Our aims in this competitive renewal application are shaped by our observations during the previous funding period that confirmed the critical role of cyclooxygenase (COX)-2 in cancer invasion and metastasis. We found that COX-2 was induced in hostile environments and played a critical role in mediating invasion and metastasis. COX-2 expression also increased following treatment with a conventional chemotherapy agent, 5-fluorouracil. Molecular characterization and functional imaging have identified new functional roles for COX-2 that have created new possibilities for more effective COX-2 targeting, and for imaging COX-2 expression and activity. Our data demonstrated the importance of targeting this pathway in cancer, and finding strategies to image COX-2 expression and activity. These data highlighted the importance of expanding our understanding of the role of COX-2 in altering the tumor phenotype to identify additional pathways, networks, and targets that mediate these alterations, and the importance of noninvasively identifying tumors that have increased COX-2 expression, to select for COX-2 targeting. These observations have led us to focus on three new aims that will advance our understanding of the role of inflammation in cancer progression, treatment and metastasis. These studies will be performed using triple negative human breast cancer xenograft models with different COX-2 expression levels. Our purpose in Aim 1 will be to identify the molecular causes of the effect of COX-2 on choline metabolism. These studies can uncover new biomarkers and new targets to use in combination with COX-2 targeting, to achieve improved effectiveness.
In Aim 2 we will investigate the role of COX-2 in altering the extracellular matrix structure and function using imaging.
In Aim 3 we will develop optical and MRS based probes to report on COX-2 expression and activity that may, in the future, lead to clinically translatable 19F MRS probes to detect COX-2 activity. The studies in this application will advance our insight and identify new strategies to exploit this critically important target in cancer treatment.
COX-2 is a critically important target in cancer that significantly influences a range of characteristics such as angiogenesis, invasion and metastasis. In this application we intend to uncover new targets that interact with COX-2, and identify the effect of COX-2 expression on extracellular matrix structure and function. We also intend to develop probes to noninvasively image COX-2 expression and activity that will allow us to further understand the role of this enzyme in cancer and allow us to effectively target it.
|Bhujwalla, Zaver M; Kakkad, Samata; Chen, Zhihang et al. (2018) Theranostics and metabolotheranostics for precision medicine in oncology. J Magn Reson 291:141-151|
|Chen, Zhihang; Krishnamachary, Balaji; Penet, Marie-France et al. (2018) Acid-degradable Dextran as an Image Guided siRNA Carrier for COX-2 Downregulation. Theranostics 8:1-12|
|Shah, Tariq; Krishnamachary, Balaji; Wildes, Flonne et al. (2018) Molecular causes of elevated phosphoethanolamine in breast and pancreatic cancer cells. NMR Biomed 31:e3936|
|Goggins, Eibhlin; Kakkad, Samata; Mironchik, Yelena et al. (2018) Hypoxia Inducible Factors Modify Collagen I Fibers in MDA-MB-231 Triple Negative Breast Cancer Xenografts. Neoplasia 20:131-139|
|Bharti, Santosh K; Mironchik, Yelena; Wildes, Flonne et al. (2018) Metabolic consequences of HIF silencing in a triple negative human breast cancer xenograft. Oncotarget 9:15326-15339|
|Penet, Marie-France; Kakkad, Samata; Pathak, Arvind P et al. (2017) Structure and Function of a Prostate Cancer Dissemination-Permissive Extracellular Matrix. Clin Cancer Res 23:2245-2254|
|Krishnamachary, Balaji; Stasinopoulos, Ioannis; Kakkad, Samata et al. (2017) Breast cancer cell cyclooxygenase-2 expression alters extracellular matrix structure and function and numbers of cancer associated fibroblasts. Oncotarget 8:17981-17994|
|Mori, Noriko; Wildes, Flonné; Takagi, Tomoyo et al. (2016) The Tumor Microenvironment Modulates Choline and Lipid Metabolism. Front Oncol 6:262|
|Shah, Tariq; Wildes, Flonne; Kakkad, Samata et al. (2016) Lymphatic endothelial cells actively regulate prostate cancer cell invasion. NMR Biomed 29:904-11|
|Dore-Savard, Louis; Lee, Esak; Kakkad, Samata et al. (2016) The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts. Sci Rep 6:39460|
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