A multi‐ethnic analysis of immune‐related gene expression signatures in patients with ovarian clear cell carcinoma

10.1002/path.5769The Journal of Patholog

Targeted approaches to C5 high-grade serous ovarian cancer through novel patient derived xenografts

Epithelial ovarian carcinoma (EOC) is the fifth most common cause of cancer death in western women. It can be classified into five main histological subtypes – endometrioid, clear cell, mucinous and high grade serous ovarian carcinoma (HGSOC), as well as low grade serous ovarian carcinoma. HGSOC can be further subclassified into four sub-groups based on molecular characteristics - C1, C2, C4 and C5. The C5 subtype, which is also known as the proliferative or Stem-A subtype, is associated with stem cell-like behavior and confers a poor prognosis. Little is known about this poor prognostic subtype of HGSOC. In addition, limited pre-clinical models are available to date for therapeutic exploration. This thesis has therefore focused on establishing a clinically relevant cohort of C5/proliferative/ Stem-A HGSOC patient-derived xenografts (PDX), and subsequently undertaking detailed molecular characterization to further understand the biology of this molecular subtype as well as performing drug response analyses. Here we showed that the C5/proliferative/ Stem-A HGSOC molecular subtype is heterogenous. We also showed through a cohort of clinically relevant PDX that the MYCN expression was not a good predictor of response to the MYCN inhibitor, M606 despite promising in vitro data from neuroblastoma cell lines and transgenic mouse models. Furthermore, we showed that MYCN expression was not a faithful predictor of response to BET bromodomain inhibitor, I-BET-762. In addition, we demonstrated that resistance to BET bromodomain inhibitor, I-BET-762 in C5/proliferative/ Stem-A HGSOC, was regulated by the FZD7-TWIST1 axis. Lastly, we identified the vinca alkaloid, vinorelbine as an effective therapeutic agent in C5/proliferative/ Stem-A HGSOC, relevant for further exploration in the clinical setting. Taken together, research completed in this thesis has greatly enhanced our understanding of C5/proliferative/ Stem-A HGSOC biology. The established cohort of clinically relevant C5/proliferative/ Stem-A HGSOC PDXs are an invaluable laboratory resource to enable accurate in vivo testing of novel therapies in the future. Furthermore, we identified a suitable effective therapeutic strategy to inform a C5/proliferative/ Stem-A -specific clinical trial

Update on immune checkpoint inhibitors in gynecological cancers

10.3802/jgo.2017.28.e20JOURNAL OF GYNECOLOGIC ONCOLOGY28

PARP Inhibitors in Breast and Ovarian Cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples of clinical translation of targeted therapies in medical oncology, and this has been demonstrated by their effective management of BRCA1/BRCA2 mutant cancers, most notably in breast and ovarian cancers. PARP inhibitors target DNA repair pathways that BRCA1/2-mutant tumours are dependent upon. Inhibition of the key components of these pathways leads to DNA damage triggering subsequent critical levels of genomic instability, mitotic catastrophe and cell death. This ultimately results in a synthetic lethal relationship between BRCA1/2 and PARP, which underpins the effectiveness of PARP inhibitors. Despite the early and dramatic response seen with PARP inhibitors, patients receiving them often develop treatment resistance. To date, data from both clinical and preclinical studies have highlighted multiple resistance mechanisms to PARP inhibitors, and only by understanding these mechanisms are we able to overcome the challenges. The focus of this review is to summarise the underlying mechanisms underpinning treatment resistance to PARP inhibitors and to aid both clinicians and scientists to develop better clinically applicable assays to better select patients who would derive the greatest benefit as well as develop new novel/combination treatment strategies to overcome these mechanisms of resistance. With a better understanding of PARP inhibitor resistance mechanisms, we would not only be able to identify a subset of patients who are unlikely to benefit from therapy but also to sequence our treatment paradigm to avoid and overcome these resistance mechanisms

A multicenter phase II randomized trial of durvalumab (MEDI-4736) versus physician's choice chemotherapy in recurrent ovarian clear cell adenocarcinoma (MOCCA)

10.1136/ijgc-2020-001604INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER3081239-124

A Phase I, First-in-Human Study of PRL3-zumab in Advanced, Refractory Solid Tumors and Hematological Malignancies

10.1007/s11523-023-00962-wTARGETED ONCOLOGYcomplete