Hyperthermia Induced Synthetic Lethality in Tumour Biopsies from Women with Cervical Cancer

Cervical cancer is the 4th most common cause of cancer death in women
worldwide. In The Netherlands the 5 year survival rate is 65% and has only
marginally improved in the last 25 years despite more effective combined
radiotherapy with cisplatin, or radiotherapy with hyperthermia. More effective
treatment strategies are urgently needed.
Repair of DNA damage is an important cause of resistance to radiotherapy or
cisplatin treatment in cancer cells. Targeting DNA repair mechanisms offers the
possibility to sensitize tumour cells to cytotoxic treatments. Earlier, we
discovered two different molecular mechanisms by which hyperthermia gives a
tumour selective sensitization to radiotherapy and cisplatin: (1)
Down-regulation of the DNA repair protein BRCA2, one of the key proteins of
homologous recombination (HR) repair, and (2) down-regulation of HPV-E6 and
restoration of p53 in HPV-positive cervical cancer cells, both in vitro and in
animals. Translation of these promising results to patients requires further
studies on optimal combination in terms of tumour response and toxicity.
Combination of hyperthermia with experimental targeted inhibitors of
DNA-repair, such as PARP1, will lead to so-called synthetic lethality that will
further sensitize tumour specific damage from radiotherapy and/or cisplatin.
Before we wish to start a clinical study, additional pre-clinical studies are
needed.

This study is part of a larger project funded by the KWF-Dutch Cancer Society
(UvA 2015-7820) to establish a new cancer treatment based on a combination of
PARP1-inhibition with hyperthermia and radiotherapy and/or cisplatin.

Objective of this study: Collection of human cervical cancer biopsies for in
vitro and in vivo studies of hyperthermia induced synthetic lethality.

Prospective cohort study.

All women with newly diagnosed cervical cancer who will have a standard
gynaecological investigation under general anaesthesia will be asked for this
study. During this investigation, usually including a standard diagnostic
biopsy, an extra tumour biopsy will be obtained for this study.

The major burden to the patient is the risk of tumour bleeding directly after
taking the biopsy.
Cervical cancers are easily bleeding tumours; many patients present with
vaginal bleeding as the first sign of cervical cancer. Tumour bleeding may be
provoked by any tumour manipulation, such as taking a biopsy. Such a bleeding
is usually minor, mostly stops spontaneously, or can be stopped by simple
haemostasis, coagulation, or a vaginal gauzes.
Fistula formation and infection can theoretically be caused by a biopsy,
although these risks are more likely to be related to extensive tumour invasion
and necrosis.