In a 2014 Cell paper, the team — led by Patrik Ernfors at the Karolinska Institutet — reported that they had identified a small molecule that could target and kill glioblastoma cells — the cancer that U.S. Senator John McCain was just diagnosed with — and prolong survival in mice with the disease.
Satish Srinivas Kitambi, the paper’s first author, who is also based at the Karolinska Institutet, said the results got the team “really excited:”
We believed we had found a molecule that raised a new therapeutic hope for patients with glioblastoma.
Given the promising results, Kitambi said, “Our [goal] was to use this molecule as a monotherapy.” Unfortunately, their initial excitement soon faded.
The study created buzz. The paper was featured in Research Highlights in Nature Reviews Drug Discovery and in commentaries in Cell and Cell Research, all of which explained why the findings could be important for treating glioblastoma; Cell called the 2014 paper “a true tour de force.”
To carry on the work, the paper’s second-to-last author, Lars Hammarström, told us that the authors performed follow-up studies “to validate the compound’s efficacy” and “to make sure we had a robust response in vivo and to probe minimum efficacious dosing, toxicity etc before proceeding with further preclinical development.”
But when the researchers attempted to test the molecule’s effectiveness in rats and other mouse models of glioblastoma, they could not replicate the original results. Kitambi explained:
We repeated our experiment multiple times and saw that the molecule only extended survival in the animals sometimes, not all the time. That was a cause for concern.
Hammarström, a senior scientist at the Karolinska Institutet, told us:
In the new studies, the control mice lived much longer than we had observed in the initial Cell study.
We were puzzled by these results for a long time until we did careful additional histopathological analysis of the brains from the original study, which we fortunately had kept in formalin.
When the researchers re-examined the data from the 2014 paper, for “Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule,” they identified another possible explanation for why the untreated mice didn’t live as long as the treated ones: The control mice had developed a tumor in another location in their brain, called the meningeal compartment, which the researchers believe may have caused the control mice to die more quickly. Hammarström added that the the mice in the treatment group may have also developed tumors in the meningeal compartment, but were “cured” by the compound.
Kitambi said the researchers initially missed this other tumor in the control mice because “We never looked at meningial regions … there was [no] real reason to do at that time.”
When performing subsequent experiments, the researchers modified their protocol to ensure the mice did not develop tumors in the meningeal compartment. As a result, Hammarström explained, “the life expectancy was much longer and overall survival unaffected by the compound.”
Hammarström said that the authors immediately contacted Cell to inform the editors:
We chose to retract the paper so that others would not do any additional study on the compound expecting to repeat the original results.
It’s of course a pity since the remaining 95% of data, including all in vitro data in the paper have been thoroughly validated by both us and others, but in the end a retraction was the right decision since the in vivo data was the most important piece of the puzzle.
Kitambi agreed that a retraction was “the best way to move forward:”
We feel a high degree of responsibility when it comes to treating patients. We do not want to create false hope.
Here’s the retraction notice:
This article has been retracted at the request of the authors.
Our study reported the discovery of a class of small molecules that induces the massive vacuolization and cell death of glioblastoma cells in vitro, attenuates disease progression, and prolongs survival in a glioblastoma animal model. In the process of generating additional pre-clinical data to support the transition of vacquinol-1 to the clinics, we found that we are unable to replicate the original results showing that vacquinol-1 treatment extends overall survival of mice implanted with glioblastoma cells (Figure 7U in the original paper). Retrospective histopathological analysis of the brains from the original Figure 7U in vivo study indicates that tumor growth in the meningeal compartment of mice in the control group may have contributed to the difference in survival observed between vehicle and vacquinol-treated animals. These results call into question the extent of in vivo efficacy of vacquinol-1 as a monotherapy, and we therefore believe that the responsible course of action is to retract the paper. We apologize for any inconvenience we may have caused.
The 2014 paper has been cited 56 times, according to Clarivate Analytics’ Web of Science.
Hammarström told us:
We are continuing to investigate the mechanism of action of the compound and what is causing the discrepancy between in vitro-in vivo results.
Kitambi hopes the decision to retract the paper will highlight the fact that “retractions are not necessarily a bad thing.” In this case, Kitambi felt that retracting the study and alerting readers to the replication issue would:
…improve what compounds actually reach the clinic and hopefully help researchers engineer more efficient patient therapies. Ultimately, our goal is to help patients.
Hat tip: Rolf Degen
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