Glioblastomas are highly lethal cancers for which conventional therapies are essentially palliative. We recently demonstrated that a subset of glioblastoma cells that share characteristics with somatic neural stem cells, cancer stem cells, are resistant to radiation and highly angiogenic. In combination with data from other laboratories, our results suggest that cancer stem cells are important determinants of the overall behavior of glioblastomas and that cancer stem cell directed therapies may be effective in controlling glioblastoma growth. Anti- angiogenic therapies may function as anti-stem cell therapies not only through the disruption of cancer stem cell angiogenesis but may also disrupt the vascular niche promoting cancer stem cell maintenance. This approach has direct therapeutic relevance as Bevacizumab (Avastin), a VEGF neutralizing antibody, has demonstrated activity in clinical trials for glioblastoma patients supporting potential utility of anti-angiogenic therapies for brain tumors. Critical to the success of anti-cancer stem cell approaches will be the limitation of toxicity to normal stem cells. Cancer cells reside in relative hypoxia, which has been linked to tumor angiogenesis, invasion, and resistance to therapy. Hypoxia increases stem cell maintenance suggesting that effects of hypoxia on cancer stem cells may contribute to tumor malignancy. To investigate the role of tumor vasculature in cancer stem cell biology and lay the foundation for potential new therapeutic approaches, we propose to: 1) Interrogate the response of cancer stem cells to hypoxia in survival, secretion of angiogenic factors, and invasion. 2) Determine the molecular mechanisms driving cancer stem cell specific responses to hypoxia relative to normal neural stem cells. 3) Determine if cancer stem cells provide a biomarker for patient response to bevacizumab therapy. The successful completion of these studies will better define the role of cancer stem cells in glioblastoma biology and provide direct therapeutic benefit. 4) Determine if targeting cancer stem cell hypoxic responses sensitizes tumors to cytotoxic therapies (radiotherapy, chemotherapy). The cancer stem cell hypothesis may offer novel insights into glioblastoma angiogenesis and radiation resistance. We now seek to build on our prior studies of glioblastoma stem cells to understand the mechanisms by which these cells display preferential angiogenesis and survival upon treatment with radiation and chemotherapy. These studies may permit the selective targeting of cancer stem cells to improve tumor response to therapy.
2. Targeting brain tumor stem cells through novel therapeutic combinations
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. 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.