- A report published by researchers at MIT and Harvard has highlighted the details of a study involving the test of thousands of existing drugs on close to 600 types of cancer cells in humans
A report published by researchers at Massachusetts Institute of Technology (MIT) and Harvard University has highlighted the details of a study involving the test of thousands of existing drugs on close to 600 types of cancer cells in humans. And they found nearly 50 that may kill cancer.
The drugs have either been U.S. Food and Drug Administration-approved or were deemed as safe in clinical trials. In the paper — which was recently published in the “Nature Cancer” journal — the drugs tested were not meant for cancer therapies. And Study first author, Drug Repurposing Hub founder, and Broad Institute Oncologist Dr. Steven Corsello noted that in the past, scientists would start with a target inside of a cancer cell in mind. From there, they would find a drug that worked against that target.
“We thought we’d be lucky if we found even a single compound with anti-cancer properties, but we were surprised to find so many,” said Todd Golub, chief scientific officer and director of the Cancer Program at the Broad and pediatrics professor at Harvard Medical School in a statement.
The researchers had tested all the compounds in the Drug Repurposing Hub on 578 human cancer cell lines from the Broad’s Cancer Cell Line Encyclopedia (CCLE). And using a molecular barcoding method known as PRISM — which was developed in the Golub lab, the researchers tagged each cell line with a DNA barcode — allowing them to pool several cell lines together in each dish and quickly conduct a larger experiment. From there, the team then exposed each pool of barcoded cells to a single compound from the repurposing library and measured the survival rate of the cancer cells.
The team founded nearly 50 non-cancer drugs, including those initially developed to lower cholesterol or reduce inflammation that killed some cancer cells while leaving others alone.
“We created the repurposing hub to enable researchers to make these kinds of serendipitous discoveries in a more deliberate way,” explained study first author Steven Corsello, an oncologist at Dana-Farber (a member of the Golub lab) and founder of the Drug Repurposing Hub. “Most existing cancer drugs work by blocking proteins, but we’re finding that compounds can act through other mechanisms,”
A number of the compounds had killed cancer cells in unexpected ways. Some of the four-dozen drugs he and his colleagues identified appear to act not by inhibiting a protein but by activating a protein or stabilizing a protein-protein interaction. For example, the researchers found that nearly a dozen non-oncology drugs killed cancer cells that express a protein called PDE3A by stabilizing the interaction between PDE3A and another protein called SLFN12 — which is a previously unknown mechanism for some of these drugs.
A majority of the non-oncology drugs that killed cancer cells in the study did this by interacting with a previously unrecognized molecular target. And the anti-inflammatory drug tepoxalin — originally developed for use in people but approved for treating osteoarthritis in dogs — killed cancer cells by hitting an unknown target in cells that overexpress the protein MDR1, which commonly drives resistance to chemotherapy drugs.
Plus. the researchers were also able to predict whether certain drugs could kill each cell line by looking at the cell line’s genomic features like mutations and methylation levels — which were included in the CCLE database. And this implies that these features could one day be used as biomarkers for identifying patients who will most likely benefit from certain drugs. For example, the alcohol dependence drug disulfiram (Antabuse) killed cell lines carrying mutations that cause the depletion of metallothionein proteins. And compounds containing vanadium — originally developed to treat diabetes — killed cancer cells that expressed the sulfate transporter SLC26A2.
