Our overall goal is to improve the cure rates of glioblastoma multiforme (GBM) and of head and neck tumors: human cancers for which the current treatment is radiotherapy (with or without surgery and chemotherapy) and for which treatment failure leading to patient death is largely the result of inability to control the primary tumor. To do this we will exploit the novel hypothesis that the failure to cure these tumors despite high dose radiotherapy is the result of regrowth of the tumor vasculature from bone marrow derived cells (BMDCs) following the course of radiotherapy. We have obtained strong evidence for the validity of this hypothesis by showing that MMP-9 expressing CD11b+ monocytes are recruited to tumors following irradiation, that tumors cannot grow in an irradiated site without MMP-9, that depletion of CD11b+ cells following irradiation enhances tumor response to irradiation, and that inhibition of the interaction of SDF-1 with CXCR4, a key receptor on the monocytes that recruits them to the tumor vasculature, sensitizes GBM to fractionated irradiation. To determine if this hypothesis can be exploited for clinical benefit we will use both mouse and human GBM implanted intracranially and the FaDu human head and neck tumor inplanted subcutaneously in Rag1 knockout mice respectively. We will evaluate the influence of MMP-9 on tumor radiosensitivity and host cell infiltration using appropriate combinations of tumor cells and BMDCs with and without MMP-9 transplanted into wild type and MMP-9 knockout mice. We will also evaluate the contribution of VEGF and SDF-signaling and pericyte progenitors using appropriate neutralizing antibodies and inhibitors. We will also test imatinib mesylate (GleevecTM) to block the mobilization of BMDCs by inhibition of the receptor c-kit on bone marrow cells. To determine the contribution of BMDCs to tumor growth after irradiation we will replace the bone marrow in the host mice with bone marrow from syngeneic actin-EGFP transgenic mice and evaluate the host cells in the tumor using FACS analysis and immunohistochemistry. Targeting both the local tumor and the bone marrow derived cells is a novel paradigm and could lead to a major increase in the curability of tumors by radiotherapy. Our project combines the expertise of two laboratories, that of Dr. Brown, an expert in tumor radiation biology, and that of Dr. Bergers, an expert in tumor angiogenesis and bone marrow derived cells in tumors.

Public Health Relevance

The overall goal of this project is to improve the cure rates of glioblastoma multiforme (GBM) and of head and neck tumors: human cancers for which the current treatment is radiotherapy (with or without surgery and chemotherapy) and for which treatment failure leading to patient death is largely the result of inability to control the primary tumor. To do this we plan to exploit the novel hypothesis that the failure to cure these tumors despite high dose radiotherapy is the result of regrowth of the tumor vasculature from bone marrow derived cells (BMDCs) following the course of radiotherapy. We will develop strategies to inhibit this contribution of BMDCs to the tumor vascular that can be tested immediately in cancer patients as all the drugs to be used are clinically approved. Targeting both the local tumor and the bone marrow derived cells is a novel paradigm and could lead to a major increase in the curability of GBM and head and neck tumors by radiotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA128873-05
Application #
8267090
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
2008-07-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$494,069
Indirect Cost
$108,276
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Brown, J Martin; Carlson, David J; Brenner, David J (2014) The tumor radiobiology of SRS and SBRT: are more than the 5 Rs involved? Int J Radiat Oncol Biol Phys 88:254-62
Liu, Shie-Chau; Alomran, Reem; Chernikova, Sophia B et al. (2014) Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats. Neuro Oncol 16:21-8
Brown, J M (2014) Vasculogenesis: a crucial player in the resistance of solid tumours to radiotherapy. Br J Radiol 87:20130686
Martin, Brown J (2013) Inhibiting vasculogenesis after radiation: a new paradigm to improve local control by radiotherapy. Semin Radiat Oncol 23:281-7
Kioi, Mitomu; Vogel, Hannes; Schultz, Geoffrey et al. (2010) Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 120:694-705
Brown, Martin (2010) Henry S. Kaplan Distinguished Scientist Award Lecture 2007. The remarkable yin and yang of tumour hypoxia. Int J Radiat Biol 86:907-17
Coffelt, Seth B; Lewis, Claire E; Naldini, Luigi et al. (2010) Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. Am J Pathol 176:1564-76
Ahn, G-One; Tseng, Diane; Liao, Cho-Hwa et al. (2010) Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci U S A 107:8363-8
Ahn, G-One; Brown, J Martin (2009) Influence of bone marrow-derived hematopoietic cells on the tumor response to radiotherapy: experimental models and clinical perspectives. Cell Cycle 8:970-6
Ahn, G-One; Brown, J Martin (2009) Role of endothelial progenitors and other bone marrow-derived cells in the development of the tumor vasculature. Angiogenesis 12:159-64