GenSpera plans to initiate G-202 Phase II trial in prostate cancer

 We know that, a Mediterranean plant (see pic), 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.

A recent study of  G202,  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.  

Now its  good news that,......

GenSpera plans to initiate G-202 Phase II trial in prostate cancer

Drug from Mediterranean weed kills tumor cells in mice

The drug G202 is chemically derived from a weed called Thapsia garganica that grows naturally in the Mediterranean region. The plant makes a product, dubbed thapsigargin (see the structure,  that since the time of ancient Greece has been known to be toxic to animals. In Arab caravans, the plant was known as the "death carrot" because it would kill camels if they ate it, the researchers noted.

Thapsigargin is, 

(3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-(acetyloxy)-4-(butyryloxy)-3,3a-dihydroxy-3,6,9-trimethyl-8-{[(2Z)-2-methylbut-2-enoyl]oxy}-2-oxo-2,3,3a,4,5,6,6a,7, 8, 9b-decahydro azuleno[4,5-b]furan-7-yl octanoate)

"Our goal was to try to re-engineer this very toxic natural plant product into a drug we might use to treat human cancer," says lead study author Samuel Denmeade, M.D., professor of oncology, urology, pharmacology and molecular sciences. "We achieved this by creating a format that requires modification by cells to release the active drug."

By disassembling thapsigargin and chemically modifying it, the researchers created a form that Denmeade likens to a hand grenade with an intact pin. [Thapsigargin prodrug G-202, is a cytotoxic analog of thapsigargin, 8-O-(12Aminododecanoyl)-8-O debutanoylthapsigargin (12-ADT) linked, via a carboxyl group, to the targeting peptide containing aspartic acid].

The drug can be injected and can travel through the bloodstream until it finds the site of cancer cells and hits a protein called prostate-specific membrane antigen (PSMA). PSMA is released by cells lining tumors of the prostate and other areas, and in effect "pulls the pin" on G202, releasing cell-killing agents into the tumor and the blood vessels that feed it, as well as to other cells in the vicinity. Specifically, G202 blocks the function of a protein called the SERCA pump, a housekeeping protein necessary for cell survival that keeps the level of calcium in the cell at the correct level, the researchers report.

"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.

Because the drug is targeted to the SERCA pump, which all cells need to stay alive, researchers say it will be difficult for tumor cells to become resistant to the drug, because they cannot stop making the protein.

More : http://stm.sciencemag.org/content/4/140/140ra86

Drug from Mediterranean weed kills tumor cells in mice