Research And Grants

Targeting lactate production pathways as a novel therapy against DIPG

Cancer cells secrete lactic acid, creating an inhospitable glucose-poor and lactate-rich tumor environment that would otherwise be lethal to most cells. Recent advances trying to understand DIPG development demonstrated that lactic acid was three times higher in DIPG cells. Furthermore, our laboratory found that the enzyme which makes the lactic acid is higher in tumor tissues analyzed from children with DIPG compared to other lower grade brain tumors. We have identified two non-toxic drugs which reduce lactic acid in DIPG cells. We found that blocking the over-production of lactic acid with these novel chemotherapies, significantly decreased the growth of DIPG cells, with one therapy even curing mice with DIPG.

Our work suggests that DIPG tumors are addicted to high secretions of lactic acid.

With this grant we will test novel, non-toxic drugs that block lactic acid over-production in animals with DIPG tumors. We will also characterize how lactic acid enables DIPG cells to be more aggressive by changes to DIPG DNA structure.

Although lactic acid is greatly over-produced by DIPG cells, it’s unclear what advantage the lactic acid gives to the DIPG tumor cells, because its yet to be investigated. We do have clues from experiments performed in adult cancers. Importantly, in other cancers high lactic acid in tumors promoted the immune escape of tumors and radiation resistance. Lactic acid even decreases the effectiveness of emerging therapies such as CAR-T cells in glioblastoma.

Lactic acid is likely an underlying general resistance mechanism in DIPG which is easily targeted with existing drugs. Giving hope that by reducing lactic acid in DIPG, children would respond better to currently trialed and emerging DIPG therapies, such as radiation or CAR-T.  

Our strategy targets a well reported DIPG characteristic that scientists have not investigated yet. We believe that targeting lactic acid over-production in DIPG is a feasible and novel treatment against DIPG, with the drugs already available and protocols for their use in children already available.

So why are we interested in lactic acid production? We discovered that H3K27M mutated DIPG cells are more sensitive to a copper depletion drug (copper chelator) compared to non-mutated DIPG. Amazingly we found that copper depletion cured 25% of mice bearing the common H3K27M mutated DIPG, as well as increased mouse survival. We demonstrated for the first time that copper depletion has an anti-DIPG cancer effect, which crosses the blood brain barrier and is non-toxic. We performed follow-up work trying to understand why the copper chelation was working against the DIPG cells. These experiments showed that the copper chelator was changing the metabolism in the cells. Specifically, copper chelation was blocking lactic acid production and changing downstream lactic acid effects on DNA structure. We realized there are no studies yet investigating lactic acid effects in DIPG, especially looking for any changes to DNA structure, which is known to be uniquely important in DIPG. Thus, our proposed work could help explain why these mutations lead to DIPG. Normal tissue in the brain is not dependent on copper and lactate over-production at the levels observed in DIPG tumors. Thus, our investigations could provide a novel therapeutic target that would only target cancer tissues and not the surrounding healthy tissue in the brain.

Copper chelation and lactate production drugs are used against other diseases already. The glycolysis pathway has a plethora of drugs available that are active in humans, and in other cancers such drugs are already being utilized in clinical trials. Copper chelation is already given orally to kids with genetic diseases and FDA approved. Thus, our treatment strategies could be easily incorporated into clinicals trials, because we already have information regarding what amounts are safe and effective for use in children. Note that the equivalent same amounts safely given to children with genetic diseases, we have shown to cure some mice with DIPG.