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Ovarian cancer (OC) is estimated to be diagnosed in over 225, 000 women per year worldwide and remains a significant cause of gynecological cancer mortality (approximately 140, 000 deaths per year). Unfortunately, the majority of women continue to present at advanced stages and the overall five-year survival rate is around 40%. The current standard of care for newly diagnosed ovarian cancer is a combination of optimal cytoreductive surgery and platinum-based chemotherapy. Key advances in radical surgery and chemotherapy strategies have led to improved, albeit modest, clinical outcomes. Despite advances, there remains a significant risk of recurrence and resistance to therapy and when this occurs, ovarian cancer is currently incurable. Hence there is an urgent need to develop smarter treatment options.
FSHR and ovarian cancer progression
The follicle-stimulating hormone receptor (FSHR) is a G-protein–coupled receptor which is primarily expressed in the granulosa cells of the ovary and the Sertoli cells of the testis of adults. In the early stage of epithelial ovarian cancer (EOC) initiation, FSH may induce PI3K/AKT signaling in an FSHR-dependent manner, which promotes HIF-1α degradation by elevating the gankyrin level. This contributes to increased cyclin D1 level by promoting HIF-1α binding with the cyclin D1 promoter, finally resulting in EOC cell expansion. Thus, in the later stage of EOC, aberrant expression of FSHR may promote cell proliferation independently. Meanwhile, elevated gankyrin may activate PI3K/AKT signaling by feedback.
In vitro results from overexpressing cell lines suggest that the protein may play a role as a stimulator of cancer cell proliferation, and treatment of some ovarian cancer cells with FSH, the ligand for FSHR, can result in growth stimulation in a dose- and time-dependent manner in vitro, which suggests that FSHR-targeted therapy could be effective in ovarian cancer. Furthermore, recent biodistribution studies from Radu and colleagues show ubiquitous ectopic expression of FSHR in the tumor-associated blood vessels of various tumor types, including prostate adenocarcinoma, urothelial carcinoma, renal cell carcinoma, and ovarian cancer, without detectable expression in surrounding healthy vasculature, although this finding has yet to be confirmed by others. The biologic significance of its expression in tumor blood vessels remains unknown, but the FSHR expression level correlates with the response to antiangiogenic therapies and suggests that anti-FSHR therapy could be used broadly as a tumor vasculature disruption agent across solid malignancies. Thus, FSHR expression by both ovarian cancer cells and its tumor-associated vasculature may provide a unique opportunity to deliver synergistic effects from a single, anti-FSHR therapy, thus making FSHR targeting particularly attractive in ovarian cancer.
FSHR as a target in the redirected T-cell therapy for cancer
T-cell targeting of antigens on the cancer cell surface can now be achieved through the genetic modification of primary T cells to express a chimeric antigen receptor (CAR). Adoptive immunotherapy using CAR T cells specific for CD19 has been shown to induce durable remissions in hematologic malignancies. In the absence of tumor-restricted antigens, other antigens that are expressed by tumor cells and cells of healthy organs with nonessential function for patient survival, such as reproductive organs, may be attractive targets for CAR-based immunotherapy. FSHR is a member of this class of antigens. The restricted expression pattern of abundant FSHR in ovarian cancer, tumor vessels and gonadal tissues, relative to that found in adult somatic tissues, lowers the risk for on-target, off-tumor toxicity and makes FSHR an appealing target for T-cell–based immunotherapy. Some researches have developed a strategy for treatment of human ovarian cancer via the redirection of primary human T-cells against FSHR. Anti-FSHR immunoreceptors (FSHR-IR), specific for human and mouse FSHR, have be created using peptides derived from the natural FSHR ligand, FSH, for redirected T-cell activity. And recently studies show that anti-FSHR-IR T-cells are capable of targeting and killing FSHR-expressing cancer cells, resulting in significant suppression of FSHR-expressing tumor outgrowth in vivo.
FSHP modified nanoparticle drug delivery system in ovarian cancer therapy
Traditional chemotherapy drugs have an obvious drawback of nonspecific biodistribution in treating ovarian cancer. FSHR is mainly expressed in reproductive system, is an important drug target in developing novel therapeutics. Using a polypeptide of follicle-stimulating hormone (named as FSHP), a conjugated nanoparticle, FSHP-NP is developed to target FSHR in lymphatic metastasis of ovarian cancer and it is tested for recognition specificity and uptake efficiency on FSHR-expressing cells. A paclitaxel (PTX)-loaded FSHP-NP (FSHP-NP-PTX) is further developed and its anti-tumor effect is determined in vivo and in vitro. Researches indicate that FSHP-NP-PTX displays significantly stronger anti-cell proliferative and anti-tumor effects in a dose- and time-dependent manner when compared with free PTX or naked PTX-loaded nanoparticles (NP-PTX) in vitro. In vivo examinations show that the size and weight of the lymph nodes are reduced in the FSHP-NP-PTX group. FSHR as a novel therapeutic target in ovarian cancer and delivery of PTX via conjugated nanoparticle (FSHP-NP) might represent a new therapeutic approach in ovarian cancer.
Understanding more about how best to utilize our increasing knowledge of the molecular abnormalities involved in ovarian cancer will be critical in improving clinical outcome in ovarian cancer. Of the many targeted therapies currently under evaluation in phase I/II and III studies, the most promising strategies developed so far are the anti-angiogenic agents and PARP inhibitors. The restricted expression pattern of abundant FSHR in ovarian cancer, tumor vessels, and gonadal tissues, relative to that found in adult somatic tissues, lowers the risk for on-target, off-tumor toxicity and makes FSHR an appealing target for T-cell–based immunotherapy. Until the day when these technologies fulfill their potential in creating a broadly applicable and permanent ovarian cancer cure.
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