A study recently published in Nature outlined the importance of targeting tetrahydrobiopterin (BH4) as a possible treatment for cancer.
Pain researcher Clifford Woolf, MB, BCh, PhD, Director of the F.M. Kirby Neurobiology Center at Boston Children's Hospital, and chemist Kai Johnsson, PhD, Professor at the Institute of Chemical Sciences and Engineering of the École Polytechnique Fédérale de Lausanne, discovered in 2013 that BH4 is a protein that modulates neuropathic and inflammatory pain sensitivity. Dr. Woolf and Dr. Johnsson, the co-founders of Quartet Medicine, believed that inhibiting BH4 could be a potential way to relieve pain without causing addiction. However, they had to discontinue this line of research in 2017 when toxicology reports revealed that BH4 inhibition led to neurologic side effects.
The research took a different turn when the investigators discovered that BH4 also acts as a T-cell regulator, with the ability to increase or decrease the activity levels of the T cells. Dr. Woolf and his team at Boston Children's Hospital, Dr. Johnsson, and immunologists from the Institute of Molecular Biotechnology (IMBA) at the Austrian Academy of Sciences were able to inhibit T-cell production by blocking the BH4 pathway in animal models of autoimmune disease and human cell lines. In addition, they were able to enhance T-cell responses by elevating BH4 levels in models of cancer.
"By targeting BH4, we are able to suppress T cell activity in inflammatory conditions and increase their activity in the case of cancer. The ability to target the same pathway in opposite directions is significant and represents a whole new therapeutic approach," claims Dr. Woolf.
The researchers report that BH4 regulates the balance of available iron for mitochondria, which is important because higher levels of iron are needed to produce mitochondrial energy. This energy is then used to activate T cells. When T cells are under pressure, more BH4 is produced, increasing available iron and allowing the cells to divide and activate. However, when BH4 levels are low, iron is not available for mitochondria; therefore, T-cell activity is stifled. In terms of cancer, tumors produce a metabolite that blocks BH4, inhibiting T-cell activation and cancer surveillance. This response could be opposed by increasing BH4.
According to Dr. Woolf, "The beauty of it is that the effect is upstream of specific types of T cell function. Most drugs being developed now to treat autoimmune conditions are targeting specific kinds of T cells. This covers them all."
The BH4 pathway is active only when there are cases of infection or if proliferation needs to occur. For the normal formation of T cells, the BH4 pathway is not required to become active.
The researchers also discovered QM385, a highly potent small molecule which works to block the BH4 pathway and in turn inhibits T-cell production and autoimmunity.
Researchers found after boosting levels of BH4 in mouse models of cancer, tumors shrank, and metastasis stopped. Now, they are searching for compounds to enhance BH4 in cancer patients. Potentially, these compounds could be used alone or in combination with other therapies, such as immune checkpoint inhibitors.
"There are many interesting discoveries to be made at the intersections and borders of fields if one keeps an open mind and is willing to follow what nature tells us," emphasizes immunologist Josef Penninger, MD, PhD, Scientific Director of IMBA, co-senior author of the study.
For More Information
Cronin SJ, Seehus C, Weidinger A, et al (2018). The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature. [Epub ahead of print] DOI:10.1038/s41586-018-0701-2