University Researchers near Cancer Drug Breakthrough
Published: March 21, 2005
In a new study, researchers report seeing a reduction in the growth of both colon and lung cancer tumors with the inhibition of a target gene called methylenetetrahydrofolate reductase or MTHFR. The group from McGill University Health Center (MUHC), Montreal is now working on finding a commercially viable inhibitor that will be marketed through a university spin-off company.
“We believed that MTHFR, because it is required for synthesis of methionine and folate, would be a good target,” says Rima Rozen, PhD, professor, McGill University, scientific director, Montreal Children’s Hospital. “There are other anti-folate drugs on the market for treating cancer.” Folate is needed for DNA synthesis and MTHFR is an enzyme that is required for making an active form of the nutrient. The gene is also required for the synthesis of methionine an amino acid and nutrient, which is known to help tumor cells thrive. “It’s been well documented that tumor cells deprived of the ability to synthesize methionine stop growing,” she says.
Rozen’s group, which studied the enzyme’s function for several years and was the first to clone it, decided to examine the effects of inhibiting the enzyme on cells and tumors.
The cell work, which was done a few years ago, involved using cultured tumor lines of various types including, colon, lung and breast. “We showed that tumor lines that were exposed in vitro to an antisense against the MTHFR gene stopped growing,” says Rozen.
The most recent study, published in the online edition of the journal Clinical Cancer Research, expands on their in vitro work and demonstrates the positive effects of injecting the antisense into mice with solid colon and lung tumors.
“We knew the sequence of the antisense was good in vitro, but you never know when you go from in vitro to whole animal whether it will work,” says Rozen. “We were pleased that it did work and it clearly inhibited tumor growth.”
The group also tested a combination therapy of antisense with other drugs that are commonly used to treat cancer. In the case of lung tumors they used the antisense in combination with cisplatin. In the colon tumors they used antisense in combination with 5-fluorouracil. In both cases, the combinations were more effective than either one alone, she says.
One of the objectives for cancer therapy now, says Rozen, is to find combination therapies that use two drugs together at lower doses, which may be less toxic than using one drug against the same pathway at very high doses. “We are pleased that our antisense worked at a low dose in conjunction with some of the classic cancer drugs that are currently in use,” she says. She also reports that in the two week study, they did not see any toxicity. “Other antisense drugs in clinical trial tend to use larger doses,” she says.
The goal now is to develop a more classic type of small molecule drug to inhibit MTHFR. Strida Pharma, a McGill University spin-off company, which Rozen founded in 2002, will be fulfilling this goal. Strida has partnered with Tripos Inc., St. Louis, MO, and NovaScreen Biosciences Corporation, Hanover, MD, to screen for small molecule inhibitors of MTHFR.
“We will analyze the data and use a published crystal structure of MTHFR to develop hypotheses on what properties make a good inhibitor of the gene,” says Mike Lawless, PhD, molecular design senior team leader, Tripos. Compounds from proprietary and public libraries will be screened against those hypothesized criteria.
Tripos will then perform virtual screens against the crystal structure. NovaScreen has developed a high throughput MTHFR assay and will perform all of the biological in vitro assays to test these candidates. Tripos will then evaluate the resulting hits and score them based on synthetic feasibility. The synthesis will take place at Tripos’ facilities in England. “We will go through iterations of testing compounds, refining our hypothesis and synthesizing more compounds, optimized to meet the properties Strida wants,” says Lawless. “There are not many known inhibitors of MTHFR so that is one of the challenges of this.”
“This is a fairly standard looking enzyme, with a well defined function, so we believe it should be fairly easy to identify drugs that will inhibit this enzyme,” says Rozen. “The antisense provided a way to prove our principle and justification for us to look for a drug.”
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