Anti-cancer “hand grenade” G202 in clinical trials

Anti-cancer “hand grenade” G202 in clinical trials

A cancer drug in development, G202, has had promising results in mice and is moving forward in clinical trials. A creative approach to drug design renders the molecule harmless until it reaches a tumor, where a specific tumor protein activates the toxicity of the compound. Researchers are hopeful about the applications for G202; cautious optimism is called for as it makes its way through the drug development process.

A cancer drug in development, G202, has had promising results in mice and is moving forward in clinical trials. A creative approach to drug design renders the molecule harmless until it reaches a tumor, where a specific tumor protein activates the toxicity of the compound. Researchers are hopeful about the applications for G202; cautious optimism is called for as it makes its way through the drug development process.

 

This past Monday, MyScienceWork looked at a potential new therapy for Alzheimer’s disease and brain injury, discovered thanks to effective communication between two fields of biomedical research. Now, scientists are testing in clinical trials an anti-cancer drug inspired by nature, modified with some clever molecular engineering, and capable of seeking out its target. Activated only in the presence of a tumor, the specificity of the drug spares healthy cells, the innocent bystanders in its path. The efficacy of the drug, G202, in destroying tumors in mice is described in the June 27 issue of Science Translational Medicine.

Thapsia garganica
Thapsia garganica, the source of a potential new cancer drug, G202.

A Mediterranean plant, Thapsia garganica, a simple weed, is the original source of G202. For millennia, the plant has been known to be poisonous to animals; in the days of desert caravans, it was called the “death carrot” for the unfortunate fate awaiting any camel that ingested it. Researchers at the Johns Hopkins Kimmel Cancer Center in the US and their Danish collaborators hoped to harness the toxicity of the plant in a controlled way that could be used to treat cancer in people.

They did so by taking apart the toxic compound, thapsigargin, produced by the plant and altering its chemical structure. The resulting prodrug, G202, is not active until it comes into contact with a particular protein produced by certain tumors. This prostate-specific membrane antigen (PMSA) is released by cells lining the outside of prostate and other tumors. Samuel Denmeade, the study’s lead author, uses the image of a hand grenade. The presence of PMSA essentially “pulls the pin” of the G202 grenade. In its active form, the drug is able to kill not only the tumor, but the blood vessels that provide it with nutrients.

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"The exciting thing is that the cancer itself is activating its own demise," says senior study author John Isaacs, Ph.D., professor of oncology, urology, chemical and biomedical engineering at Johns Hopkins.

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The recent G202 study looked at the effects of the drug on human prostate tumors grown in mice, and compared it to docetaxel, a chemotherapy drug already in use. G202 clearly came out on top, reducing by half the size of seven out of nine tumors; docetaxel achieved the same effect on only one out of eight tumors. Similar results for G202 were also seen in experiments with human breast, kidney and bladder cancer.

These promising results encouraged doctors to test the safety of G202 in a phase I clinical trial, involving 29 cancer patients at advanced stages of the disease. The next step, a phase II trial, will test the drug in patients with prostate cancer and liver cancer. No problems of resistance to the drug are expected to arise, as G202 works by blocking a protein essential for cell survival – the SERCA pump; without this molecule responsible for maintaining proper calcium levels, no cell could hope to survive.

Cancer is among the most troubling illnesses facing us today, likely to have an impact on nearly all of us, even if indirectly. Not infrequently, hopes are raised by the possibility of new treatments, only to be abandoned when safety concerns arise or efficacy proves less than expected. Given this context, it is important to keep in mind that G202 may not live up to its early success and survive the long, expensive, rigorous drug development process. Still, pursuing new therapies, with creative approaches drawing from multiple fields, is the only way forward, and even failure adds to our understanding of disease.