Identification of therapeutic targets in uterine sarcoma

Uterine sarcomas account for only 3-4% of all uterine corpus malignancies, nevertheless they entail a high mortality rate due to their clinical aggressiveness and limited response to current treatments. All uterine sarcoma patients are first treated by complete surgical resection, whenever possible (hysterectomy, often associated with bilateral salpingo-oophorectomy). However, recurrence rates are high in most subtypes even after complete resection, underscoring the need for more effective therapies.

Leiomyosarcoma (LMS) is the most frequently diagnosed and a very aggressive subtype (60% of all uterine sarcomas), followed by the less aggressive low-grade endometrial stromal sarcomas (LGESS; 20%). The remaining 20% of uterine sarcomas comprises high-grade ESS (HGESS), undifferentiated uterine sarcomas (UUS) and adenosarcomas (AS).

Overall, the effect of available treatments for uterine sarcoma patients is limited and associated with substantial toxicity. Setting up clinical trials is challenging, especially for small patient groups, emphasizing the role of pre-clinical models in optimizing treatment regimens and biomarker identification, which will ideally lead to robust and reliable patient stratification criteria.

The lack of effective treatment strategies and the poor prognosis for uterine sarcoma patients underscore the need for prognostic markers and for personalized, new therapeutic approaches. The final aims of this PhD project are to identify prognostic biomarkers and novel therapeutic options for uterine sarcoma patients.

To this end, the following research objectives are pursued:

1) Identification of potential therapeutic targets and prognostic markers in uterine sarcomas, by:

   a) immunohistochemistry (IHC) screening of therapeutic targets for which targeted therapies are available, in a large sample set including all subtypes;

   b) integration of commonly detected alterations identified from next-generation sequencing (NGS) methods in uterine leiomyosarcomas;

2) Establishment and validation of patient-derived in vitro and in vivo uterine sarcoma models;

3) In vitro and/or in vivo pre-clinical validation of targets identified by the IHC screen and/or NGS integration.