Ovarian Cancer Targeted Theranostics

Abstract

Ovarian cancer is a leading cause of death from gynecological malignancies. Although the prognosis is quite favorable if detected at an early stage, the vast majority of cases are diagnosed at an advanced stage, when 5-year survival rates are only 30-40%. Most recurrent ovarian tumors are resistant to traditional therapies underscoring the need for new therapeutic options. Theranostic agents, that combine diagnostic and therapeutic capabilities, are being explored to better detect, diagnose and treat ovarian cancer. To minimize morbidity, improve survival rates, and eventually cure patients, new strategies are needed for early detection and for delivering specifically anticancer therapies to tumor sites. In this review we will discuss various molecular imaging modalities and targets that can be used for imaging, therapeutic and theranostic agent development for improved diagnosis and treatment of ovarian cancer.

Keywords: diagnosis and therapy; molecular imaging; ovarian cancer; targeted therapy; theranostic.

Figure 1

(A) Serial PET images of an athymic nude mouse bearing a CA125-positive OVCAR3 xenograft after tail vein injection of ⁸⁹Zr-DFO-mAb-B43.13 after (10.2–12.0 MBq). Coronal planar images intersect the middle of the tumor. (B) Coronal (top) and maximum-intensity projection (MIP; bottom) PET image obtained 72 h after administration of ⁸⁹Zr-DFO-mAb-B43.13 to a mouse 8 week post implantation of an OVCAR3 xenograft on the right shoulder. (C) Coronal (top) and MIP (bottom) PET images obtained 72 h after administration of ⁸⁹Zr-DFO-mAb-B43.13 to the same mouse 11 week post tumor implantation. (D) PET/CT image obtained 120 h after administration of ⁸⁹Zr-DFO-mAb-B43.13 to the same mouse 11 week post tumor implantation. ALN, axillary LNs; BLN, brachial LN; L, liver; p.i., post-injection; SML, submandibular LN; T, tumor. Adapted with permission from Sharma et al. (13).

Figure 2

Biopsies of lesions found histologically to be metastases of serous adenocarcinoma. In total, 57 fluorescent lesions that were identified during surgery were resected. Of these resected lesions 44 (77%) appeared to be malignant on histopathology. Seven (16%) of these 44 lesions were not detected by visual inspection with the naked eye or palpation either because they appeared benign or because they were missed during inspection due to small size (<10 mm) and flat nature. Adapted with permission from Tummers et al. (22).

Figure 3

(A) Transverse endovaginal (EV) low mechanical index reference B-mode ultrasound image of the right ovary in a 50-year-old woman showing a 5.2-cm cystic and solid lesion (yellow arrows point to solid portion). (B) 13 min post iv injection of KDR-targeted contrast MBs (MBKDR), strong imaging signal is seen in the solid portion of the lesion (yellow arrows) on contrast mode ultrasound molecular image. (C,D) IHC performed on adjacent tissue sections demonstrating strong KDR expression on tumor-associated neovasculature (CD31+) (red arrows). (E) Histology showing endometrioid carcinoma. (F) Transverse endovaginal low mechanical index reference B-mode ultrasound image of right ovary showing a 4.8-cm cystic and solid ovarian lesion (yellow arrows point to solid portion) in a 65-year-old woman. (G) 15 min post iv injection of MBKDR, only minimal background signal is seen in 1.3-cm solid part of the lesion (yellow arrows) on contrast mode ultrasound molecular imaging. (H,I) IHC demonstrating minimal KDR expression (green arrow) on CD31+ vasculature. (J) Histology showing benign serous cystadenofibroma. Adapted with permission from Willmann et al. (37).

Figure 4

(A) IR700, RFP fluorescence, and luciferase activity in extracted mesentery from a SHIN3-luc-RFP tumor bearing mouse 3 h after i.p. injection of GSA-IR700. IR700 fluorescent signal and luciferase activity were mostly coincident with RFP positive foci. (B) in vivo serial IR700 fluorescence images of SHIN3-RFP (upper row) and SHIN3-luc (lower row) of tumor-bearing mice after administration of GSA-IR700. The distribution of GSA-IR700 correlated with the fluorescence of RFP or luciferase activity without evident accumulation in other organs up to 6 h after GSA-IR700 administration. (C) BLI of SHIN3-luc tumor bearing mice was obtained every day up to day 7. Luciferase activity decreased only in the NIR-PIT group. (D) Quantitative analysis of BLU ratio. Significant suppression of increment of BLU ratio was seen in the NIR-PIT group compared to other groups. Adapted with permission from Harada et al. (38).