Targeting nucleotide excision repair in combination cancer therapy

Project: Research project

Project Details

Description

Abstract
First line treatment of ovarian cancer includes combination therapy with a platinum drug (Pt), either cisplatin or
carboplatin (1). A major impediment to the successful treatment of epithelial ovarian cancer (EOC) is
resistance to Pt-based chemotherapeutic agents (3). Even in EOCs that initially respond to treatment, most
will recur and will be Pt resistant; with an extremely poor prognosis as second line therapies are largely
ineffective. The difficulties in providing effective treatment of EOC highlights the importance of tailoring
therapies based on the biology of the individual disease. Recent advances in our understanding of the
homologous recombination (HR)/BRCA pathway in breast and ovarian cancer (4;5) and the common alteration
of HR in these cancers has led to targeting poly-ADP-ribose polymerase (PARP) by exploiting the concept of
synthetic lethality. While PARP inhibitors have had some success in single agent studies in BRCA mutant
cancers, combination of PARP inhibitors with Pt therapy has been considerably less effective. Pt agents
impart their therapeutic effect by the formation of Pt-DNA adducts, which block DNA replication and
transcription. Repair of Pt-DNA adducts reduces the efficacy of platinum-based treatment and contributes to
cellular resistance. Importantly, repair of Pt-DNA damage is catalyzed by the PARP-independent pathways,
nucleotide excision repair (NER) and homologous recombination repair (HRR). Thus, in HRR deficient
cancers, targeting NER would be expected to have a significant impact on sensitivity to Pt therapy. Germ line
mutations in BRCA1 or 2 predispose women to hereditary breast and ovarian cancer which are HRR deficient.
Therefore we will address the hypothesis that synthetic lethal interactions can be exploited targeting the
NER pathway with small molecules in HRR deficient cancers and, when combined with cisplatin will
provide increased efficacy with minimal toxicity. Cisplatin treatment, in combination with an NER inhibitor,
will differentially alter the repair capacity of different cells dependent on their HRR status. Non-cancerous,
HRR proficient cells can repair or tolerate the cisplatin damage via HRR and thus will have reduced toxicity
compared to the HRR deficient cancer cells which are unable to repair the cisplatin damage via either pathway.
To address our hypothesis we will employ our recently discovered NER inhibitors targeting the xeroderma
pigmentosum group A (XPA) protein (6) and replication protein A (RPA) (7-9) in two specific aims. Aim 1 will
develop and characterize novel inhibitors of the XPA protein and assess efficacy in combination with cisplatin
in cell culture models of HRR proficient and deficient human ovarian and breast cancers. We will then
determine the impact of XPA inhibition in combination with cisplatin therapy on cytotoxicity, DNA damage
signaling and repair of cisplatin-DNA damage in cell culture and xenograft models of breast and ovarian
cancer. In aim 2 we will determine the mechanism by which small molecules targeting the RPA protein inhibit
the RPA-DNA binding interaction, achieve single agent activity and synergize with cisplatin and etoposide in
BRCA1 deficient cancers. Our previous data identified two classes of RPA inhibitors, both of which decrease
StatusFinished
Effective start/end date9/30/138/31/18

Funding

  • National Institutes of Health: $323,700.00
  • National Institutes of Health: $313,989.00
  • National Institutes of Health: $323,700.00

ASJC

  • Medicine(all)

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