'Hard To Treat' Cancer Tricked Into Consuming Tumor-Shrinking Drugs

A new blood cancer treatment has been found to prevent cancerous cells from growing and multiplying.

The treatment works by combining a drug that prevents cancer cells from growing uncontrollably with a protein that allows the drug to enter the cells. Using this approach, scientists have stopped the cancer from thriving in mice.

"Our new approach targets cancers that have been very hard to treat," study lead author Nathan Beals, a postdoctoral researcher in the Department of Biochemistry and Molecular Pharmacology at NYU Langone, said in a statement. "We are taking advantage of a process that is significantly overactive in cancer cells, which focuses the treatment effect on abnormal cells."

The findings were presented in an oral abstract by the researchers at the 2023 annual meeting of the American Society of Hematology in San Diego on December 9.

The cancer in question is multiple myeloma, which is a cancer of a type of white blood cell called a plasma cell. These plasma cells live in the bone marrow, and usually help the body to fight infections by producing proteins called antibodies that allow the immune system to recognize and destroy infections. When cancerous, the multiple myeloma builds up in the bone marrow and crowds out the healthy cells, churning out faulty antibody proteins.

Around half of multiple myeloma (MM) cases are caused by mutations in a gene called RAS, which encodes a protein switch that regulates the growth of the plasma cells. When mutated, the RAS protein switch becomes stuck "on", causing the cells to grow uncontrollably. The RAS mutation also impacts a pathway called macropinocytosis, during which cells engulf proteins and fats outside and pull them inside of themselves. This provides resources that allow the cancer cells to multiply rapidly. Until now, researchers had not managed to figure out a way to treat this mutated RAS gene.

"To create a strategy for targeting RAS mutant MM, we have investigated whether RAS-mutant MM cells undergo [macropinocytosis] and whether this process can be exploited as a therapeutic vulnerability," the authors wrote in the oral abstract.

In mice, the researchers found a way to combine a drug called MMAE—that prevents cells from multiplying—with proteins called monobodies. The protein is readily pulled into the cell via macropinocytosis, allowing the drug to enter the cell and act against the RAS gene mutation. Without the protein, MMAE is not easily pulled into the cells.

"Monomethyl auristatin E [MMAE, vedotin] is a very potent anti-mitotic agent that inhibits cell division by blocking the polymerisation of tubulin. It is often described as a 'warhead' and is used combined to a monoclonal antibody as an ADC [antibody-drug conjugate], in cancer therapy," Faith Davies, study co-author and professor of medicine at NYU Langone Health, told Newsweek.

The protein-drug combo blocked the action of cell scaffolding structures called microtubules, preventing the cell from multiplying. After 21 days, the mice with mutant RAS multiple myeloma tumors saw a sixfold decrease in tumor size.

"The novelty of our approach is that it is specific to mutant RAS. Unlike ADCs that utilize a surface protein to deliver the warhead, we have used a cellular process called macropinocytosis to deliver it," Davies said. "The process is upregulated in mutant RAS cells as they use it to scavenge for extracellular nutrients such as amino acids for fueling cell growth.

"We have hijacked the process and instead of ingesting amino acids the cells ingest the monobody with the MMAE warhead attached to it leading to cell death. In short, a totally new approach to killing cells."

The researchers also found that the conjugate of the protein and drug caused up to five times more RAS cancer cell deaths compared to normal cells, meaning that it is less likely to damage healthy tissue surrounding it

"Our conjugate improved survival in early tests and has the potential to be important clinically against multiple myeloma," study author Dafna Bar-Sagi, a senior vice president, vice dean for science, and chief scientific officer at NYU Langone, said in the statement.

Additionally, when the drug-protein combo was used alongside other anticancer treatments, even more improved outcomes were observed. This may mean that lower doses of these anticancer treatments can be used, leading to fewer side effects.

"The next steps will be to continue to develop the approach for human trials. Excitingly the approach is not tumor-type specific and should be appropriate for any RAS-driven cancer—in addition to multiple myeloma, a blood cancer, we would hope it may be effective for a range of solid tumors including pancreatic cancer," Davies explained.

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Update 12/14/23, 11:17 a.m. ET: This article was updated with comment from Davies.