…my attention was raised to another mitochondrial glycolysis inhibitor being touted for anticancer utility. From a 1 April New York Times Op-Ed by Ralph W. Moss entitled, “Patents Over Patients“:
In 2004, Johns Hopkins researchers discovered that an off-the-shelf compound called 3-bromopyruvate could arrest the growth of liver cancer in rats. The results were dramatic; moreover, the investigators estimated that the cost to treat patients would be around 70 cents per day. Yet, three years later, no major drug company has shown interest in developing this drug for human use.
I don’t know Moss personally, but he is on the record as a critic of what his 1980 book entitled, The Cancer Industry. I can’t comment on a book I haven’t read so I linked to a review of it; instead, I’ll focus instead on the content of his op-ed. His essay castigates drug companies for not developing unpatentable compounds but I’m not so sure the examples he uses are the best to support his case for a change in drug approval legislation.
3-bromopyruvate, or 3-bromopyruvic acid (3-BrPA), is an inhibitor of an enzyme called hexokinase II. Hexokinase II is required for the first step of using glucose as a substrate to make ATP and or lactate. Unfortunately, 3-BrPA will inhibit both glycolysis and normal oxidative phosphorylation (the latter resulting from its complexing with ATP synthase), requiring that the drug be injected directly into the artery that feeds the tumor, and still at very high concentrations (5 mM). One of the papers I know best on the topic comes from Johns Hopkins mitochondrial expert, Dr Pete Pedersen, whose team tested this compound against animal models of liver cancer. (Here’s a great review, also with Pedersen as senior author, on the promise and challenges of hexokinase II as a drug target – if your institution has access to Oncogene).
3-BrPA is a great experimental tool but it cannot be taken orally, so there’s no risk of sites popping up like those now selling dichloroacetate.
Funny thing is that I actually agree with the conclusion in Moss’ NYT Op-Ed:
One solution might be for the government to enlarge the Food and Drug Administration’s “orphan drug” program, which subsidizes the development of drugs for rare diseases. The definition of orphan drug could be expanded to include unpatentable agents that are scorned as unprofitable by pharmaceutical companies.
In fact, late in my 3 February post on dichloroacetate, I noted that the existing US orphan drug legislation has allowed development of another relatively simple chemical, sodium phenylbutyrate for urea cycle disorders. (By the way, phenylbutyrate has been tested against cancer but the doses required were so high that patients experienced toxicity from the sodium counterion – instead, drug companies have developed more potent compounds (Zolinza/vorinostat) that act via the same mechanism: inhibition of histone deacetylases.)
Moss uses as examples 3-BrPA, dichloroacetate, and melatonin, perhaps not the best candidates but certainly more plausible than things like laetrile or hydrazine sulfate. The first two have only been tested in animal models of cancer and require extremely high concentrations to kill cancer cells, even in culture. 3-BrPA appears to require injection directly into tumor blood supply and, therefore, would be a challenge to administer in most settings and would not be useful against micrometastases (not to mention that the costs of such a procedure are not included in his “70 cents a day” projection). But I am on the record as supporting a controlled clinical trial of dichloroacetate in cancer patients since it appears to have a more discrete effect on aerobic glycolysis by inhibition pyruvate dehydrogenase kinase (the “other” PDK).
Some government and academic groups are already examining melatonin as an adjunct to chemotherapy and radiation therapy based on work of the Italian researcher, Dr Paolo Lissoni. (review here). Small trials in patients with advanced cancer show some benefit of melatonin at 20 mg/day, certainly doable but much higher than the doses used as a sleep aid. However, some of these trials are not published in very high-impact journals and a meta-analysis of melatonin in cancer treatment cited that all the trials were done within the same hospital network and were unblinded, perhaps detracting from the influence of Lissoni’s hypotheses of melatonin as a pro-apoptotic, anti-angiogenic, immunomodulatory compound.
This is a long way of saying that perhaps the reason unpatentable drugs are not being developed for cancer is because they have not yet met the burden of proof worthy of the investment of the hundreds of millions of dollars needed for governmental approval. I can’t speak for the rationale of a drug company since I just have a small academic lab, but I’d guess that many folks like me don’t even apply for grant funds because these compounds, especially 3-BrPA and DCA, require such high concentrations to have any effect even in cell culture systems. Outstanding scientists like Pedersen can probably get funded for this work because of their long history in mitochondrial research and the stature and focus of their institution. But if academicians shy away from working on these compounds it’s no wonder that drug companies aren’t interested, patentable or not. (Any readers from pharma are welcome to add their comments below.).
I sense from the tone of the op-ed that Moss was aiming for the “conspiracy against a cure for cancer” audience and I’m kind of surprised that the New York Times published the piece.
However, Moss does raise an important point: when better but unpatentable compounds for cancer do come down the pike, who will sponsor their development?