Scientists at the AstraZeneca IMED Biotech Unit have published preclinical findings in Science Advances showing that inhibiting ATM, a key DNA damage response (DDR) mechanism can resensitise radiotherapy-resistant cells in brain tumour models. The researchers also showed that the inhibitor could cross the blood–brain barrier (BBB), making this treatment strategy potentially suitable for treating brain malignancies, for example glioblastoma multiforme (GBM), an aggressive and difficult-to-treat form of brain cancer.
GBM is the most common and lethal form of primary brain cancer, accounting for over half of all brain tumours. Standard treatment for GBM involves surgery followed by chemotherapy and radiotherapy. Whilst brain metastases, most commonly arising from metastatic lung, melanoma and breast cancers, are ten-fold greater in occurrence than GBM, are frequently refractory to current chemo/radiotherapy regimes.
Radiotherapy kills cancer cells by damaging their DNA. If cells are able to repair this damage, treatment can become ineffective. A new study published in the recent issue of Science Advances shows that a new compound, AZD1390 has the potential to resensitise treatment-resistant cells in vitro to radiotherapy by blocking their ability to repair DNA. The compound is a highly potent and selective inhibitor of ATM, a key protein in DNA damage response, and has been optimised to cross the BBB making it potentially suitable for use in brain malignancies.
ATM is often upregulated in radiotherapy-resistant GBM but drugs used to treat brain tumours must be able to cross the BBB effectively for adequate tumour exposure.
Amongst their investigations, researchers used three sophisticated models developed previously by the IMED Biotech Unit to test the suitability of the compound as a potential treatment for GBM. Until recently, it has been difficult to test the ability of compounds to cross the BBB. One model consisted of cell lines expressing human efflux transporter genes – these were used to see whether transporters at the blood–brain barrier actively exclude compounds from entering the brain. The second were mouse models of GBM and lung-brain metastases in which tumour cells were injected either directly into the brain or through the carotid artery and allowed to establish in the brain. These confirmed both the ability of the inhibitor to cross the BBB as well as its anti-tumour activity and survival benefit in combination with just five or less fractions of radiotherapy. The third model used positron emission tomography (PET) data in animal models to confirm the compound’s ability to cross the BBB, as well as showing the concentration that ended up in tumours. These data have supported progression into clinical investigation.
By inhibiting the activity of ATM, we can block the ability of brain tumor cells to protect themselves from the cytotoxic effects of radiotherapy. The activity of this brain-penetrant ATM inhibitor combined with radiation is extremely compelling in a variety of pre-clinical brain tumour models we tested. This has been a truly global effort across AstraZeneca sites in Cambridge, Boston, and Shanghai and with the AstraZeneca/ Karolinska Institutet joint PET imaging laboratory. I am honoured to have worked with so many people to publish this work.
The structure and mechanism of the compound, AZD1390, were disclosed at the American Association for Cancer Research (AACR) triple meeting in October 2017, and an oral presentation of the published results was given at the AACR meeting in April 2018, reinforcing AstraZeneca’s position as a leader in targeting DNA damage response as a target in cancer treatment.
The publication follows a meeting held at 10 Downing Street that was attended by Susan Galbraith, Head of Oncology at AstraZeneca’s IMED Biotech Unit, along with Ultan McDermott, a Chief Scientist at IMED Oncology. The meeting was part of an event aimed at creating a global, standardised framework for the treatment of GBM, and securing funding for clinical trials in the area. The event was inspired by Baroness Tessa Jowell, who was diagnosed with GBM in May 2017, and brought to public attention the limited treatment options for patients with the disease. Baroness Jowell sadly passed away aged 70 on 12 May 2018. This led to a UK government announcement that brain cancer research will have its funding doubled to £40 million and the use of adaptive clinical trials will be accelerated. In the US, Former vice president Joe Biden, who sadly lost his eldest son, Beau Biden, to glioblastoma has led the ‘Cancer Moonshot initiative’. This includes the dedicated Glioblastoma Moonshot research fund.
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