A new type of cancer drug developed at Johns Hopkins University in Baltimore, Maryland, but not yet tested in clinical trials may have triggered the deaths of three patients who were undergoing an alternative cancer treatment by a non-medical practitioner in Germany, says a Science report. Germany has many such practitioners, and the field is loosely regulated. The public prosecutor in Germany is now investigating whether the case constitutes involuntary manslaughter.
The drug in question, 3-Bromopyruvate (3BP), has been hailed by some researchers as a potential breakthrough, but so far the only human data about its efficacy and safety are anecdotal. Many scientists say the drug should not be administered to patients except in carefully controlled experimental settings. If the link to the three deaths is confirmed, that could cloud 3BP’s commercial prospects.
German police took action on 4 August after two patients from the Netherlands and one from Belgium died shortly after undergoing treatment at the Biological Cancer Centre, run by alternative practitioner Klaus Ross in the town of Brüggen, Germany, 50km west of Düsseldorf. Two other patients had to be treated for life-threatening conditions, the prosecutor’s office said.
The report says police in Germany, the Netherlands, and Belgium have urged other patients treated at the centre to contact local health authorities; at least 26 have done so. Media reports suggest that cancer patients often sought Ross’s help after they ran out of conventional therapy options, or to avoid aggressive chemotherapy. He offered a 10-week “basic therapy” against cancer for €9,900 ($11,057).
On his website, Ross touted 3BP as “currently the best compound to treat tumours.” In its press release, the prosecutor said the investigation has “reinforced” suspicions that the three deceased patients actually received the compound, as media interviews with relatives and other sources had previously suggested.
The report says Ross did not respond to requests for comment. In a statement published on his website concerning the first death, he wrote that he is “in shock” and that he regrets the impression created in the media that alternative medicine may be responsible.
The report says 3BP, part of a class of compounds known as small molecule drugs, was first studied as an anti-cancer agent more than a decade ago at Johns Hopkins by biochemists Young Hee Ko and Peter Pedersen, together with radiologist Jeff Geschwind. It is believed to “starve” tumour cells to death by inhibiting glycolysis, the breakdown of glucose molecules to provide cells with energy. The hope is that 3BP specifically kills certain cancer cells – while leaving normal cells alone – because they rely more on glucose metabolism than on an alternative pathway called oxidative phosphorylation. In studies on rats and mice, 3BP was reported to reduce growth of tumours or even shrink them, and experiments on human cancer cell lines showed that combining another chemotherapeutic with 3BP increased its efficacy. However, animal studies also showed clear toxicity with certain administration regimes.
In 2009, Pederson and Ko teamed up with radiologist Thomas Vogl at the University Hospital Frankfurt in Germany for what appears to be a first experiment in a single patient. With the approval of the local ethics committee, a 16-year-old boy with a rare type of liver cancer called fibrolamellar hepatocellular carcinoma was given infusions of 3BP into the blood vessels supplying the tumor, formulated in a proprietary and patented fashion. Although he died at age 18, the researchers described the experiment as a success in a 2012 paper.
“The rate of tumour necrosis due to 3BP treatment seems to exceed all known cytostatic drugs,” they wrote. No major toxic effects were observed, and the patient “was able to survive a much longer period than expected with an improved quality of life, which is clearly attributable to the treatment with 3BP,” the scientists concluded.
In retrospect, Vogl says it would have been better to write “probably” instead of “clearly” because a single case report isn’t strong evidence. Still, “we were surprised how long the patient survived and that we saw no toxic side effects,” he says.
A few other case reports have emerged more recently, the report says. For instance, in a paper published in 2014, Egyptian oncologists describe treating a 28-year-old man with 3BP; they reported that the compound appeared safe but not very effective if used alone.
But, the report says, 3BP has yet to undergo formal clinical trials. PreScience Labs, a US company founded by Geschwind, received approval for a phase I study from the US Food and Drug Administration in 2013. Geschwind says the trial has yet to start because the company needs partners to finance it.
Both Vogl and Geschwind say they are concerned about inappropriate use of the drug. The 2012 paper co-authored by Vogl warned that “unformulated 3BP may be harmful in some cases,” and Vogl says doctors should “absolutely” not perform systemic infusions, in which the drug circulates through the entire body. “I am concerned about the drug being used without having first conducted the proper clinical studies,” Geschwind adds.
The report says 3BP can be purchased from chemical companies, and practitioners around the world offer it to patients. Local health authorities report that Ross says he obtained the compound from a German pharmacy. A spokesperson for the public prosecutor says that a preliminary assessment by health authorities has found that Ross was authorised to administer the substance; he declined to say how this was possible, given that 3BP is not approved.
Eugen Brysch, head of the German Foundation for Patient Rights in Dortmund, says that the government should regulate practitioners of alternative medicine more strictly. “Creativity in therapy must not negatively affect patent safety,” Brysch is quoted in the report as saying. “It cannot be the case that plumbers or chip shops are supervised more strictly than medical service providers.”
A spokesperson for Germany’s federal health ministry says there are no plans to overhaul regulation for traditional practitioners; local authorities are responsible for oversight of the field, she says. Those normally take action only after incidents or complaints, however.
In the wake of the three deaths, the district of Viersen, where Ross had his centre, has banned him from practicing in the district.
The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells’ energy metabolism, both its high glycolysis (“Warburg Effect”) and mitochondrial oxidative phosphorylation. This inhibits/ blocks total energy production leading to a depletion of energy reserves. Moreover, 3BP as an “Energy Blocker”, is very rapid in killing such cells. This is in sharp contrast to most commonly used anticancer agents that usually take longer to show a noticeable effect. In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells. Therefore, 3BP can be considered a member, perhaps one of the first, of a new class of anticancer agents. Following 3BP’s discovery as a novel anticancer agent in vitro in the Year 2000 (Published in Ko et al. Can Lett 173:83–91, 2001), and also as a highly effective and rapid anticancer agent in vivo shortly thereafter (Ko et al. Biochem Biophys Res Commun 324:269–275, 2004), its efficacy as a potent anticancer agent in humans was demonstrated. Here, based on translational research, we report results of a case study in a young adult cancer patient with fibrolamellar hepatocellular carcinoma. Thus, a bench side discovery in the Department of Biological Chemistry at Johns Hopkins University, School of Medicine was taken effectively to bedside treatment at Johann Wolfgang Goethe University Frankfurt/Main Hospital, Germany. The results obtained hold promise for 3BP as a future cancer therapeutic without apparent cyto-toxicity when formulated properly.
YH Ko, HA Verhoeven, MJ Lee, DJ Corbin, TJ Vogl, PL Pedersen
3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.
Salah Mohamed El Sayed, Walaa Gamal Mohamed, Minnat-Allah Hassan Seddik, Al-Shimaa Ahmed Ahmed, Asmaa Gamal Mahmoud, Wael Hassan Amer, Manal Mohamed Helmy Nabo, Ahmed Roshdi Hamed, Nagwa Sayed Ahmed, Ali Abdel-Rahman Abd-Allah