Cancer is a major health problem worldwide and new therapies are critically needed, especially for glioblastoma the most fatal brain tumor. Unpublished studies in our lab have revealed a new bystander effect for tumor suppressor p53. Upon activation by chemo- or radiation therapies p53 induces the death of adjacent tumor cells, while sparing normal cells. We discovered that the effecter mechanism relies upon the secretion of galectin-3, a ?-galactose-recognizing lectin, which induces apoptosis. We also found that secreted galectin-3 reduced tumor formation in vivo. In this proposal we will extend these initial findings by dissecting the underlying mechanisms and determine whether Gal3 has clinical potential. We will determine the type of apoptotic signaling pathways activated in tumor cells by extracellular galectin-3 (Aim 1), whether secreted galectin-3 selectively binds to a specific cell surface receptor, with tumor-specific characteristics (Aim 2), and whether Gal-3 delivery can be used as a viable therapeutic for cancer using an in vivo mouse glioma model (Aim 3). Our working hypothesis is that p53 exerts a tumor suppressive bystander effect by stimulating exosomal secretion of Gal3, which in turn binds in a tumor-selective fashion to ? 1-integrin complexes due to unique N-glycanation in cancer, and induces a therapeutic effect by activating apoptosis. These studies are important because we identified a new p53-induced tumor suppressive mechanism mediated by soluble Gal3, which has therapeutic implications. Examining the role of extracellular Gal3 in glioma apoptosis and tumor growth in vivo is novel. These studies will provide proof-of-principle data for targeting cancer with Gal3 (or agonists such as peptidomimetics or small molecules). Successful outcome of this project will support the clinical translation of Gal3 for the treatment of malignant glioma and possibly other cancers, which is highly relevant to public health.

Public Health Relevance

This proposal studies a novel mechanism through which tumor cells can be killed, while sparing normal healthy tissue. It uses cell culture of human cells and experimental models in animals to study how galectin-3 can be used as a cancer therapeutic. Understanding this novel mechanism of galectin-3-induced cell death can be exploited to devise novel anti-cancer therapeutic strategies that will benefit public health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA163722-01A1
Application #
8439983
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Ault, Grace S
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$323,700
Indirect Cost
$116,200
Name
Emory University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Way, Gregory P; Sanchez-Vega, Francisco; La, Konnor et al. (2018) Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas. Cell Rep 23:172-180.e3
Ge, Zhongqi; Leighton, Jake S; Wang, Yumeng et al. (2018) Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types. Cell Rep 23:213-226.e3
Ricketts, Christopher J; De Cubas, Aguirre A; Fan, Huihui et al. (2018) The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. Cell Rep 23:313-326.e5
Knijnenburg, Theo A; Wang, Linghua; Zimmermann, Michael T et al. (2018) Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 23:239-254.e6
Zhu, Dan; Osuka, Satoru; Zhang, Zhaobin et al. (2018) BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation. Cancer Cell 33:1004-1016.e5
Peng, Xinxin; Chen, Zhongyuan; Farshidfar, Farshad et al. (2018) Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers. Cell Rep 23:255-269.e4
Huang, Kuan-Lin; Mashl, R Jay; Wu, Yige et al. (2018) Pathogenic Germline Variants in 10,389 Adult Cancers. Cell 173:355-370.e14
Chiu, Hua-Sheng; Somvanshi, Sonal; Patel, Ektaben et al. (2018) Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context. Cell Rep 23:297-312.e12
Ding, Li; Bailey, Matthew H; Porta-Pardo, Eduard et al. (2018) Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics. Cell 173:305-320.e10
Seiler, Michael; Peng, Shouyong; Agrawal, Anant A et al. (2018) Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types. Cell Rep 23:282-296.e4

Showing the most recent 10 out of 51 publications