CCBIO webinar: Frédéric Amant
Exploiting patient-derived preclinical models to identify biomarkers of therapy response/resistance in high-grade gynecological cancers
Department of Obstetrics and Gynecology, University Hospitals Leuven, and Department of Oncology, KU Leuven, Belgium
The availability of reliable pre-clinical models in oncology research is paramount to biomarker discovery, development of new therapeutic strategies and the investigation of the molecular mechanisms underlying resistance to conventional and novel therapies. Several patient-derived in vitro and in vivo models have been developed over the years, each with its inherent advantages and disadvantages. In our lab, we aim to exploit their complementarity to identify new therapeutic strategies and biomarkers for therapy response/resistance in high-need gynecological cancer patients’ populations.
Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. The high recurrence and mortality rates associated with this cancer emphasize the urgent need for novel therapeutic strategies. So far, no molecular prognostic or predictive biomarkers are available to guide treatment choice and modality. Using patient-derived xenograftmodels (PDXs), we described the central role the PI3K/mTOR pathway played in uterine leiomyosarcoma (uLMS) tumor progression and validate its potential as a therapeutic target, identifying p-S6s240 as a predictive biomarker for response to PI3K/mTOR inhibition. In addition, we are using humanized PDX models to assess the role of the immune system in determining drug response and explore combinatorial treatment strategies involving immune checkpoint inhibitors in uLMS.
Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, particularly for epithelial ovarian cancer. While most patients initially respond to treatment, patients often experience several response-relapse events, until tumors start to resist the treatment. Resistant patients have low response rate to other chemotherapy regimens, with life expectancy of 12-15 months, explaining ovarian cancer’s high mortality rate. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, and no novel drugs have been approved for resistant disease in decades. Since metabolism is intertwined with pathways controlling cell death, we investigated the functional link between metabolic adaptations and platinum resistance. We discovered that resistant cells modify their serine metabolism. By combining cell line results, data mining in the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas, PDX, PDX-derived organoid models, and paired primary-recurrent patient biopsy samples, we confirmed that serine synthesis downregulation is a clinically relevant metabolic adaptation of resistant cells that can potentially be used as novel biomarker for platinum sensitivity.
Chairperson: Camilla Krakstad, CCBIO