Oncogene targeting is a frequent strategy in cancer research. In the July 13, 2011 , issue of Nature, scientists reported preclinical successes using a different strategy: by targeting what they termed a non-oncogene co-dependency. “Normal cells become tumor cells through a variety of genetic alterations,” said co-author Anna Mandinova, explaining the co-dependency concept. Most often, those genetic alterations are mutations, though other changes such as insertions and deletions also occur. By the time it starts dividing uncontrollably, a tumor cell has picked up an average of eight to 12 such mutations. Targeted therapies on the market today usually target such oncogenes directly. But the mutated genes are not the only ones whose expression levels change in cancerous cells. A tumor cell undergoes metabolic changes, and is in a hostile environment of low oxygen and nutrients. And “in order to survive these changes,” Mandinova explained, “the cell . . . starts to overexpress or underexpress housekeeping genes.”
Cancer cells are often addicted to the oncogenes themselves. But because they are living on a razor’s edge between rapid growth and outright death, they also become co-dependent on the housekeeping genes that react to the changed environment. And targeting such codependent processes, co-author Sam Lee told BioWorld Today, might have advantages over targeting the oncogenes themselves: “Most of the targeted drugs out there easily pick up resistance. . . . We are very different.”
In their paper, Mandinova, Lee and their colleagues targeted one such housekeeping process – the levels of free radicals – with the compound piperlongumine, which is derived from a type of pepper plant. Cancer cells have to keep their levels of free radicals or reactive oxygen species under much tighter control than normal cells.
The authors did not specifically set out to target free radical control processes. They identified piperlongumine in the course of screening for compounds that would raise the levels of the tumor suppressor p53. But the researchers’ follow-up experiments showed that piperlongumine’s effects were independent of p53 levels. And the compound killed cancer cells while having little effect on normal cells, including rapidly dividing normal cells.
And when their team searched studies for piperlongumine’s binding partners, they found that more than half of the proteins that the compound interacted with were involved in the cellular response to oxidative stress. The authors next tested the compound both in mice with xenografted tumors, and in genetically engineered mouse models of breast cancer. They found that piperlongumine blocked tumor growth and metastases.
Paclitaxel, which stabilizes microtubules, also increases the levels of free radicals in cells. But in contrast to paclitaxel, piperlongumine had little to no effect on even rapidly dividing normal cells. Another recent paper in Nature reported that cancer cells are sensitive to both low and high levels of reactive oxygen species. Those findings, Mandinova said, “fit very well with our idea that in order to exist in this oncogenic environment, they need just the right amount of housekeeping to keep them alive.”
Mandinova, Lee and their co-author Michael Foley have founded a company, Canthera Therapeutics Inc., to usher their fi ndings into the clinic. Founded about 2.5 years ago, the company is still largely virtual; in addition to investment by its co-founders, it has secured “Minimal angel funding,”
Lee said, which it has used to improve piperlongumine’s pharmacological properties, especially its solubility, and to search for analogues. For now, the company is a one-trick pony, and the primary focus of the founders has been on piperlongumine itself, and the scientifi c side of discovering more about its mechanism of action.
But, Lee said, they are “ready to move on” – not just with piperlongumine and its analogues, but with targeting “the bigger picture of cancer codependency.” ■
BioWorld Today – Jul 27, 2011