miércoles, 31 de julio de 2013

On Target: A New Generation of Cancer Therapies

Sarah Byrne
29th July 2013
Targeted therapies are helping boost current cancer treatments. Image from: Flikr

Though much progress has been made in our understanding of cancer, the front-line treatments: surgery, chemotherapy and radiotherapy, have remained remarkably similar for decades. Often effective if used early enough, but seemingly barbaric in their blunt-instrument approach and unpleasant side-effects. Surely modern medicine should be able to provide treatments with a little more precision? That is the principle of so-called ‘targeted therapies’, an active and growing area of cancer research.

The diverse group of diseases we call cancer are characterised by uncontrolled and abnormal cell growth. This process is usually controlled by regulatory proteins called kinases and their receptors, which become overactive or otherwise malfunction in cancer. This is usually due to a problem at the genetic level, i.e. DNA damage. Targeted therapies are normally small-molecule or antibody-based drugs aimed at these kinases, and designed specifically to disable or inhibit them. Better-known examples include transtuzumab (Herceptin) for some types of breast cancer, and imatinib (Gleevec) for chronic myeloid leukaemia.

When targeted therapies started to emerge, many of them were hailed as miracle breakthroughs, the long-awaited cure for this much-feared disease. Unfortunately, that’s not always the case. Often there are problems such as resistance and off-target effects — due to the complexity of our cellular machinery at the biochemical level, some ‘targeted’ therapies turn out to be not-so-precisely targeted after all. Sometimes there is difficulty in actually getting the drug into the tumour cells and getting it to stay there long enough to be effective. They certainly haven’t revolutionised oncology in the way we might have imagined, or replaced the more traditional treatments.

Does this mean targeted therapies have failed? No, but the success stories are often more small-scale and complex than headlines and news stories demand, and so we don’t tend to hear so much about them. Targeted therapies are, for example, often given alongside conventional treatments, helping to boost their chances of success.

Recent research at the Dana-Farber Cancer Institute has shown that the targeted therapy drug crizotinib improved outcomes in certain types of lung cancer. Some non-small cell lung carcinoma patients have an abnormality in a gene called anaplastic lymphoma Kinase (ALK). Crizotinib targets the abnormal gene product and blocks its activity, causing the tumours to shrink or stop growing. In the Phase III trials, the oral medication was given to patients with advanced disease, following conventional treatment with chemotherapy. [1]

The results might not sound dramatic, but they were significant: patients who received the drug got an extra four months on average before their disease eventually progressed and worsened, compared with those who continued to receive the chemotherapy. The data on survival rates was less clear, but the crizotinib group survived for a median of 20 months from the start of treatment, remarkable considering that the expected survival time with conventional treatment is six months. Their quality of life was better as well, with fewer symptoms. [2]

However, the ALK abnormality is only present in a minority of cases, making the treatment only suitable for around 2-7% of the proportion of lung cancer patients with the non-small-cell variant of the disease. Hardly a sweeping cure for cancer, but this will provide hope all the same for the minority it is relevant for.

Encouraging results published by the Memorial Sloan-Kettering Cancer Center also emerged this month from trials of selumetinib , developed by Astra Zeneca for metastatic uveal melanoma. This rare cancer of the eye has been referred to as an ‘untreatable’ disease, with survival rates virtually unchanged for decades, mostly due to the fact that it does not respond to the chemotherapy drugs used successfully for the more common melanomas of the skin. The initial results were announced at the 2013 Annual Meeting of the American Society of Clinical Oncology, and were received as evidence of a ‘major breakthrough, with improved survival rates seen for the first time with a new therapy for this disease, and over half of recipients of the drug experiencing tumour shrinkage. [3]

Like crizotinib, selumetinib also targets an abnormal kinase: in this case the MEP protein, which drives tumour growth. In contrast to the ALK abnormality, over 85% of patients with uveal melanoma have the mutation for the abnormal MEP, making the treatment suitable for the majority of cases. Larger-scale trials of selumetinib are needed to confirm the results, but there is good reason to be optimistic.

Both these stories demonstrate how targeted therapies are finding their niches, augmenting traditional treatments and providing a new angle of attack on some of the most difficult-to-treat diseases. They also show the importance of personalised medicine.

The moral of the story, perhaps, is that it’s time to stop waiting for the big miracle breakthrough that cures cancer once and for all — and to start paying attention to the seemingly small discoveries that little by little add to survival rates, life expectancy and quality of life.

Shaw, AT, Kim, D-W, Nakagawa, K, et al. (2013), Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. NEJM. http://www.nejm.org/doi/full/10.1056/NEJMoa1214886#t=abstract
2013 Annual Meeting of the American Society of Clinical Oncology. Abstract CRA9003. Presented June 1, 2013. http://www.medscape.com/viewarticle/805169

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