Synta Pharmaceuticals (SNTA) may look like the typical American biotech company: A promising phase III compound, which is, of course, partnered with a pharma giant, two agents in early clinical stages, a list of failed trials, and an alarming cash burn rate. Nonetheless, the story behind the company’s lead product, elesclomol, is shaping up as one of the most interesting events in oncology in recent years. Elesclomol is currently in a registrational phase III trial for metastatic melanoma, a major achievement by itself, however, if successful, this trial will mark two events on a historical scale.
The first and more immediate title elesclomol might claim is being the first chemotherapy agent to show benefit in metastatic melanoma in over 30 years. In fact, since the only approved agent for this condition has never shown benefit in a placebo controlled trial in accordance to current standards, elesclomol might be viewed as the first ever chemo agent to show a clear benefit in metastatic melanoma.
The second achievement, which is more impressive and potentially rewarding, is the introduction of a novel class of anti-cancer therapy: Oxidative stress elevation. Just as Gleevec® and Avastin® marked the birth of tyrosine kinases inhibition and anti-angiogenesis as important concepts in cancer treatment, elesclomol might be the first drug in a long dynasty of oxidative stress inducing drugs useful for the treatment of a wide range of malignancies.
Oxidative Stress And Cancer
Oxidative stress is a state in which there is a high level of reactive oxygen species (ROS) within a cell. ROS, which are produced by every living cell as a by-product of its metabolism, are highly reactive entities that can interact and damage biological components such as DNA and proteins. In normal cells, the production and neutralization of ROS is tightly regulated by several defense mechanisms. These mechanisms include enzymes and vitamins, generally termed antioxidants as well as specialized repair proteins whose role is to contain ROS and their hazardous effect. Therefore, in normal cells there is a balance between ROS and antioxidants. A disruption of this balance in which ROS outnumber antioxidants leads to a state of oxidative stress. This state implies that a cell cannot cope with the amount of ROS, which in turn cause damage to cellular components. When the oxidative stress reaches a certain threshold a cell usually “commits suicide” through a process termed apoptosis (programmed cell death).
Since cancer cells originally derive from healthy tissues, they are almost identical to normal cells. Therefore, the fundamental mission in developing anti-cancer treatments is finding a trait that distinguishes between cancer and normal cells, and use this difference for killing the former. Cancer cells, for example, typically divide at a faster rate than normal cells, so most anti-cancer compounds utilize this difference by blocking the process of cell division. Another characteristic of advanced cancer is the formation of new blood vessels (angiogenesis), a process which rarely occurs in the adult body, leading to a whole class of compounds that utilize this difference for damaging cancer cells while sparing normal ones.
A growing body of evidence suggests that cancer cells operate at a substantially higher level of oxidative stress than normal cells, mainly due to fast proliferation and a low level of antioxidant activity. High levels of oxidative stress have been even suggested as a mechanism that helps cancer cells to proliferate and spread. Although this does not represent a normal state, there is a fairly wide range of oxidative stress levels in which cancer cells can function without reaching a threshold that will trigger programmed cell death. Nevertheless, cancer cells are much closer to that breaking point and because they have impaired anti-oxidant abilities, a relatively modest increase in oxidative stress may push cancer cells over the edge, and force them to commit suicide. This concept can serve as a basis for a novel type of anti-cancer treatment: a drug which elevates oxidative stress in all cells, indiscriminately, but has a much stronger effect on cancer cells.
