educating and consenting our gynecologic patients. Jolijn W. Groeneweg, MD received financial support via a scholarship awarded by the VSB Foundation . Finally, we want to give special thanks to all the patients who have consented to allow their malignant tumors to be part of our research efforts.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Objective Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. Methods NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C + BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. Results In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p < 0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p < 0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p < 0.05). Synergistic tumor growth suppression (p < 0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels. Conclusion Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.
AB - Objective Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. Methods NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C + BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. Results In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p < 0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p < 0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p < 0.05). Synergistic tumor growth suppression (p < 0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels. Conclusion Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.
KW - Endometrial cancer
KW - PI3K inhibitor
KW - PI3K/AKT/mTOR pathway
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U2 - 10.1016/j.ygyno.2014.02.022
DO - 10.1016/j.ygyno.2014.02.022
M3 - Article
C2 - 24561032
AN - SCOPUS:84899585031
SN - 0090-8258
VL - 133
SP - 346
EP - 352
JO - Gynecologic Oncology
JF - Gynecologic Oncology
IS - 2
ER -