The overall survival for patients diagnosed with advanced or metastatic cancers has changed little despite the development of novel targeted therapeutics. The basis of most cancer care remains cytotoxic therapy - radiation and chemotherapy - that kills rapidly proliferating cells. Current drug development continues to screen for agents under permissive growth conditions with readouts that are surrogates for proliferation. However, these strategies provide only incremental improvements as in vivo microenvironmental tumor conditions and the complex cellular involvement promote heterogeneity within the tumor through genetic and non-genetic variations associated with therapeutic resistance, angiogenesis, and tumor progression. Multiple approaches are under development to improve the identification of druggable targets within these critical tumor cell variants. We and others are investigating one source of tumor heterogeneity - the differentiation hierarchy incorporated within the cancer stem cell hypothesis. We believe that the cancer stem cell phenotype is plastic and defined by both cell autonomous and external cues so high throughput analyses, although reported, may not fully represent the cancer stem cell state. We have previously demonstrated that brain tumor stem cells are resistant to radiation and also promote tumor angiogenesis. Based on this background, we hypothesize that inhibiting key survival pathways active in brain tumor stem cells but not normal tissue stem cells will augment the efficacy of current brain tumor therapies. Specifically, we propose to: 1. Evaluate the anti-angiogenic capacity of a novel brain tumor stem cell targeting agent. 2. Determine the therapeutic efficacy of a novel brain tumor stem cell targeting agent in combination with bevacizumab. 3. Determine the therapeutic efficacy of a novel brain tumor stem cell targeting agent in combination with radiation and chemotherapy. We hope that these studies will lay the foundation for direct translation into therapeutic trials.

Public Health Relevance

Glioblastomas are among the deadliest of all human cancers despite treatment with radiation, chemotherapy, and - most recently - drugs that block new blood vessel growth to feed tumors. Within glioblastomas, cells called cancer stem cells have been found that in laboratory studies are resistant to radiotherapy and chemotherapy and also stimulate new blood vessels to grow. We will test ways of attacking the cancer stem cells to sensitize them to the effects of current brain cancer treatments.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Lathia, Justin D; Li, Meizhang; Sinyuk, Maksim et al. (2014) High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor. Cell Rep 6:117-29
Xie, Qi; Flavahan, William A; Bao, Shideng et al. (2014) The tailless root of glioma: cancer stem cells. Cell Stem Cell 15:114-6
Liu, J K; Lubelski, D; Schonberg, D L et al. (2014) Phage display discovery of novel molecular targets in glioblastoma-initiating cells. Cell Death Differ 21:1325-39
Yan, Kenneth; Wu, Qiulian; Yan, Diana H et al. (2014) Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy. Genes Dev 28:1085-100
Hale, James S; Otvos, Balint; Sinyuk, Maksim et al. (2014) Cancer stem cell-specific scavenger receptor 36 drives glioblastoma progression. Stem Cells 32:1746-58
Sukhdeo, Kumar; Koch, Catherine E; Miller, Tyler E et al. (2014) The Lgr5 transgene is expressed specifically in glycinergic amacrine cells in the mouse retina. Exp Eye Res 119:106-10
Venere, M; Hamerlik, P; Wu, Q et al. (2014) Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ 21:258-69
Schonberg, David L; Lubelski, Daniel; Miller, Tyler E et al. (2014) Brain tumor stem cells: Molecular characteristics and their impact on therapy. Mol Aspects Med 39:82-101
Sukhdeo, Kumar; Paramban, Rosanto I; Vidal, Jason G et al. (2013) Multiplex flow cytometry barcoding and antibody arrays identify surface antigen profiles of primary and metastatic colon cancer cell lines. PLoS One 8:e53015
Kim, Youngmi; Wu, Qiulian; Hamerlik, Petra et al. (2013) Aptamer identification of brain tumor-initiating cells. Cancer Res 73:4923-36

Showing the most recent 10 out of 24 publications