The phrase 'the war against cancer' might have become clichéd over the decades, but it does help to portray how much we have relied on advances in weaponry to score numerous victories against the disease. Tamoxifen proved that cancer treatments can behave like 'magic bullets' (see Milestone 5) and avoid the toxic effects of traditional chemotherapy treatments. Yet, the discovery of oncogenes offered the possibility of creating 'laser-guided' treatments — drugs that strike at the heart of tumours by zeroing in on the genetic abnormalities that make cells grow uncontrollably.
The first of these molecular-targeted treatments was a monoclonal antibody called trastuzumab (Herceptin; Genentech). Trastuzumab blocks the human epidermal growth factor receptor 2 (HER2) protein that is overexpressed by gene amplification in around 25% of breast cancer cases. Patients with this form of breast cancer have a worse prognosis; however, in the first trial carried out with trastuzumab, Dennis Slamon and colleagues found that women with advanced breast cancer who received the new drug as well as the usual chemotherapy fared better than those who received chemotherapy alone.
If trastuzumab proved that molecular-targeted treatments could effectively treat cancer, then a drug for chronic myeloid leukaemia (CML) called imatinib mesylate (Glivec; Novartis) changed our thinking about the power of designing such therapies. CML is a rare cancer that is characterized by the union of chromosomes 9 and 22, which fuses two genes called breakpoint cluster region (BCR) and Abelson murine leukaemia viral oncogene homologue 1 (ABL; also known as ABL1), to form a tyrosine kinase that signals myeloid cells to grow and proliferate continuously (see Milestone 10). Imatinib mesylate was rationally designed to block the BCR–ABL active site, and when Brian Druker and colleagues carried out the first trial with the drug they found that almost all patients (98%) with therapy-resistant CML saw their blood counts return to normal. Yet, it turns out that imatinib mesylate is not as selective as first thought, and this promiscuity could help to treat other cancers. George Demetri and colleagues were the first to show that imatinib mesylate could treat patients with advanced gastrointestinal stromal tumours by blocking c-KIT.
Designing targeted drugs for more common and complex cancers, however, presents added challenges, as illustrated by the story of gefitinib (Iressa; AstraZeneca). Gefitinib blocks the activity of a tyrosine kinase called epidermal growth factor receptor (EGFR) that is overexpressed in 40–80% of lung cancers. Yet, gefitinib turns out to be effective in only 10–19% of lung cancer patients. Thomas Lynch, Daniel Haber and colleagues explained how the target protein governs whether the drug will work. Patients who respond to gefitinib have specific mutations clustered around the ATP-binding pocket of the EGFR protein where the drug binds, whereas patients who do not respond tend not to carry these mutations.
Equally important as knowing who will respond to treatments is knowing who will develop resistance, and Charles Sawyers and colleagues showed that this is also determined by the target protein. Six out of the nine patients studied, who had relapsed after imatinib mesylate treatment, acquired the same amino-acid substitution in the ABL kinase domain, which affects the interaction of the drug with the kinase; the other three showed BCR–ABL gene amplification.
Understanding the molecular underpinnings of response and resistance to these, and other molecular-targeted treatments, is helping to create a new wave of drugs that can harness or circumvent these mechanisms — some of which are already beginning to enter the clinic. The war against cancer might be far from being won, but the era of molecular-targeted treatments could prove to be one of the most important turning points in determining the outcome.
Source: Nature Medicine Milestones
by
Akshaya Srikanth
Pharm.D Internee
Hyderabad, India
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