Glioblastoma (GBM) ranks among the most lethal of human cancers with conventional therapy offering only palliation. Great strides have been made in understanding GBM genetics and modeling these tumors, and new targeted therapies are being tested but these advances have not substantially translated into improved patient outcomes. Multiple chemotherapeutic agents, including temozolomide, a first-line treatment in glioma, have been developed to kill cancer cells. However, the response to temozolomide in GBM is modest. Radiation is also moderately effective but this approach is plagued by limitations due to collateral radiation damage to eloquent brain tissue and development of radio-resistance. There is clearly an unmet clinical need, to develop either a novel treatment strategy or an adjuvant strategy to enhance efficacy of existing treatments. This unmet clinical need becomes even more pressing as systemic cancer treatments improve and brain metastases become an ever increasing challenge. This grant application represents the merged efforts of two recognized research programs to develop new paradigms for brain cancer treatment. The Connor laboratory, with their new discovery that reduction of H-ferritin in models of brain tumors sensitizes the tumors to radio and chemotherapy has combined with the Rich laboratory with their extensive knowledge of cancer models and tumor microenvironments to create a synergy between two productive research groups to maximize the potential for sustained impact on the field of Neuro-Oncology. The temporal disruption in cellular iron homeostasis appears linked to activation of hypoxic pathways that may underlie therapy resistance. When coupled with the loss of specific contributions of H- ferritin to DNA protection and transcription, a window of opportunity is evident for evaluation of H-ferritin down-regulation as an adjuvant therapy in brain cancers. This proposal will also provide new data into the role of ferritin in tumor propagation and survival. Thus the proposed studies are innovative because (i) they introduce a new function for a critical regulatory protein in cancer cells, (ii) they address the mechanism of how H-ferritin expression is induced, (iii) identify H-ferritin as a novel molecular target in cancer (v) provide a novel cellular-specific targeting of H-ferritin using a therapeutic relevant liposomal delivery system of H-ferritin. Based on the evidence both laboratories have generated, we hypothesize that H-ferritin promotes GBM growth by maintaining tumorigenic hierarchical growth patterns and chemo-/radio-resistance and that targeted anti-ferritin therapies will disrupt GBM growth. These two laboratories have joined efforts utilizing state of the art nanotechnology, including cell-specific drug delivery to cancer cells and multi-photon imaging and novel and highly informative glioma mouse models address the potential therapeutic value of targeting H-ferritin and advance the basic scientific field by demonstrating novel functions for ferritin that was once considered only an intracellular iron storage protein.

Public Health Relevance

Glioblastoma multiforme is the most prevalent primary malignant brain tumor. Its resistance to conventional therapies, rapid growth and highly infiltrative nature necessitate the use of highly aggressive therapies including tumor resection, radiation, and chemotherapy. Even with such therapies, prognosis is dismal with the median patient survival between 14-16 months. Two productive laboratories have combined their expertise in iron biology, drug delivery and cancer to provide innovative insights and approaches into the disruption of intracellular iron management as a potential therapeutic approach to the treatment of brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA169117-01A1
Application #
8596915
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Pelroy, Richard
Project Start
2013-07-01
Project End
2018-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$546,861
Indirect Cost
$120,195
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Hubert, Christopher G; Rivera, Maricruz; Spangler, Lisa C et al. (2016) A Three-Dimensional Organoid Culture System Derived from Human Glioblastomas Recapitulates the Hypoxic Gradients and Cancer Stem Cell Heterogeneity of Tumors Found In Vivo. Cancer Res 76:2465-77
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Ahluwalia, Manmeet S; Rich, Jeremy N (2015) Growth Factor Receptor Fusions Predict Therapeutic Sensitivity. Clin Cancer Res 21:3105-7
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Hitomi, Masahiro; Deleyrolle, Loic P; Mulkearns-Hubert, Erin E et al. (2015) Differential connexin function enhances self-renewal in glioblastoma. Cell Rep 11:1031-42
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Xie, Qi; Wu, Qiulian; Mack, Stephen C et al. (2015) CDC20 maintains tumor initiating cells. Oncotarget 6:13241-54
Schonberg, David L; Miller, Tyler E; Wu, Qiulian et al. (2015) Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells. Cancer Cell 28:441-55

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