Decoy nanoparticles to disrupt cancer cell-stromal cell networks



 DESCRIPTION (provided by applicant): Decoys are used in strategies to achieve distraction or misdirection. In this application we intend to develop biomimetic nanoparticles (NPs) that are covered with cancer cell membranes to act as decoys to misdirect or distract cancer cells, or cancer associated stromal cells. Stromal cells such as cancer associated fibroblasts (CAFs) mediate many of the aggressive characteristics of cancer but have reservoirs that are largely left intact by our current therapeutic strategies. Therefore following surgery or chemotherapy, a few surviving cancer cells that ordinarily would not survive on their own, continue to have a host of stromal cells to assist them in re- establishment, either at the primary site or at a distant site. Because of their important functional roles, destroying stromal cells that assist cancer cells is not a viable solution. Instead, disrupting communications between cancer cells and stromal cells may be a useful strategy. Once developed and characterized, the NPs will be evaluated for their ability to attach to cancer cells, and activated fibroblasts in circulation and at primary or distat tumor sites. These NPs will be decorated with an imaging reporter to characterize their biodistribution in vivo and ex vivo. Such NPs have not been previously developed for applications in cancer. Our ultimate purpose is to determine if these NPs attract circulating cancer cells, circulating stromal cells, or disrupt the spontaneous or experimental metastatic cascade in triple negative breast cancer. Since the CXCL12-CXCR4 axis has a wide spectrum of roles in facilitating breast cancer invasion and metastasis through breast cancer cell-CAF signaling, we will initially investigate the role of high and low CXCR4 expressing cancer cell membrane coated NPs in disrupting cancer cell-CAF interactions. CAFs also play a major role in the formation of collagen 1 (Col1) fibers in tumors. We can therefore evaluate the functional effects of these NPs on Col1 fiber patterns in primary and metastatic tumors. In the future, such NPs may be loaded with a therapeutic cargo for targeting the premetastatic niche or eliminating circulating cancer cells, or they may be used to assist in the activation of the immune response. These NPs can also, in the future, be labeled with MR contrast agents or radiolabeled for detection using human MR or PET scanners. These studies will potentially identify new, clinically translatable strategies to disrupt the metastatic cascade in breast cancer, and represent a new strategy in developing effective treatments to prevent metastatic breast cancer.