This proposed work will define the potential of treating ovarian cancer with magnetic nanoparticle (mNP) mediated hyperthermia (mNPHT). It will investigate how best to destroy both tumor cells and leukocytes that suppress antitumor immunity and support angiogenesis. Studies will be done in vivo in mice using syngeneic mouse ovarian cancer and human xenografts and in vitro using viable dissociated primary human ovarian cancer preparations that include tumor cells, leukocytes and endothelial cells. Our extensive experience with ovarian cancer research will inform the design of mNP selectively targeting tumor and tumor supporting cells. The hypothesis is that superior therapeutic benefits can be achieved by combining mNP-mediated thermoablation of tumor cells (including chemoresistant cancer cells) with thermoablation of crucial immunosuppressive/pro-angiogenic tumor leukocytes and these treatments will synergize with standard chemotherapies.
Aim 1 will determine the impact on tumors of using mNPHT to eliminate tumor-associated phagocytic leukocytes in immunocompetent murine ovarian cancer models.
Aim 2 will use the same murine tumor models as aim 1 to define the effectiveness of eliminating tumor cells with mNPHT, with or without tumor-associated leukocyte depletion or suboptimal chemotherapy.
Aim 3 will determine the interaction of differently targeted mNP preparations with freshly dissociated human tumors, using a unique resource of multiple aliquots of frozen cell suspensions from our large bank of freshly dissociated human ovarian cancers.
Aim 4 will define the effectiveness of mNP-hyperthermia as an individual treatment against human ovarian cancer xenografts in immunodeficient mice, and will determine how best to apply this treatment in order to synergize with otherwise ineffective doses of cisplatin. Throughout this proposal, the reagents, models and experiments have been designed to accomplish the preclinical optimization of mNP-based hyperthermia as a novel intervention against ovarian cancers. These studies will pave the way for subsequent clinical testing of mNPHT in combination with established therapeutic approaches for the treatment of otherwise lethal ovarian cancers. This project will interact with all other projects and cores: it will draw on the Nanoparticle Core for mNPs, Project 1 will provide ScFv-conjugated particles. Project 2 will test their system in our ovarian tumor models, Project 3 provides the treatment equipment, the Toxicology, Pathology, and Biodistribution Core will assess mNP location and the Biostatistics, Data Analysis, and Computation Core will provide data analysis.
Every cancer therapy should have a high therapeutic index and each cancer type has unique characteristics that impact therapeutic index. The unique biology of each cancer must inform efforts to develop novel therapies. This proposal, from a group that has extensive experience with ovarian cancer, is the first effort to develop mNP-based therapies for ovarian cancer. By working closely with the engineers, mathematicians, biologists, and physicists of this CCNE, the therapeutic index against ovarian cancer will be maximized.
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