A potential new approach to glycolytic tumors
HOUSTON—Moleculin Biotech, Inc., a clinical-stage pharmaceutical company with a portfolio of drug candidates targeting highly resistant tumors, announced today that it has begun preclinical testing of its drug candidate, WP1122. Moleculin believes that WP1122 may present a new approach to treating highly glycolytic tumors like pancreatic cancer and glioblastoma.
“WP1122 represents an opportunity to attack the metabolism of cancer by exploiting the Warburg principle, which explains that some tumors are highly dependent on glycolysis, a specific metabolism of glucose, for growth and survival,” said Walter Klemp, Moleculin’s chairman and CEO. “What this means in practice is that tumors are vulnerable by being highly dependent on glucose availability.”
“Cancer cells often consume up to 18 times as much glucose as their healthy normal cells’ neighbors, suggesting that we may be able to starve tumors by supplying them with glucose decoys that would inhibit glucose-based energy production. However, until the creation of WP1122, glucose decoys like 2-deoxy-D-glucose (‘2-DG’) lacked the drug-like properties to be effective, primarily because of rapid metabolism and a very short circulation time in the body, which then limits desired organ and tumor uptake,” Klemp continued.
According to Moleculin’s website, WP1122 and its analogs have shown activity against brain tumor cell lines in in vitro testing and in an orthotopic brain tumor animal model. “We believe that WP1122 and similar compounds address a significant unmet need in the treatment of brain tumors and should be applicable to other difficult-to-treat, glucose dependent tumors, such as pancreatic cancer.”
“Our approach was inspired by the same principle that distinguishes morphine from heroin. Heroin is chemically the diacetyl ester of morphine. While morphine has a limited ability to cross the blood brain barrier (making it a good candidate for pain killing without impairing mental function), its diacetyl form, heroin, has the ability to accumulate in the brain by 10 to 100-fold more than morphine,” the website explains. “Once across the blood brain barrier, the acetyl groups shown in this chemical diagram are cleaved off by natural enzyme esterases, leaving pure morphine to accumulate in the brain. We believe based on pre-clinical testing that, just like heroin, WP1122 crosses the blood brain barrier where its acetyl groups are cleaved off, allowing the resulting 2-DG to accumulate in the brain at a much higher rate than free 2-DG can do by itself.”
The problem with using 2-DG for targeting tumors is that the relatively short half-life of 2-DG and its general lack of drug-like properties prevents adequate accumulation in targeted organs; 2-DG itself is metabolized and rendered ineffective.
“In contrast, WP1122 has a much longer half-life, making it much more feasible to deliver quantities adequate for a therapeutic effect,” the website notes. “As well, animal studies have now shown that the prodrug structure of WP1122 results in accumulation in certain targeted organs, including the pancreas, making it a potentially good candidate for targeting pancreatic cancer.”
“WP1122 is a prodrug of 2-DG that has been shown in animal models to significantly increase the half-life of 2-DG and allows for increased uptake to targeted organs and tumors like the brain tumors and pancreatic cancer. Recent discoveries now also suggest that such a glucose decoy could critically impact a process known as glycosylation and glycan formation and that this type of activity can directly impact the function of PD-L1, enabling increased immune system response to cancer cells,” added Dr. Don Picker, chief science officer for Moleculin. “We have been working on the clinical formulation of WP1122 for some time, and we are eager to now be taking the next key steps to getting WP1122 into the clinic.”