“Dr. Vukovic has a unique combination of scientific and clinical
experience that will benefit Synta. His research into the biology of
oxidative stress induction, the mechanism by which our lead cancer drug
candidate, elesclomol, acts, and his experience in developing Sutent(R)
and other anti-cancer success stories, make him a terrific addition to
our oncology team,” said
“This is a tremendously exciting time to be joining Synta. I believe we are at the cusp of establishing oxidative stress induction as a new therapeutic approach in oncology,” said Dr. Vukovic. “This treatment approach, if confirmed with the lead indication of metastatic melanoma, has great potential in other high-oxidative-stress tumor types such as breast, prostate, ovarian, and pancreatic cancers. It is a very rare opportunity to join a team that is developing a potential new therapeutic class of drugs in oncology; it is rarer still to be able to do so in an environment that combines a dynamic, high-energy, entrepreneurial culture; multiple first-in-class programs, all internally developed; a proven discovery platform; and a strong financial position. I am very pleased to join Synta and to be able to contribute to realizing the potential of these programs to benefit patients around the world.”
Elesclomol is an investigational first-in-class oxidative stress inducer that triggers apoptosis (programmed cell death) in cancer cells. Cancer cells operate at high levels of reactive oxygen species, or oxidative stress. Elesclomol acts by increasing the level of oxidative stress in cancer cells even further, beyond sustainable levels, inducing apoptosis. This mechanism of action, called oxidative stress induction, represents a novel way of selectively targeting and killing cancer cells.
In a double-blind, randomized, controlled Phase 2b clinical trial in 81 patients with stage IV metastatic melanoma, elesclomol in combination with paclitaxel met the primary endpoint, doubling the median time patients survived without their disease progressing, compared to paclitaxel alone (p = 0.035). The most common adverse events in the elesclomol plus paclitaxel group included fatigue, alopecia, constipation, nausea, hypoaesthesia, arthralgia, insomnia, diarrhea, and anemia.
A pivotal Phase 3 clinical trial of elesclomol in combination with paclitaxel in patients with stage IV metastatic melanoma (the SYMMETRY trial) has completed enrollment; a Phase 1/2 trial in hormone-refractory prostate cancer, in combination with docetaxel, is ongoing. Phase 2 trials in other indications, and in combination with other agents, are planned.
About Oxidative Stress
Oxidative stress in cells is the presence of elevated levels of reactive oxygen species (ROS) such as oxygen radicals and hydrogen peroxide. ROS can be generated by many processes and stimuli, including ordinary cell metabolism, exposure to heat or radiation, or attack by bacteria or viruses. Because ROS can react chemically with different proteins and other elements of a cell, altering their normal function, prolonged exposure to elevated levels of ROS can cause serious damage to a cell. To protect against this damage, cells have natural defense mechanisms – anti-oxidant abilities – to clear excessive levels of ROS and to repair the disruption they cause.
Normal, non-cancer cells typically function at a low, steady-state level of oxidative stress. Their strong anti-oxidant capacity guards against prolonged, excessive levels of ROS. Cancer cells, however, typically operate at a much higher level of oxidative stress than normal cells, and have a greatly diminished anti-oxidant capacity. This diminished capacity to clear ROS leaves them vulnerable to further increases in oxidative stress. In particular, when ROS levels exceed a natural breaking point, continued survival of the cell becomes unsustainable. At levels of ROS above this breaking point, a switch inside the mitochondria is triggered that causes the cell to initiate programmed cell death, also known as apoptosis.
By elevating ROS, an oxidative stress inducer such as elesclomol exploits this difference between cancer cells and normal cells. Elesclomol has been observed to have little to no effect in vitro on most normal cells. In contrast, elesclomol has been observed to potently induce apoptosis in cancer cells. In preclinical models elesclomol showed potent anti-cancer activity against a broad range of cancer cell types, as well as an ability to enhance the efficacy of certain chemotherapy agents with minimal additional toxicity.
Oxidative stress induction represents a novel approach to treating cancer. It is distinct from chemotherapy, from "targeted" agents such as kinase inhibitors and antibodies, and from angiogenesis inhibitors in that OS inducers exploit a fundamentally different vulnerability of cancer cells – the elevated levels of reactive oxygen species.
For more on oxidative stress and cancer see for example J. Fruehauf et
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Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7125
MacDougall Biomedical Communications
Doug MacDougall, 781-235-3060