Synta reawakens 40-year-old anticancer mechanism
cells don't have the anti-oxidant protective capabilities of normal
cells, it seems that only one pharma company has developed a drug
to exploit this fact.
Synta Pharmaceuticals, based in Massachusetts, US, is preparing to test its lead drug, STA-4783, on skin cancer patients in the final stage of clinical development. "We are all taught free radicals are really bad, but scientists have found that cancer cells have increased levels of ROS and their ability to keep that in check is severely compromised," explained Dr Tony Williams, vice president of clinical research at the company. By increasing the number of reactive oxygen species (ROS) in cells, STA-4783 can tip tumours cells beyond the breaking point into a death pathway (apoptosis). While these cells die, normal cells have less ROS and can shield themselves against the drug's effects. In fact, when the drug has been tested in normal cell lines, there is no measurable increase in ROS levels, according to Williams. Although the interest in this mechanism has rocketed in recent years (in 2006, there were over 3500 papers in journals about it, almost doubling the total number ever), Synta claims to be the only pharmaceutical industry pursuing it. Williams explained that although some anticancer drugs increase ROS levels indirectly to a lesser extent, none do it as or directly, like Synta's molecule. The drug is not potent enough to work as a monotherapy unless the dose is dangerously high, said Williams; instead the drug is seen as a method of increasing a cell's sensitivity to chemotherapy. In this setting, it has shown promising results in clinical studies so far. Dr Williams was speaking to DrugResearcher.com before presenting the Phase II trial results to delegates at the European Congress of Clinical Oncology (ECCO) in Barcelona, Spain. "The median progression free survival was 1.8 months in the group who got chemotherapy alone, but 3.7 months in the group who got the combination," he said. "This doubling in progression free survival is impressive for this cancer, and the result was achieved without substantial additional toxicity." He added: "Progression-free survival was linked to improvements in overall survival. Patients on the experimental combination survived on average for 12 months after being diagnosed, while those getting only paclitaxel survived on average 7.8 months. This is the first time an improvement in survival has been seen in a randomised, double-blind, multi-centre controlled trial for metastatic melanoma." While investigating the drug's mechanism, the team at Synta discovered that once melanoma cells are exposed to the drug, levels of Heat Shock Protein 70 (Hsp70) shoot up over 300-fold in just one to three hours. However, this is a "futile response," said Williams and over the next two to three hours, a switch inside the cell's mitochondria is triggered and the cells begin to die. Although Hsp70 is not the target of the drug, as some have mistakenly thought, the increase in Hsp70 is, however, useful as a biomarker to prove the therapy is working. For example, if the drug is given alongside antioxidants (such as NAC, N-AcetylCysteine), no extra Hsp70 is produced and the cells survive as normal. Williams said the company is unwilling to disclose the target as yet but hopes to soon once the programme is fully protected in terms of intellectual property (IP). NAC is normally administered to people who have taken a paracetamol (acetaminophen) overdose, and Williams assured DrugResearcher.com that normal dietary levels of antioxidants shouldn't prevent STA-4783 from working, although he did say that patients in the upcoming Phase III trial were told not to take any vitamin E supplements (an antioxidant). Melanoma is easily treated with surgery in its early stages and five-year survival rates are 99 per cent for localised disease, according to the American Cancer Society. However, once the cancer progresses to later stage, metastatic disease, survival rates plummet to just 15 per cent. STA-4783 is being tested in patients with advanced disease (stage IV metastatic melanoma), who desperately need more treatment options. Most of the world's biggest pharma companies are developing drugs for melanoma. Pfizer's CP-675206 (tremelimumab/ticilimumab) and Bristol-Myers Squibb's (BMS) ipilimumab are both in Phase III clinical trials, the latter being developed in conjunction with Medarex. The drugs are antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4), which is thought to suppress the immune system's T cell response to cancer. AstraZeneca is testing a MEK inhibitor in Phase II trials. MEK is so called after the MAPK/ERK kinase pathway it belongs to. This cascade of extracellular signal-regulated kinases (ERK) or mitogen-activated protein kinases (MEPK) are thought to be involved in a number of processes that promote cancer, including cell growth and survival. Novartis is utilising a different target in the same pathway, namely b-RAF kinase to design melanoma drugs. RAF265 is currently in Phase I clinical trials. Roche and Plexxikon's PLX4032/R7204 is at the same stage of development and targets the same protein. Genzyme is looking at a transforming growth factor (TGF)-beta inhibitor, GC-1008, as a means of treating melanoma in Phase I/II clinical trials. Astellas Pharma's YM155, a survivin expression inhibitor is in Phase II trials. With these and other melanoma drugs filling oncology pipelines globally, the outlook for patients with advanced melanoma might not be so bleak in the future.
