ProCA1.GRPR: a new imaging agent in cancer detection.

Precision molecular imaging addresses major medical gaps including the early detection of small lesion and biomarker expression, especially for high-risk patients, and monitoring the dynamic changes of biomarkers during disease progression and upon therapeutic treatment. One of the major challenges in achieving precision medicine is developing our capabilities to select patients with genetic and phenotypic heterogeneity while monitoring treatment responses. Current golden standard of histological analysis coupled with biopsy has many limitations, such as invasiveness, significant sampling errors especially for small lesions and risks of tumor peritoneal seeding [1]. Important avenues to achieve these goals include identifying biomarkers whose expression are capable of accurately reflect disease stages and treatment effects, and developing sensitive and noninvasive precision molecular imaging methodology for early responsive, predictive and prognostic biomarkers with increased levels of spatial and temporal resolution [2]. Here, we will first discuss GRPR as an attractive biomarker for molecular imaging of various types of cancers. We will then report our development of protein-based MRI contrast agent against GRPR with significantly improved sensitivity and spatial resolution. GRPR is a G-protein coupled receptor belonging to the bombesin receptor family [3]. The nature ligand for GRPR is gastrin releasing peptide (GRP). The C-terminal peptide sequence of GRP is highly similar to its amphibian counterpart, bombesin, a 14 amino acid peptide with high affinity to both GRPR and neuromedin B receptor. GRP and bombesin have strong affinity to GRPR at nanomolar range. The binding of these peptides to GRPR triggers downstream signaling cascades and activates a series of physiological and biological events, such as hormone release in endocrine organs [4]. GRPR is an attractive biomarker expressed on a series of human malignancies including prostate cancer, lung cancer, breast cancer, colon cancer, ovarian cancer, pancreatic cancer, gastrointestinal carcinoid tumor, head and neck cancer, various CNS/neural tumors, renal cell cancers and uterine cancer. As investigated by PCR, immunohistochemistry and radionuclide binding assay of clinic samples, GRPR is expressed in almost 100% on the prostate tumors. The expression level of GRPR in prostate cancer is significantly higher than that of other normal tissues. In addition, 33–72% of breast cancer, 40–50% of gastric cancer, 85% of carcinoids cancer and 29–85% of small cell lung cancer also have high GRPR expression [5]. GRPR is highly expressed in prostatic intraepithelial neoplasias, primary prostate cancer and invasive prostate carcinomas, whereas the expression level in normal prostate tissue and benign prostate hyperplasia are relatively low [6,7]. The distribution of GRPR in prostate cancer is heterogeProCA1.GRPR: a new imaging agent in cancer detection