New CRISPR Study Suggests Dietary Supplement Could Enhance the Effectiveness of Chemotherapy

There’s good news coming out of MIT this week. In an article on Medical Xpress, new findings are coming out using CRISPR, a tool that is known for its ability to help precise gene editing. Researchers hope that the tool can also be used for screening cells, so that we could attain a better understanding of how cells work by using CRISPR to open them up and look inside. Research coming out of the Whitehead Institute may have the potential to validate this.  

New Information

Whitehead Institute Member David Sabatini’s lab has a focus on applying CRISPR to cancer cells specifically. They have already successfully unearthed a boat load of previously ill-defined information on how both normal cells and cancer cells really operate.

Treating Acute Lymphoblastic Leukemia

Naama Kanarek, a postdoc in Sabatini’s laboratory has been researching methotrexate, a form of chemotherapy drug used for decades. Her objective was to apply CRISPR/Cas9 to the process. Methotrexate is usually used to treat a form of pediatric leukemia known as acute lymphoblastic leukemia (ALL). Like other chemotherapy drugs, methotrexate can be very effective in attacking cancer cells, but can be equally detrimental to healthy cells as well. Any child administered the drug must remain in the hospital for the extent of their treatment to be monitored.

There is still a lot left to be understood about methotrexate itself. The drug is more effective in treating ALL than other cancers, and when treating other cancers it has about a 65% success rate, meaning it works more than half the time, but not much more. The question is: why? What exactly is it that makes the drug so effective sometimes?

Potential Answers

Sabatini’s team have made another step in hopefully answering this question. In the July 11th issue of the online journal Nature, they report their findings that an amino acid called histidine that is used to construct proteins, is also instrumental to determining a cancer cells sensitivity to methotrexate.

These results not only help us understand how a treatment we’ve been using for decades actually works biologically, but it also suggests that the effectiveness of methotrexate could be improved as simply as adding a dietary supplement to the treatment plan.

“This study is an example of the power of modern genomic tools to shine a bright light on longstanding questions in human biology,” says senior author David Sabatini.

For the majority of methotrexate’s history, people had a vague understanding of its principle operations. The drug administers dihydrofolate reductase (DHFR) to the body. This enzyme makes a functional form of folate inside the body known as tetrahydrofolare (THF). The body then uses the THF to make more healthy DNA and RNA to compete with the rapidly replicating unhealthy cancer cells.

So for the most part, this much was understood. Kanarek’s CRISPR/Cas9 research has uncovered another piece to the puzzle. There is another previously unnoticed enzyme called FTCD at work within the cells as well. This enzyme helps to break down the histidine of the cancer cells, weakening them and giving the healthy cells the leg up they need. However, FTCD also requires THF to do its job.

“Under normal conditions, this pool (of THF) is sufficiently full, so there is no competition for resources, even in rapidly dividing cells,” Kanarek says.

 

The problem comes when the THF supply within the body is being exhausted by both enzymes. When the FTCD and DHFR combine in their efforts to break down histidine and recreate DNA and RNA, two necessities when treating ALL, the entire store of THF is used up. This causes the cells die.

Kanarek is considering using histidine as a way to disrupt the natural activity of FTCD. It is possible that by cranking up the availability from minimum to maximum, she could affect the metabolism of the cancer cell, making it more sensitive to methotrexate.

So far, the theory has been tested on mice. Two separate injections, one of the classic methotrexate and another of histidine were administered and thus far has worked as the researchers had hoped. The two injections tag-teamed to expedite the process of FTCD and drain the THF supply more rapidly. The cells didn’t have what they needed and subsequently died.

The team are moving their findings towards preclinical trials with their ultimate goal to get their research into clinical trials, provided their hypothesis continues to test out positive.

There is still a variable of the drug– its propensity to not work for everyone– that needs to be addressed. There are another two enzymes that also work with FTCD to break down histidine. More work is needed to further devine how ALL cells operate. Further research trials are already scheduled.


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