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Publication

Serine auxotrophy: a novel metabolic vulnerability of platinum resistant ovarian cancers?

Book - Dissertation

Ovarian cancer is the eight most common type of cancer in women and accounts for the second highest number of gynecological cancers associated deaths in the developed world. While for many cancer types the overall survival increased over the last years, this is unfortunately not true for ovarian cancer, showing a stagnation over the last decades. For over 40 years standard of care consists out of platinum-based chemotherapy, with or without taxanes. The high mortality rate is mainly attributed to the development of resistance to conventional platinum-based therapies. Although a lot of research has been done on chemoresistance, translation into the clinic has been failed. In addition, there are no trustworthy biomarkers to distinguish platinum resistant from platinum sensitive tumors, often leading to ineffective platinum treatment. That is why the identification of resistance biomarkers and development novel therapeutic strategies is of crucial importance in translational cancer research. In recent years it has become clear that cellular metabolism is of major importance in the regulation of cell survival and cell death signaling, that is why we in this PhD project we aimed to investigate metabolic changes that are potentially linked to the resistant phenotype. To underline the clinical importance of our findings we combined state-of-the-art molecular technologies and relevant pre-clinical patient derived xenograft (PDX) mouse models and patient derived data. By applying unbiased metabolomics and isotope labeled tracer analysis in vitro, we managed to identify changes in serine metabolism in platinum resistant cells compared to its platinum sensitive counterpart. Moreover, we found that resistant cancer cells down regulate serine biosynthesis by reducing the intracellular amounts of its rate limiting enzyme phosphoglycerate dehydrogenase (PHGDH). Based on this finding we hypothesized that PHGDH can potentially be used as biomarker for platinum sensitivity. In addition, we also showed that platinum resistant cells are auxotroph for serine in vitro. Next, we investigated the underlying mechanism of PHGDH downregulation by integrating our metabolic findings and we found that serine synthesis down regulation is a part of global metabolic changes in central carbon metabolism towards a NAD+ generating phenotype. We found that NAD+ availability is required to sustain poly-(ADP)ribose-polymerase (PARP) activity under platinum treatment. PARPs are enzymes needed for many cellular functions, including DNA repair. By combining PARP inhibitors and carboplatin we managed to overcome platinum resistance in vitro. To further investigate if our findings are clinically relevant we used patient-derived xenograft mouse models (PDX), their derived organoid cultures and patient data. We showed that PHGDH are also reduced in resistant models in vivo. These findings are in concordance with TCGA derived data. In addition, we showed that PHGDH gradually decrease and PARP1 levels increase after platinum-based treatment in different PDX models, suggesting that this is an adaptive mechanism to platinum exposure. Finally, we were able to acquire matched primary and recurrent tumor biopsies from patients from the clinic and we showed that, also in patients, PHGDH levels decrease when tumors became resistant to platinum after different cycles of platinum exposure. The identified changes in PHGDH can subsequently potentially be used as biomarker to distinguish platinum sensitive from resistant tumors. Our data provide evidence that combining platinum-based chemotherapy and PARP inhibitors might be a relevant method to overcome platinum resistance. Eventually we validated these results in PDX derived organoid models where we observed a synergistic effect of combining platinum with olaparib. To conclude, with this PhD project we managed to identify a novel potential biomarker for platinum resistance. We showed that resistant cancer cells down regulate serine biosynthesis by specifically decreasing PHGDH levels compared to sensitive cells. Investigation of the underlying mechanism led to a novel potential metabolic target, moreover PARPs, to overcome platinum resistant. We were able to overcome platinum resistance by combining PARP inhibitors with carboplatinum in vitro and in different ex vivo organoid models. These findings need further confirmation in clinical settings in future studies.
Publication year:2022
Accessibility:Open