The ability to diagnose cancer at the earliest stages of molecular dysregulation before any overt physiologic symptoms have developed would permit immediate therapeutic intervention resulting in higher survival rates. In our original application RO1 CA135650 "Multi-parameter monitoring of breast cancer progression and therapeutic response" we established that underglycosylated mucin1 tumor antigen (uMUC1) is altered in the premalignant stage and that we can detect this premalignant transformation using noninvasive MR imaging in a mouse model of breast cancer. This coincided with analysis of uMUC1 expression in human biopsy samples from breast cancer patients that showed a marked upregulation of the antigen in the normal tissues adjacent to cancer lesions (but identified as "Normal" on pathology reports) compared to tissues from women with no cancer history. Furthermore, we observed downregulation of the uMUC1 antigen in chemotherapy studies in a transgenic human breast tumor model using noninvasive MRI. These data indicate that uMUC1 is altered very early in the process of breast carcinogenesis and could serve as a predictive biomarker for cancer detection and therapy. In this renewal application we propose to extend these studies to evaluate uMUC1 for a wide- ranging predictive cancer diagnostics and therapy response considering that it is over expressed and underglycosylated on over 50% of human cancers. This will be done by first establishing relevance of uMUC1 to other adenocarcinomas (pancreatic, colorectal, and ovarian) in non-cancerous, adjacent normal, and malignant clinical tissue samples. Next, we will use animal models of pancreatic, colorectal, and ovarian cancers expressing human uMUC1 and test whether we can predict and monitor malignant transformation using our imaging approach by quantitatively tracking the relative abundance of the uMUC1 tumor antigen. As in our original application, for MR imaging and uMUC1 targeting we will utilize tumor-specific contrast agent (MN-EPPT) that consists of iron oxide nanoparticles (MN, detectable by magnetic resonance imaging) conjugated to peptides (EPPT), specific for uMUC1. Finally, we will evaluate global relevance of uMUC1 as a predictive biomarker of chemotherapy response by performing therapy studies in established animal models. We expect to observe changes in uMUC1 availability prior to changes in tumor size as monitored by MRI based on MN-EPPT accumulation during the course of chemotherapy. This will be correlated with tumor stage, as well as with chemotherapeutic success, as defined by relative survival and induction of tumor cell apoptosis.
The ability to diagnose cancer at the earliest stages of molecular dysregulation would be highly advantageous for cancer patients resulting in higher survival rates. In this renewal application we will investigate global relevance of underglycosylated mucin1 tumor antigen (uMUC1) as a biomarker of cancer progression and response to chemotherapy. We will first use state-of-the-art magnetic resonance imaging approach for detection of uMUC1 expressing tumors in vivo starting at pre-malignant stage. Next, we will investigate the utility of this antigen for imaging of tumor response to chemotherapy. If successful, these studies will establish the value of uMUC1 as a wide-ranging predictive cancer biomarker. More importantly, they will prove the feasibility of predictive cancer diagnostics using molecular MRI.
|Ghosh, Subrata K; Pantazopoulos, Pamela; Medarova, Zdravka et al. (2013) Expression of underglycosylated MUC1 antigen in cancerous and adjacent normal breast tissues. Clin Breast Cancer 13:109-18|
|Medarova, Zdravka; Rashkovetsky, Leonid; Pantazopoulos, Pamela et al. (2009) Multiparametric monitoring of tumor response to chemotherapy by noninvasive imaging. Cancer Res 69:1182-9|