23 August 2013
A pair of targeted treatments could be used to attack colorectal tumours that have become resistant to treatment, a new study reports.
The two new drug classes appear able to overcome resistance in bowel cancer cells to a molecule called TRAIL, which initially encourages cancer cells to die, but loses its effectiveness with time.
Scientists at The Institute of Cancer Research, London, combined TRAIL with drugs that block the activity of PI3 Kinase and HSP90, two important proteins that play a major role in cell survival.
They found that by blocking proteins involved in cell survival, the drugs made colorectal cancer cells that had been resistant to TRAIL sensitive to it once again.
The discovery is reported in the journal Oncotarget, and could lead to new ways to treat TRAIL-resistant colorectal cancer.
The research was funded by a grant from the European Union with additional funding from Cancer Research UK and The Institute of Cancer Research (ICR).
Colorectal cancer is the third most common cancer in the UK, with around 40,000 new cases registered each year.
The protein TRAIL (a TNF-related apoptosis-inducing ligand) has been shown specifically to target tumour cells, inducing apoptosis – or programmed cell death – without affecting normal tissues.
TRAIL could be a promising treatment for colorectal cancer as it has fewer side-effects than standard chemotherapy, but some colorectal tumours develop resistance to TRAIL, limiting its usefulness in patients.
ICR researchers treated colorectal cancer cells with TRAIL and either the prototype drug PI-103, which inhibits PI3 Kinase, or 17-AAG, a drug which blocks HSP90, to investigate whether they could reverse TRAIL resistance and induce tumour cell death in the lab.
In TRAIL-resistant tumours, the ICR researchers found that PI-103 and 17-AAG decreased the level and activation of proteins that promote cell survival – amplifying TRAIL’s cell death signal.
In contrast, healthy colon cells resistant to TRAIL showed little change in their levels of pro-survival proteins and were less sensitive to the combination treatment.
Study co-author Professor Paul Workman, Deputy Chief Executive of The Institute of Cancer Research, said: “TRAIL has generated a lot of interest as a potential treatment for a range of cancers because it promotes death by apoptosis, or programmed cell death, specifically in tumour cells. Unfortunately results from many clinical trials have been disappointing because most cancers find a way to become resistant to the treatment. We proposed that resistance to TRAIL occurred through signals that promoted tumour cell survival, and that drugs that target PI3 Kinase or HSP90 – which block survival signalling – could be a way to overcome this tumour resistance and promote cancer cell death without harming healthy cells.”
“Our team at the ICR has played a leading role in the discovery of PI3 Kinase and HSP90 inhibitors so we were excited to try combining these new drugs with TRAIL to defeat colorectal cancer. Our new paper shows that the combination approach works really well in the lab and supports the initiation of clinical trials combining TRAIL and related agents with drugs that inhibit survival signalling. Hopefully our results will encourage the research community to move forward with these drug combinations to overcome drug resistance in colorectal and potentially other cancers.”
Notes
(1) PI-103 is an inhibitor of PI3 Kinase/mTOR discovered by scientists at the ICR in collaboration with Piramed – a biotech company which was spun out from the ICR, Cancer Research UK and the Ludwig Institute for Cancer Research. Piramed was acquired by Roche in 2008 and drugs based on PI-103 are now in clinical trial with Genentech/Roche.
(2) 17-AAG is an inhibitor of the molecular chaperone HSP90. Scientists at the ICR carried out pioneering laboratory and clinical work to help establish the therapeutic potential of HSP90. They also discovered a new class of HSP90 inhibitors which led, in collaboration with the biotech company Vernalis, to the clinical candidate AUY922 that is now undergoing clinical trials with Novartis.