Prolactin Receptor–Mediated Internalization of Imaging Agents Detects Epithelial Ovarian Cancer with Enhanced Sensitivity and Specificity

Abstract

Poor prognosis of ovarian cancer (OvCa), the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack high sensitivity to detect small tumors and high specificity to distinguish malignant from benign tissue, both impeding diagnosis of early and metastatic cancer stages and leading to costly and invasive surgeries. Tissue microarray analysis revealed that >98% of OvCa express the prolactin receptor (PRLR), forming the basis of a new molecular imaging strategy. We fused human placental lactogen (hPL), a specific and tight binding PRLR ligand, to magnetic resonance imaging (gadolinium) and near-infrared fluorescence imaging agents. Both in tissue culture and in mouse models, these imaging bioconjugates underwent selective internalization into OvCa cells via PRLR-mediated endocytosis. Compared to current clinical magnetic resonance imaging techniques, this targeted approach yielded both enhanced signal-to-noise ratio from accumulation of signal via selective internalization and improved specificity conferred by PRLR upregulation in malignant OvCa. These features endow PRLR-targeted imaging with the potential to transform OvCa detection.

Prolactin signaling drives tumorigenesis in human high grade serous ovarian cancer cells and in a spontaneous fallopian tube derived model

“…This study found that human FTE actually produce their own PRL as well as many HGSOC cell lines, thus PRL as a biomarker might be a reflection of the fallopian tube origin. In addition to the ligand, MRI or infrared fluorescence imaging bioconjugates were previously designed that specifically bind to the PRL-R [39]. These conjugates effectively underwent selective internalization and facilitated the PRL-R targeted diagnosis of ovarian cancer [39].…”

“…In addition to the ligand, MRI or infrared fluorescence imaging bioconjugates were previously designed that specifically bind to the PRL-R [39]. These conjugates effectively underwent selective internalization and facilitated the PRL-R targeted diagnosis of ovarian cancer [39]. Therefore, both the ligand and the receptor of prolactin are not simply biomarkers, but also active drivers of fallopian tube derived HGSOC.…”

Gonadotropin-Releasing Hormone Receptor-Targeted Near-Infrared Fluorescence Probe for Specific Recognition and Localization of Peritoneal Metastases of Ovarian Cancer

“…False-positive lymph nodes were also observed in a phase II trial of OTL38 in ovarian cancer (21). Sundaram reported a prolactin receptor-specific probe using placental lactogen (hPL) conjugated to MRI and NIRF imaging agents and showed improved specificity over currently used contrast agents (11). However, continuous exposure (16 days) to hPL conjugates caused increased activity in ovarian cancer cells.…”

“…Since ovarian cancer has a peritoneal dissemination pattern, imaging agents can bind to malignant lesions more directly through peritoneal injection. Several studies have testified the viability of the peritoneal administration of imaging agents for detecting peritoneal metastasis (11,33,34). Nonetheless, systemic administration of the probe will be attempted to detect distant metastasis or deep lesions in further studies.…”

“…Over the past two decades, researchers have attempted to improve the fluorescence imaging system, identify potential targetable biomarkers, and develop tumor-specific fluorophores for clinical applications (9)(10)(11). In particular, near-infrared fluorescence (NIRF) imaging is advantageous for clinical use owing to its improved penetration depth and limited autofluorescence compared with visible-light fluorescence imaging (12).…”