A new approach to tackling cancer cells

Research by a scientific team from WEHI suggests that cancers may be more successfully treated with a new combination therapy: by using a new and targeted drug to block a mutated and cancer-causing pathway in melanoma; and then by adding a novel anti-cancer drug, called ABT-737, which disables the cell survival machinery within the tumour cells.

Cancerous melanoma and colon carcinoma cells are able to survive in the body because the normal and healthy internal mechanism for controlling or killing cancer cells (apoptosis) is no longer able to counteract the dangerous pro-cell growth mutation of B-RAF. This mutation might arise from a number of sources — in the case of melanoma, exposure to excessive sunlight that can damage the genetic instructions in our DNA.

The errant signals or instructions emanating from the mutated signalling pathway enable cancer cells to multiply uncontrollably and to invade healthy tissue at distant parts of the body (metastases). In most cases currently, anti-cancer drugs for melanoma are not able to overcome this deadly process. Other new drugs that specifically inhibit cancer cells are being tested, but it is likely that those newer drugs will work better when combined with a drug, such as ABT-737, that disables the tumour cells’ survival machinery.

Using a mouse model of disease, the scientific team, led by WEHI’s Professor Andreas Strasser, Dr Clare Scott and Dr Mark Cragg (now at University of Southampton, UK), found that notoriously drug-resistant melanoma and colon carcinoma cells could be closely targeted and successfully treated by combining two new drugs.

While this treatment greatly reduces the ability of the corrupted signalling pathway to issue instructions for cancer cells to multiply uncontrollably, it also reinvigorates the process of apoptosis, which directs damaged or mutated cells to self-destruct. By using a specific inhibitor (eg, the MEK inhibitor), which has a greater effect on the cancer cells than the body’s normal cells, to direct the anti-cancer drug ABT-737, the combination can do its job much more effectively — even at lower doses that are less toxic for the patient.

Dr Clare Scott says, “In summary, there are three major innovations emerging from this research:

• First, we have established that a dangerously mutated cancer-causing pathway, B-RAF, is more susceptible to effective therapeutic intervention than previously believed;
• Second, we have specifically targeted and overcome the behaviour of mutant B-RAF with the combination of a pathway inhibitor and an anti-cancer drug, ABT-737; and
• Third, we have established that by using such combination therapy, lower doses of cancer-killing drugs can be used to eliminate cancer cells, with potentially fewer undesirable side effects for the patient.”

Dr Scott adds that the next step in the scientific process is to design a human clinical trial, using similar combinations of drugs, which may take some years to develop and implement. Prof Strasser’s group has also shown that this approach may be effective for a variety of solid cancers, including lung cancer, in addition to melanoma, colon cancer and some forms of leukaemia.

ABT-737 was discovered by Abbott, the US-based healthcare company.

The team of WEHI-based and international collaborators includes: Mark S Cragg (WEHI and Southampton University, UK); Elisa S Jansen (WEHI); Michele Cook (WEHI); Claire Harris (Southampton University); Andreas Strasser (WEHI); and Clare L Scott (WEHI).

The research was published in the Journal of Clinical Investigation.