Preclinical Models to study the Biology and Therapy of Ovarian Cancer

Bizzaro, Francesca (2019). Preclinical Models to study the Biology and Therapy of Ovarian Cancer. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000e718

Abstract

Ovarian cancer (OC) is one of the most common gynaecological malignancies and a cause of mortality among western women. Standard-of-care treatment consists of platinum/taxane-based chemotherapy, but 5-years survival rate remains low.

Germline and somatic mutations in BRCA are present in half of the high grade serous (HGS) ovarian cancer. Olaparib, a PARP inhibitor affecting DNA damage repair pathway, has been approved in the treatment of germline-BRCA-mutated patients. The combination with cediranib, an angiogenesis inhibitor, has shown promising results, increasing progression-free survival in women with recurrent HGS ovarian cancer.

In this thesis, patient-derived ovarian cancer xenografts (OC-PDX) were used to study olaparib therapy and mechanisms underlying the observed benefit of the combination.

Next Generation Sequencing and gene expression analysis were performed on OC-PDX to identify mutations/aberrations in BRCA1/2 and other genes connected to the DNA repair pathway. A cohort (n=13) of OC-PDX was selected and classified as BRCAness and Not BRCAness, accordingly to their proficiency or deficiency in DNA damage repair. Olaparib and cediranib were administered in short-term (4 weeks) or maintenance (until progression) regimens.

Olaparib showed activity in BRCAness OC-PDX; the effect was improved by cediranib, inducing durable responses even after treatment suspension. Of note, the combination was also beneficial in Not BRCAness OC-PDX, promoting stable disease and regression.

The effect of the combination on changes in tumor-associated vasculature and hypoxia (likely due to cediranib) and DNA damage repair (due to olaparib), together with preliminary data on gene expression and mutational status, suggested a potential “cumulative” effect of the combination after 4 weeks of treatment. Studies are ongoing, to understand the molecular determinants that accompany the response of OC-PDX to the combination.

The results obtained compel us to believe that the combination of olaparib with cediranib is advantageous both in DNA repair proficient and, most importantly, in deficient patients, and has to be administered until tumor progression.