We and others have demonstrated that the phosphatidylinositol-3-kinase (PI3K)/PTEN/AKT/mT0R pathway is activated in over 60% of endometrial cancers by mutations in the PTEN (30-50%), PIK3CA (20-40%), PIK3R1 (20%) and AKT1 (-2%) genes. Further, we and others have shown that the RAS/RAF pathway is activated by KRAS mutations in -20% of endometrial cancers. In contrast to other cancer types, none of these mutations are mutually exclusive and two or more thus frequently occur in the same endometrial tumor. We and others have also recently demonstrated that KRAS mutations predict a lack of response to PISK pathway-targeted therapies in cancer cells and vice versa. Thus, in this application, we will test the hypotheses in vitro and in vivo in endometrial cancer that: 1. PISK pathway-targeted drugs will be selectively active in tumors with mutations in the PISK pathway in the absence of KRAS mutations, 2. Specific aberrations in the PISK pathway will determine the response to targeting different nodes in the PISK pathway, 3. Aberrations in the RAS/RAF pathway in the absence of PISK pathway mutations will render tumors responsive to RAS/RAF-pathway targeted drugs (e.g. MEK inhibitors), and 4. Cells with coordinate mutations in both the PISK and RAS/RAF pathways will be resistant to PISK pathway inhibitors and MEK inhibitors alone but sensitive to concurrent targeting of both pathways.
Our specific aims are thus:
Aim 1 : To determine effects of mutations in the PISK and RAS/RAF pathways on downstream signaling events and clinical correlates in endometrial cancer.
Aim 2 : To determine whether specific aberrations in the PISK and RAS/RAF pathways predict effects of targeting specific nodes in the PISK and RAS/RAF pathways.
Aim 3 : To identify and validate predictive and pharmacodynamic markers of antitumor efficacy for PISK- and RAS/RAF-targeted therapies in endometrial cancer.
Aim 4 : To determine whether predictive and pharmacodynamic markers indicate responsiveness to the dual PISK/mTOR inhibitor GSK2126458A in a phase II clinical trial in advanced endometrial cancer.

Public Health Relevance

PISK and RAS/RAF pathway mutations occur in >65% of endometrial cancers. It is therefore likely that our studies of these two pathways as therapy targets in endometrial cancer will benefit a significant proportion of women with endometrial cancer when translated to the clinic. In addition, these mutations are seen frequently in a broad spectrum of tumor types including breast and colorectal cancers. Thus, the proposed studies of PISK and RAS/RAF pathway inhibition in endometrial cancer will likely also have broad applicability to other tumor types.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA098258-08
Application #
8382325
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$196,542
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Pakish, Janelle B; Zhang, Qian; Chen, Zhongyuan et al. (2017) Immune Microenvironment in Microsatellite-Instable Endometrial Cancers: Hereditary or Sporadic Origin Matters. Clin Cancer Res 23:4473-4481
Zang, Yong; Yuan, Ying (2017) Optimal sequential enrichment designs for phase II clinical trials. Stat Med 36:54-66
Haemmerle, Monika; Taylor, Morgan L; Gutschner, Tony et al. (2017) Platelets reduce anoikis and promote metastasis by activating YAP1 signaling. Nat Commun 8:310
Noh, Kyunghee; Mangala, Lingegowda S; Han, Hee-Dong et al. (2017) Differential Effects of EGFL6 on Tumor versus Wound Angiogenesis. Cell Rep 21:2785-2795
Kurnit, Katherine C; Kim, Grace N; Fellman, Bryan M et al. (2017) CTNNB1 (beta-catenin) mutation identifies low grade, early stage endometrial cancer patients at increased risk of recurrence. Mod Pathol 30:1032-1041
Harjes, U; Bridges, E; Gharpure, K M et al. (2017) Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4. Oncogene 36:912-921
Suh, Han Na; Kim, Moon Jong; Jung, Youn-Sang et al. (2017) Quiescence Exit of Tert+ Stem Cells by Wnt/?-Catenin Is Indispensable for Intestinal Regeneration. Cell Rep 21:2571-2584
Soliman, Pamela T; Westin, Shannon N; Dioun, Shayan et al. (2017) A prospective validation study of sentinel lymph node mapping for high-risk endometrial cancer. Gynecol Oncol 146:234-239
Bruegl, Amanda S; Kernberg, Annessa; Broaddus, Russell R (2017) Importance of PCR-based Tumor Testing in the Evaluation of Lynch Syndrome-associated Endometrial Cancer. Adv Anat Pathol 24:372-378
Nagaraja, Archana S; Dood, Robert L; Armaiz-Pena, Guillermo et al. (2017) Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. JCI Insight 2:

Showing the most recent 10 out of 541 publications