MEDICAL ARCHEOLOGY. An old drug candidate, from the 1980s, can help new clinical trials find the right patient category for new cancer drugs. That was the conclusion of a researcher couple at Sahlgrenska Academy that dug through the medical literature and discovered a forgotten drug molecule.
Work with a new molecule, called RVX2135, awakened interest in the discarded drug candidate. Researcher couple, Jonas and Lisa Nilsson, had shown that RVX2135 regulates genes that contribute to cancer cell death. The results were published 2014 in PNAS, Proceedings of the National Academy of Sciences, however, they had made additional findings that they wanted to examine more closely.
Namely, that RVX2135 also had the ability to affect genes involved in cell differentiation, that is, the process that leads to maturation from stem cells to a mature, specialized cell type. Differentiation has previously been a hot item in cancer research, and Jonas and Lisa decided to readdress the older medical literature. They found another PNAS article from 1971, where the renowned American virologist, Charlotte Friend, had shown that the substance dimethyl sulfoxide, DMSO, stimulated maturation of erythroleukemia cells into red blood cells. The finding was considered to be the basis for a new drug against leukemia.
“DMSO cannot be given to people, as it is a type of solvent. In New York, Paul Marks realized this, and, together with organic chemist Richard Breslow, they developed the molecule HMBA, which is similar to DMSO, but not so toxic,” explains Lisa who, like her husband Jonas, is a researcher at Sahlgrenska Cancer Center at the University of Gothenburg.
Tested on an acute form of leukemia
HMBA is short for hexamethylene bisacetamide. The molecule was tested as a drug for patients with acute leukemia, a form of blood cancer, where, among other things, stem cell maturation does not work. In the early trails during the 1980s, the molecule was highly effective against many forms of cancer when it was tested on cultured cells in the laboratory. These laboratory trials went so well that the American food&drug administration, the FDA, allowed Paul Marks to go on to trials with patients, despite unconvincing animal experiments. The patient response was, however, mixed – only one out of four patients improved.
HMBA was archived and forgotten.
“The poor result of the clinical evaluation was probably what made the researchers focus on other, more interesting candidates. Paul Marks worked in parallel with several potential drugs, one of which, a so-called HDAC inhibitor, ran the gamut and actually resulted in a new cancer drug,” says Jonas.
Medical archeology
Only now, with current modern research methods, has it been possible to find out how HMBA actually works, namely, that the molecule binds to so-called BET bromodomain proteins. The researcher couple was able to show this, among other things, in their collaboration with SARomics Biostructures, that derived a crystal structure of a BET protein binding HMBA at the the synchrotron facility, MAX IV, in Lund. The researchers have also shown that HMBA kills cancer cells that are triggered by over-activation of the well-known cancer gene Myc. By focusing on the Myc-drived cancer cells, Jonas and Lisa have been able to show that HMBA is a highly effective molecule, even in animal models.
“By showing that this is a BET inhibitor, we now know that HMBA has an effect similar to that of currently used modern cancer drugs. A 40-year-old molecule has been able to shed new light on several of the modern BET inhibitors currently undergoing clinical trials, notes Lisa and adds,
“I think we could learn a lot more from history. Today, it is easy to access old articles, and it is highly rewarding to dig through previous research.
Unknown mechanism with many drugs
Drugs are molecules created to affect the body’s cells through special receptors or target molecules. Binding initiates signals in the cell that affect the disease or the symptoms the drug is used for. Modern drug development often focuses on identifying target molecules and the substances that naturally activate them, but there are many drugs where these mechanisms are not known.
Jonas draws a parallel with one of our most well-known drugs, Alvedon (paracetamol):
“Alvedon was developed in the late 1800s and yet, there is amazingly little knowledge on how Alvedon actually works. It might prove to be super effective for something completely different than pain and fever, if we only knew what the molecule bonded to.”
Better effect on other cancer forms
There are multitudes of new BET inhibitors that are currently in different phases of testing at different drug companies.
“Our findings on the old molecule indicate that the developers of BET inhibitors are targeting the wrong cancer form. They are again targeting acute leukemia, that is, the same cancer form that HMBA was tested on. Our results indicate that they should instead be testing the drug on Myc-driven malignancies such as B-cell lymphoma and multiple myeloma, where our animal models indicate that the molecule should have a better effect,” says Jonas.
Follow the link to read the article ”Cancer differentiation agent hexamethylene bisacetamide was likely the first BET bromodomain inhibitor in clinical trials” (Nilsson LM et al), published in Cancer Research in March 2016: http://www.ncbi.nlm.nih.gov/pubmed/26941288
Follow the link to read the article ”BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma” (Bhadury J et al), published in PNAS in June 2014: http://www.ncbi.nlm.nih.gov/pubmed/24979794
Follow the link to read the article “Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide” (Friend C), published in PNAS in February 1971: http://www.ncbi.nlm.nih.gov/pubmed/5277089
You can also find out more about Paul Marks research in his autobiography: On the Cancer Frontier that was published in 2014.
