Improving the understanding of platinum sensitivity and the tumour microenvironment in high grade serous ovarian cancer

R Medicine (General);RG Gynecology and obstetrics;RM Therapeutics. Pharmacology

Farquharson, Malcolm John ; Iain, McNeish

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: High grade serous, platinum sensitivity, microenvironment, ovarian cancer.;   

Others  :  http://theses.gla.ac.uk/31006/1/2018FarquharsonPhD.pdf

来源: University of Glasgow

【 摘 要 】

Ovarian cancer is one of the most lethal malignancies and often presents at an advanced stage, resulting in a poor prognostic outlook. Platinum chemotherapy leads to an initial clinical response, however most patients will ultimately relapse and there remains a sub-group who are intrinsically resistant to platinum.I focussed on high grade serous ovarian cancer (HGSOC), the most common subtype of ovarian cancer. The ID8 CRISPR-generated models represented a novel and simple tool to investigate the biology of HGSOC. By using this in vivo model, I aimed to further the understanding of platinum sensitivity in HGSOC by investigating the homologous recombination pathway and the tumour microenvironment. In vitro work showed that sensitivity to PARP inhibitors was clearly correlated with defective homologous recombination but the relationship with platinum sensitivity was more complicated. Using the ID8 derivatives, in vivo cisplatin experiments identified Pten and Nf1 loss to be associated with the worst prognosis with the knockout of Brca1 or Brca2 prolonging survival. A Brca1 mutation in the PALB2 domain compared to the BRCT2 domain was found to be associated with a greater sensitivity to cisplatin. The tumour microenvironment was shown to differ between genotypes and altered with the addition of platinum chemotherapy. Specifically, the loss of Pten was associated with an immunosuppressive microenvironment with increased levels of myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs). The chemokines, Ccl2 and Ccl7 were shown to be significantly increased in the Trp53-/-;Pten-/- genotype.I targeted both the cytokine/chemokine response directly by using a transgenic mouse model (CCR1, 2, 3, 5 receptors knockout) and the PI3K/AKT pathway by using a PI3K inhibitor (p110β) (AZD8186) to attempt to reverse the effect of Pten loss. The transgenic mouse model (GGTACKO) showed encouraging early results with a reduction in MDSCs and TAMs in the knockout mice injected with the Trp53-/-;Pten-/- genotype but a repeat experiment is required before valid conclusions can be made. The AZD8186 in vivo experiment showed a significant reduction in MDSC levels in the ascites following AZD8186 treatment in mice injected with the Trp53-/; Pten-/- genotype and a non-significant decrease in the tumour samples. There was also a reversal in the anaemia previously shown with the loss of Pten and a decrease in Ccl2 and Ccl7 expression. I have used a transplantable in vivo model for HGSOC to investigate potential mechanisms of platinum sensitivity and identified poor prognostic genotypes (Pten, Nf1). I have found Pten loss to be associated with an immunosuppressive microenvironment and highlighted potential therapeutic targets. By targeting the PI3K/AKT pathway I have shown that the effect of Pten loss can be reversed. The next step will be to determine whether this reversal results in a prolonged survival.