Potential Therapeutic Targets in Uterine Sarcomas

Abstract

Uterine sarcomas are rare tumors accounting for 3,4% of all uterine cancers. Even after radical hysterectomy, most patients relapse or present with distant metastases. The very limited clinical benefit of adjuvant cytotoxic treatments is reflected by high mortality rates, emphasizing the need for new treatment strategies. This review summarizes rising potential targets in four distinct subtypes of uterine sarcomas: leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Based on clinical reports, promising approaches for uterine leiomyosarcoma patients include inhibition of VEGF and mTOR signaling, preferably in combination with other targeted or cytotoxic compounds. Currently, the only targeted therapy approved in leiomyosarcoma patients is pazopanib, a multitargeted inhibitor blocking VEGFR, PDGFR, FGFR, and c-KIT. Additionally, preclinical evidence suggests effect of the inhibition of histone deacetylases, tyrosine kinase receptors, and the mitotic checkpoint protein aurora kinase A. In low-grade endometrial stromal sarcomas, antihormonal therapies including aromatase inhibitors and progestins have proven activity. Other potential targets are PDGFR, VEGFR, and histone deacetylases. In high-grade ESS that carry the YWHAE/FAM22A/B fusion gene, the generated 14-3-3 oncoprotein is a putative target, next to c-KIT and the Wnt pathway. The observation of heterogeneity within uterine sarcoma subtypes warrants a personalized treatment approach.

Clear‐cell variant of superficial cutaneous leiomyosarcoma associated with RB1 mutation: Clinical, dermoscopic, and histopathological characteristics

“…Hyperplasia of the epidermis with hyperpigmentation of basal layer overlying the LMS has been previously described and was consistent with our patient's dermatofibroma‐like features . However, the peculiar observation of the presence of clear‐cell features to the best of our knowledge has never been described in cutaneous LMS, although a few cases of clear‐cell LMS have been reported in the uterus . Interestingly, our patient's mother died from a uterine LMS with clear‐cell changes, a malignancy in which germline RB1 mutations are recognized to be a risk factor .…”

The Effect of Fucoidan, a Potential New, Natural, Anti-Neoplastic Agent on Uterine Sarcomas and Carcinosarcoma Cell Lines: ENITEC Collaborative Study

“…Some of pathways listed above were considered to be promising targets in treatment of uterine sarcomas (Cuppens et al 2015). …”

Metastasis-associated gene signature in primary myxoid liposarcoma identified through a gene expression study

“…The genes for focal adhesion included IGF1R and PDGFRA, and the cancer pathway proteins included FGFR2, IGF1R, and PDGFRA (Supplementary Table 2). Drugs targeting these proteins have already been clinically implemented for the treatment of various types of sarcomas [17][18][19][20][21] . The possible application of anti-FGFR2, -IGF1R, and -PDGFRA drugs to MLS should be further explored in preclinical studies.…”