Although advances in radiation therapy (RT, e.g., image-guided and intensity-modulated RT) have led to improved treatment outcomes, overcoming tumor recurrence still remains a challenge for a number of cancers where RT is an important therapeutic modality. There is an increasing appreciation of how dynamic interactions between malignant tumor cells and non-transformed host cells (e.g., immune cells, endothelial cells) determine not only cancer behavior (e.g., invasion and metastasis), but also responses to therapies, including RT. However, the precise mechanisms of molecular and cellular interactions within the tumor microenvironment (TME), and their impact on post-RT relapse remain to be elucidated. The central hypothesis in this application, formulated based on our preliminary data, is that scavenger receptor A (SRA), a pattern recognition molecule primarily expressed on myeloid cells, promotes tumor recurrence by facilitating the polarization of proangiogenic, tumor-associated macrophages (TAMs) and tumor revascularization following RT. Our overall objective is to comprehensively understand a previously unrecognized role of SRA as an essential host factor in governing dynamic myeloid cell-tumor crosstalk and tumor response to RT. The rationale for the proposed research is that delineating fundamental mechanisms of SRA action in modulating the TME in response to RT has the potential for developing novel targeted approaches to reduce cancer recurrence in the clinic. We will test our hypothesis by pursuing 3 specific aims: 1) Establish a crucial role for SRA in potentiating the recovery of tumor vasculature after RT and subsequent recurrence using genetic, biochemical, and cellular approaches with clinically relevant model systems;2) Determine the molecular and cellular basis of SRA functions in skewing tumor-associated macrophages toward an alternatively activated, proangiogenic phenotype;and 3) Validate the concept of targeting SRA in the TME to overcome post-RT recurrence by engaging multivalent antitumor mechanisms. In view of the established immunosuppressive functions of SRA, we will also evaluate the feasibility of blocking SRA activity in the TME to improve the effectiveness of a combinatorial RT and heat shock protein-based therapy. The concept of TAM-associated SRA as a critical, tumor-extrinsic determinant of treatment outcome following RT, and the idea of preventing cancer relapse by antagonizing SRA in the TME to abrogate tumor revascularization and concurrently enhance immune functions are innovative. The proposed research is significant because it is expected to advance the understanding of distinct aspects of dynamic host-tumor interactions and their implications in improving tumor response to RT. The insights gained from these studies will facilitate rational design of multimodality therapy to reduce treatment failure after RT.
The proposed research is highly relevant to public health because identification of molecular and cellular mechanisms involved in cancer recurrence after radiation therapy is ultimately expected to lead to development of targeted strategies for therapeutic intervention. Thus, the proposed research is relevant to the part of NCI's mission that pertains to enhancing tumor response to therapies and reducing treatment failures in cancer patients.
|Ma, Yibao; Temkin, Sarah M; Hawkridge, Adam M et al. (2018) Fatty acid oxidation: An emerging facet of metabolic transformation in cancer. Cancer Lett 435:92-100|
|Payne, Kyle K; Aqbi, Hussein F; Butler, Savannah E et al. (2018) Gr1-/low CD11b-/low MHCII+ myeloid cells boost T cell anti-tumor efficacy. J Leukoc Biol 104:1215-1228|
|Pagare, Piyusha P; Wang, Huiqun; Wang, Xiang-Yang et al. (2018) Understanding the role of glucose regulated protein 170 (GRP170) as a nucleotide exchange factor through molecular simulations. J Mol Graph Model 85:160-170|
|Tang, Yuan; Li, Huifang; Li, Junru et al. (2017) Macrophage scavenger receptor 1 contributes to pathogenesis of fulminant hepatitis via neutrophil-mediated complement activation. J Hepatol :|
|Pagare, Piyusha P; Zaidi, Saheem A; Zhang, Xiaomei et al. (2017) Understanding molecular interactions between scavenger receptor A and its natural product inhibitors through molecular modeling studies. J Mol Graph Model 77:189-199|
|PrabhuDas, Mercy R; Baldwin, Cynthia L; Bollyky, Paul L et al. (2017) A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease. J Immunol 198:3775-3789|
|Zheng, Yi; Li, Xia; Pagare, Piyusha P et al. (2017) Design, synthesis, and characterization of rhein analogs as novel inhibitors of scavenger receptor A. Bioorg Med Chem Lett 27:72-76|
|Guo, Chunqing; Fulp, Jacob W; Jiang, Yuqi et al. (2017) Development and Characterization of a Hydroxyl-Sulfonamide Analogue, 5-Chloro-N-[2-(4-hydroxysulfamoyl-phenyl)-ethyl]-2-methoxy-benzamide, as a Novel NLRP3 Inflammasome Inhibitor for Potential Treatment of Multiple Sclerosis. ACS Chem Neurosci 8:2194-2201|
|Akiel, Maaged; Guo, Chunqing; Li, Xia et al. (2017) IGFBP7 Deletion Promotes Hepatocellular Carcinoma. Cancer Res 77:4014-4025|
|Li, Yanli; Tang, Yuan; Wang, Shoujie et al. (2016) Endogenous n-3 Polyunsaturated Fatty Acids Attenuate T Cell-Mediated Hepatitis via Autophagy Activation. Front Immunol 7:350|
Showing the most recent 10 out of 28 publications