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GenSpera’s Targeted “Death Carrot” Toxin in Trials for Two Cancers
Bernadette Tansey 3/27/14
Craig Dionne has a record of experience in drug development and a lot of friends in the pharmaceutical industry. But when his friends first heard about the experimental drug he started working on some years ago, he says their initial reaction was alarm—to put it mildly.
“They told me I was a fool,” Dionne says affably. Dionne is CEO of San Antonio, TX-based GenSpera, which has now started a second round of early stage clinical trials on the experimental drug he took a chance on. He’s hoping the trials are about to show his friends he was right.
Back in the early 1990s, Dionne and his collaborators at Johns Hopkins University saw potential for a cancer drug in a highly potent toxin, thapsigargin, found in a common Mediterranean weed called Thapsia Garganica. You’ll find it described as the “death carrot’’ in online accounts.
Thapsigargin kills fast-growing cells. So far, so good; that’s a routine property of chemotherapy drugs. But the relative safety of classical chemotherapy agents rests on the fact that they’re more destructive to rapidly multiplying tumor cells than they are to slow-growing normal cells.
Thapsigargin doesn’t work that way—which initially made it alarming to Dionne’s friends. It’s an equal opportunity cell-killer.
“It can kill cells that grow slowly,” Dionne says. That makes it a threat to normal cells, unless a drug company can successfully tweak it. And Dionne saw a reason to try.
Like most normal cells, some cancer cells also grow slowly, such as those in tumors of the prostate. And such cancer cells can resist chemotherapy drugs that target fast-growing cells. Dionne and his collaborators at Johns Hopkins reasoned that thapsigargin might be an effective weapon against slow-growing tumor cells, if it could be modified to spare normal cells. The end result of their chemical tinkering is GenSpera’s experimental drug G-202, which has now moved into a second round of early stage clinical trials.
The compound was designed to allow the powerful toxin to move through the bloodstream in an inactive form until it’s released by an enzyme, PSMA, found at higher levels on the surface of certain tumor cells, Dionne says. He compares G-202 to a grenade with a pin ready to be pulled.
A molecule of G-202 contains a modified form of thapsigargin called 12ADT, which is linked to a small peptide. The effect of that peptide—a small chain of five amino acids—is to keep 12ADT soluble in the watery environment of the blood. More importantly, he peptide keeps the toxin inactive.
But when G-202 encounters a cell with the enzyme PSMA (prostate-specific membrane antigen) on its surface, the enzyme clips the peptide off the toxic 12ADT molecule. The toxin, now insoluble in water but highly soluble in fats, can sink through the lipid-rich outer membrane of a nearby cancer cell and start its deadly work.
Dionne says G-202 is similar to the new class of targeted cancer drugs called antibody-drug conjugates, which are also designed to deliver a toxin only to particular tumor cells. These drugs combine a toxin with an antibody engineered to bind to a specific molecule on the surface of a cancer cell. However, antibodies are large proteins whose unique amino acid sequences and folding patterns can help them fit selectively only with certain cell surface receptors.
Serotonin-producing cells develop early on in the ENS, and if this buy generic levitra development is affected, the second brain cannot form properly. You will be helped to prolong your erection in a more healthy levitra online devensec.com and natural way by this medicine. Sexual dysfunction is a common concern shared by many women. generic levitra cheap This levitra 20mg canada medicine may lead to allergic reaction in some individuals. By contrast, G-202‘s targeting agent, the small peptide, could theoretically be clipped away from its toxic payload by enzymes other than PSMA, Dionne says. If that happened, the toxin could be released in the vicinity of normal cells rather than tumor cells. This is one of the reasons why GenSpera has spent years on preclinical testing and animal studies before launching its first clinical trial of G-202 in humans in 2011, he says.
Dionne says the company also took a close look at the cardiovascular effects of the experimental drug because of its molecular mechanism of action. Thapsigargin works by disrupting a molecular pump that regulates the level of calcium ions inside cells—and ion exchanges are central to the functioning of the cardiovascular system, Dionne says. Once inside any cell, whether a tumor cell or a normal one, thapsigargin causes a damaging influx of calcium, which starts a process of programmed cell death called apoptosis.
GenSpera also had to watch out for off-target effects of G-202 for another reason. Although the target enzyme PSMA appears in a higher concentration on cells of the prostate than on many other cells, it has been found as well in certain normal tissues, such as sections of the brain, small intestine, and kidney. Dionne says G-202 can’t pass through the blood-brain barrier. Studies of the drug’s action in animals and in humans so far have not turned up significant damage to the other normal cells bearing the PSMA enzyme, he added.
However, the discovery of enriched PSMA levels in yet another type of tissue has expanded the possible uses of G-202. The enzyme is more abundant on the cells of blood vessels that bring nutrients and oxygen to solid tumors than it is in normal blood vessels. Based on this finding, GenSpera began widening its views beyond prostate cancer, Dionne says. If the toxin in G-202 could be released by PSMA in tumor blood vessels, these vessels might disintegrate, and the tumor might starve and die.
“The potential applications are so much broader,” Dionne says.
In GenSpera’s first small trials in 2011 and 2012, 44 participants with a range of different cancer types received doses of G-202. Dionne says the drug appeared to have no serious effects on the liver, cardiovascular system, or bone marrow. Kidney damage could be prevented by limiting the G-202 dose and giving trial participants plenty of water, he says.
Although the main goal of the first trial was to assess the safety of G-202, GenSpera noted that a few trial participants with advanced liver cancer survived longer than expected. Encouraged by those signs, GenSpera is now conducting a Phase II trial in up to 17 adults with advanced hepatocellular carcinoma who are no longer helped by sorafenib (Nexavar), a cancer drug co-owned by Bayer and Amgen.
In March, GenSpera also began a Phase II trial in up to 34 participants with the brain cancer glioblastoma multiforme at the University of California San Diego’s Moores Cancer Center. The company may also conduct trials in prostate and kidney cancer if it can raise the funding.
GenSpera (OTC: GNSZ) is a tiny virtual company, that had $3.6 million in cash at the end of 2013—enough to fund its operations through at least nine months of this year. The company last week announced a share offering to raise as much as $7.5 million.
Dionne, a former executive at Cephalon, which was acquired by Teva Pharmaceutical Industries (NASDAQ: TEVA) in 2011, co-founded GenSpera in 2003. The firm began its preclinical studies in 2007, when it raised its first funds from outside investors. Dionne, who is GenSpera’s chief financial officer as well as CEO, is one of the company’s staff of two full-time employees. GenSpera contracts out all its other work.
“We’re virtual out of choice,” he says.
GenSpera’s scientific advisory board includes company co-founders John Isaacs and Samuel Denmeade, who are oncology professors at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.
GenSpera has raised $24.3 million since its inception, and the majority has come from high net worth individuals who often continue to reinvest, Dionne says. The company went public in 2009 and trades in the OTCQB tier of the Over-The-Counter Markets Group. GenSpera’s market capitalization is about $37 million.
Dionne says the company’s ideal plan is to seek a pharmaceutical company partner or buyer after conducting Phase II trials that show the potential of G-202 in solid tumors.
“We want to be valued across a range of tumor types,” Dionne says. The company has been built with the goal of making it attractive to big drug companies, he says.
“Our customer is large pharma,” Dionne says. “That’s who is ultimately going to pay us what we’re worth.”