Biology subjects

Vandenberg, C.

Publications and source records attributed to Vandenberg, C..

2 recordsLinked to original sources

bioRxiv2020

Ovarian carcinosarcoma genomics and pre-clinical models highlight the N-MYC pathway as a key driver and susceptibility to EMT-targeting therapy

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory from a single progenitor, resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). We show OCS from 18 women to be monoclonal through analysis of DNA variants from isolated carcinoma and sarcoma components. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure ovarian carcinomas, supporting the conversion theory. We used pre-clinical OCS models to test the efficacy of microtubule-targeting drugs, including eribulin, which has been shown to reverse EMT characteristics. We demonstrated that microtubule inhibitors, vinorelbine and eribulin, were more effective than standard-of-care platinum-based chemotherapy. Eribulin reduced mesenchymal characteristics, N-MYC expression and cholesterol biosynthesis. Finally, eribulin induced a strong immune response, supporting immunotherapy combinations in the clinic.

cancer biology↗

bioRxiv2020

CHK2 inhibition provides a strategy to suppress hematological toxicity from PARP inhibitors.

Cancer patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi) experience various side effects, with hematological toxicity being most common. Short term treatment of mice with olaparib resulted in depletion of reticulocytes, B cell progenitors and immature thymocytes, whereas longer treatment induced broader myelosuppression. We performed a CRISPR/Cas9 screen targeting DNA repair genes to identify strategies to suppress hematological toxicity. The screen revealed that sgRNAs targeting the serine/threonine kinase CHK2 were enriched following olaparib treatment. Genetic or pharmacological inhibition of CHK2 blunted PARPi response in lymphoid and myeloid cell lines, and in primary pre-B/pro-B cells. Using a Cas9 base editor, we found that blocking CHK2-mediated phosphorylation of p53 also impaired olaparib response. Our results identify the p53 pathway as a major determinant of the acute response to PARPi in normal blood cells and demonstrate that targeting CHK2 can short-circuit this response. Cotreatment with a CHK2 inhibitor did not antagonise olaparib response in ovarian cancer cells. Selective inhibition of CHK2 may spare blood cells from the toxic influence of PARPi and broaden the utility of these drugs.

cancer biology↗