Halting cancer may soon be as simple as swallowing a pill or getting an injection, said David Kimball, associate vice president of the Office of Translational Sciences.
Researchers at the Cancer Institute of New Jersey recently discovered that a protein known as p53 was responsible for many forms of solid-tumor cancers, including pancreatic, breast, ovarian and prostate cancer.
Typically cells undergo apoptosis, or programmed cell death, when the DNA is disrupted, said Kimball, a research professor in the Department of Medical Chemistry. Cancerous cells shut down that signal, keeping the cell alive and replicating. P53 controls this cell death, he said.
According to a press release by the Cancer Institute of New Jersey, this was proven after more than three decades of research into p53.
“It’s been nicknamed the ‘guardian of the genome,’” Kimball said. “It controls the integrity of the genetic material during the cell cycle.”
According to the press release, this protein halts cell division if it recognizes stress and stimulates either cellular reparation or, if the damage is too severe, cell death.
Many forms of cancer require p53 to be mutated, Kimball said. The protein is completely disabled in over half of solid-tumor cancers.
Several forms of cancer are linked with a specific p53 mutation, he said. The protein unfolds, causing it to stop working.
Darren Carpizo, a surgical oncologist in the CINJ, discovered controlling zinc levels in the cell could encourage the cell to refold, Kimball said.
Initially, a lead molecule was found that killed specific types of cancer cells, said David Augeri, a research professor in the Department of Medicinal Chemistry. Researchers discovered that the cells killed had a certain mutation in p53.
The lead molecule folded p53 so it resembled a “wild-type” version, the natural form of the protein, he said. These cells then moved toward the death state.
Raising the amount of zinc in a cancerous cell very slightly would cause the p53 to fold up, Kimball said. P53 would grab the zinc and return to normal functionality.
The OTS is now trying to create a molecule that can raise the zinc levels inside a cancerous cell, he said. This molecule would not only grab zinc from outside the cell, but also completely cover it to pass through the cell membrane.
Charged zinc molecules cannot pass through a cell membrane on their own, he said. They require an organic molecule to cover them.
Augeri, the director of Translational Synthesis in the OTS, said the vital components of the lead molecule would be replicated in more drug-like molecules.
They would use multiple data points, including solubility and how effective the new molecule is, to optimize the product, he said.
Between 40 and 50 molecules have already been synthesized, he said. These molecules are being tested in cell cultures for the moment, but they plan to eventually use in in-vivo, or living, models.
“Ultimately, what we’ll do is move into a mouse model of cancer,” he said. “We’ll run [that model] for one or two months, and there’ll be endpoints for efficacy that will be assessed at the end of the study.”
Multiple promising compounds will be studied in these in-vivo models, he said. The most promising one will be developed further.
While creating this new drug is not a simple task, results should be expected soon, Kimball said.
“Conceptually, it’s easy. It’s sort of an engineering problem because we know the mechanism,” he said. “We need to fine-tune it just enough to carry the zinc.”
A prototype to demonstrate proof-of-concept should come out within the next two years, he said.
A final drug may take 10 or more years to be put on the market, Augeri said. A number of factors besides how efficiently zinc can be transferred must be looked at, including its safety.
The drug, once created, will take the medicinal molecule straight into a cancerous tumor, Kimball said. Affecting a tumor through medicine is difficult at present.
“We’ll be able to see that it’s working,” he said. “It’s not an easy problem, but there’s a clear path for us, which is really exciting because most cancer projects are very murky all the way through.”