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Cancer cells are really good at staying alive. When most normal cells become irreparably damaged, proteins within the cell and on its surface set into motion a cascade of chemical events that eventually results in programmed cell death, termed apoptosis. Some cancer cells, however, can suffer significant damage to their DNA without this triggering an automated death response.
Understanding how cancer cells cheat death can open the door to new ways of combatting the disease, and of making it more sensitive to existing treatments.
The process by which damaged cells commit suicide is a complex one – involving a network of receptors, proteins and signalling molecules. But it can be broken down to an extrinsic pathway (outside the cell) and an intrinsic pathway (inside the cell).
The extrinsic pathway to apoptosis starts with the ominously named ‘death receptor’, which sits on the cell surface. When certain signalling molecules bind to this receptor, other proteins are employed to form the even more ominously named ‘death-inducing signal complex’. This then initiates the chemical events that lead to cell death.
But these receptors don’t work in some cancer cells and stay silent when a chemical signal docks with them. This opens up the opportunity to develop drugs that can somehow ‘switch on’ the death receptors – making cancer cells more susceptible to cell death during chemotherapy or radiotherapy.
Dr Rhoda Molife, a medical oncologist at The Royal Marsden NHS Foundation Trust who holds an honorary post here at The Institute of Cancer Research in London, has just published a review with colleagues Drs Khurum Khan and Montserrat Blanco of the clinical progress of apoptosis-inducing therapies for cancer.
“Some of the therapies discussed in our paper are agonistic antibodies, rather than antagonistic. Instead of stopping the death receptor working, they ‘switch on’ the receptor, meaning apoptosis can take place within the cancer cells,” she says.
The intrinsic pathway is controlled by a delicate balance of pro-apoptotic and anti-apoptotic proteins. In normal cells, this balance is tightly regulated so that apoptosis occurs when it is needed. However, some cancer cells – such as small cell lung cancer or chronic lymphocytic leukaemia – produce more anti-apoptotic proteins than needed. These stop apoptosis from occurring, keeping that cancer cell alive, and contributing to resistance against other anti-cancer treatments.
New therapies target these anti-apoptotic proteins, allow apoptosis to proceed and ‘sensitise’ cancer cells to radiation or chemotherapy.
Dr Molife explains the importance of pro-apoptotic therapy, “What we are trying to do is to tell the body what it should be doing – removing damaged cells. This approach also tends to have a different profile of systemic side-effects from those found with more traditional cytotoxic therapies.”
But as promising as these new therapies are, Dr Molife and her co-authors argue that the medical community needs to find better ways of using pro-apoptotic therapies.
While carrying out a phase I trial of the experimental, pro-apoptotic agent navitoclax (ABT-263) in combination with docetaxel, Dr Molife and her team noticed that it was not clear why patients who derived the most benefit from the combination did so.
“We need to develop the therapies hand in hand with developments in biomarkers which can help predict which patients are likely to benefit from apoptotic therapy. Many of these apoptotic therapies entered the clinic before ‘targeted therapy’ became a buzz phrase, and before the importance of predictive and pharmacodynamics biomarkers was fully appreciated, so we really need to start finding ways of better designing clinical trials to help find drugs that will help specific patients.”
We have written before about using combination therapy to target cancer drug resistance, and the development of pro-apoptotic drugs offers new therapeutic combinations that reverse resistance.
But identifying the patients who would benefit the most from this sort of therapy is important too. By knowing what biological signs to look for, clinicians will be able to give the right treatment to patients – ultimately making the patient’s cancer cells easier to kill.