61IN - PARP inhibitors and other strategies in chemoradiation

Date 01 October 2012
Event ESMO Congress 2012
Session Biologically based treatment in head and neck squamous cell carcinoma
Topics Anticancer agents
Head and Neck Cancers
Surgical oncology
Therapy
Biological therapy
Radiation oncology
Presenter Kevin Harrington
Authors K.J. Harrington
  • Institute of Cancer Reserach, SW3 6JB - London/UK

Abstract

Chemoradiotherapy (CRT) is the treatment of choice for many locally-advanced tumour types. In particular, platin-based CRT is the gold-standard for stage III/IV squamous cell cancers of the head and neck (SCCHN). Most SCCHN have defects in the DNA damage response. For example, p53 pathway signalling is frequently defective, either through mutation or post-translational silencing by viral oncoproteins. Therefore, HNC are reliant on the G2/M cell cycle checkpoint – and this represents a potential point of attack for strategies combining RT and novel targeted radiosensitisers. In this presentation, approaches involving PARP, HSP90 and Chk1 inhibition will be discussed. Poly (ADP-ribose) polymerase (PARP) inhibitors are potent radiosensitisers and should be the subject of careful clinical evaluation in combination regimens with RT or CRT. Data relating to their development will be reviewed. HSP90 maintains the stability and activity of a number of proteins key in cell cycle arrest, DNA damage repair and apoptosis linked to cellular response to radiation. NVP-AUY922 potently radiosensitized a selection of cell lines in in vitro clonogenic assays corresponding to depletion of radioresistance markers at equivalent concentrations. Radiosensitization was verified in vivo by delayed tumour growth and increased survival. Mechanistic analysis at clinically achievable concentrations show NVP-AUY922 in combination with RT exhibits multi-target interference in both cell cycle progression and DNA damage repair. In addition, we have explored the effect of Chk1 inhibition (SAR-020106) in combination with RT in vitro and in vivo. Colony and caspase activity assays in cell lines with non-functional p53 revealed significant radiosensitization by Chk1 inhibition, in direct contrast to cell lines with functional p53. In vivo radiosensitization was confirmed by delayed tumour growth and increased survival utilizing a fractionated drug and radiation schedule. Abrogation of RT-induced G2 phase arrest using the Chk1 inhibitor was compensated by an increase in G1 phase population for cell lines with functional p53 (normal and malignant), in contrast to tumour cell lines with non-functional p53 (p53 mutant or HPV + ). In addition, Chk1 inhibition combined with RT caused inhibition of homologous recombination-mediated DDR. Disclosure: The author has declared no conflicts of interest.