Despite a vast literature showing that childhood sarcoma cells utilize insulin-like growth factors (IGFs) to maintain autocrine and paracrine-driven proliferation, antibodies that block ligand binding to the type IGF-1 receptor (IGF-1 R) have proven disappointing in the clinic. Our data show that one effect of IGF-1 R-targeted antibodies is to inhibit angiogenesis and sarcoma cell proliferation. However, tumor-secreted IGF-2, signaling through the insulin receptor (IN-R) circumvents these effects. We will take a candidate gene approach to test whether tumor sensitivity to IGF-1 R-targeted antibody therapy can be predicted from the expression of IGF/IN receptors and ligands, before treatment or after treatment. We will take a less-biased approach by screening a receptor tyrosine kinase siRNA library to identify receptors that may confer resistance to antibody treatment.
In Aim 2, we will pursue approaches to enhance the antitumor activity of IGF-1 R-targeted antibodies by blocking IGF-2 signaling using ligand binding antibodies, small molecule inhibitors of IGF-1 R/IN-R, or Akt signaling. Preliminary results demonstrate that IGF-2 robustly activates STATS signaling via TOR in both vascular endothelial and sarcoma cells. Further, STATS cross-talks with N F - K B , consequently, we will evaluate combinations of IGF-directed antibodies combined with inhibitors of these pathways and determine their effects on angiogenesis and tumor cell proliferation in vitro and in sarcoma xenograft models.
In Aim 3, we will explore the mechanism(s) by which IGFs protect against apoptosis induced by TOR inhibitors in some sarcoma cells. Our previous data showed that IGF-1 induces phosphorylation of BAD, through an Akt- independent pathway in vitro, and IGF-IR targeted antibody suppressed this in vitro and in a Ewing sarcoma xenograft model leading to rapamycin-induced apoptosis. We will explore how IGF-2 can protect cells from rapamycin or TOR kinase inhibitors, and determine whether IGF-2 protection is mediated through STATS signaling, and whether this can be inhibited by antibodies that block IGF-2/IN-R signaling or by inhibitors of STATS. pProject 3 is highly interactive with Project 2 (STATS signaling), impacts the role of N F - K B / S T A T S signaling in Project 1 and relies heavily on Cores (1-3).

Public Health Relevance

Insulin-like growth factor signaling is dysregulated in each sarcoma histotype being studied. Work proposed will elucidate the mechanism(s) of intrinsic and acquired resistance to IGF-1 R-targeted antibody therapy, and test potential combinations that will overcome or reverse this resistance. Our studies will also identify pathways by which IGFs protect sarcoma cells from apoptosis, and examine strategies for selectively sensitizing vascular endothelial cells and sarcoma cells to undergo apoptosis in response to IGF-IR block.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA165995-01A1
Application #
8516642
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (J1))
Project Start
2013-06-05
Project End
2018-05-31
Budget Start
2013-06-05
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$272,659
Indirect Cost
$36,093
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Jayabal, Panneerselvam; Houghton, Peter J; Shiio, Yuzuru (2017) EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1. Genes Cancer 8:762-770
Zhou, Xinhui; Liu, Weijin; Hu, Xing et al. (2017) Regulation of CHK1 by mTOR contributes to the evasion of DNA damage barrier of cancer cells. Sci Rep 7:1535
Yu, Peter Y; Gardner, Heather L; Roberts, Ryan et al. (2017) Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. PLoS One 12:e0181885
Murphy, Brendan; Yin, Han; Maris, John M et al. (2016) Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis. Cancer Res 76:5798-5809
Cam, Maren; Gardner, Heather L; Roberts, Ryan D et al. (2016) ?Np63 mediates cellular survival and metastasis in canine osteosarcoma. Oncotarget 7:48533-48546
Wu, Xiaojuan; Xiao, Hui; Wang, Ruoning et al. (2016) Persistent GP130/STAT3 Signaling Contributes to the Resistance of Doxorubicin, Cisplatin, and MEK Inhibitor in Human Rhabdomyosarcoma Cells. Curr Cancer Drug Targets 16:631-8
Phelps, Doris; Bondra, Kathryn; Seum, Star et al. (2015) Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma. Pediatr Blood Cancer 62:1345-52
Studebaker, Adam; Bondra, Kathryn; Seum, Star et al. (2015) Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma. Pediatr Blood Cancer 62:1768-74
Forest, Amelie; Amatulli, Michael; Ludwig, Dale L et al. (2015) Intrinsic Resistance to Cixutumumab Is Conferred by Distinct Isoforms of the Insulin Receptor. Mol Cancer Res 13:1615-26
Adamson, Peter C; Houghton, Peter J; Perilongo, Giorgio et al. (2014) Drug discovery in paediatric oncology: roadblocks to progress. Nat Rev Clin Oncol 11:732-9

Showing the most recent 10 out of 16 publications