Anticancer strategies: can we prevent severe oral mucositis?
Research presented at the 265th National Meeting and Exposition of the American Chemical Society (19–23 August 2018) suggests a new drug could prevent a common debilitating side effect of cancer treatment.
A novel drug, discovered by researchers at Galera Therapeutics (PA, USA), could prevent severe oral mucositis (SOM) in patients undergoing radiation and chemotherapy for the treatment of head, neck, nasal and oral cancers. The research, presented at the 265th National Meeting and Exposition of the American Chemical Society, highlights the development of the first drug candidate that could prevent SOM, which has been designated by the US FDA as a “breakthrough therapy.”
Oral mucositis is a common complication during radiochemotherapy, occurring when the epithelial cells lining the mouth break down. This can cause severe pain, inflammation, ulceration and bleeding, and in severe cases can lead to patients unable to swallow or consume liquids and food. SOM, defined by the WHO as grade 3/4 of oral mucositis, develops in 70–80% patients treated with radiation.
"It is exciting to publicly report on the structure and synthesis of GC4419 for the first time," remarked Dennis Riley, leader of the study. "We believe GC4419 has the potential to address an important unmet medical need in the treatment of cancer patients undergoing radiation therapy, and we look forward to commencing a Phase III trial with GC4419 in head and neck cancer patients this year."
It is elevated superoxide radical levels, caused by radiation therapy, that are thought to be responsible for a large number of the side effects seen, including SOM. The researchers aimed to design a synthetic superoxide dismutase enzyme to reduce levels of superoxide radicals in the body.
"The synthetic enzyme we designed and made mimics the function of the naturally occurring superoxide dismutase, an enzyme that converts superoxide to molecular oxygen and hydrogen peroxide," says Riley.
"Hydrogen peroxide is very toxic to cancer cells but not to normal cells. Thus, we create two opportunities to improve radiation therapy: reducing toxicity for normal cells while increasing the toxicity to the cancerous ones."
The design and synthesis of GC4419 was a long and complicated process, as the team had to work out which isomer of the four-chiral-center molecule would be the most ‘druggable’.
"Our current synthesis involves using a template to make the 15-membered macrocylic ring complex in a single GMP step. It uses pyridine-2,6- dicarboxyaldehyde, manganese(II) chloride and a linear tetramine synthesized from S,S-1,2 diaminocyclohexane. It is an elegantly simple 'one-pot' synthesis that yields the desired molecule with more than 99.5 percent chemical purity," Riley added.
GC4419 has completed Phase I and II clinical trials, showing safety and efficacy in preventing SOM in patients undergoing radiation therapy. If the compound gains FDA approval, the team see no reason it could not be used to prevent SOM during treatment for other cancers. The compound is also being studied for its anticancer effect in a Phase I/II trial for pancreatic cancer at MD Anderson Cancer Center (TX, USA).
“If successful, this drug has the potential to change the management of radiation therapy, since 70 percent of all solid tumors are treated with radiation," concluded Riley.
Source: Riley DP. Design and development of a synthetic enzyme for use as a pharmaceutical agent to reduce the undesired side effects of radiation treatment in cancer therapy. ACS National Meeting and Exposition (19–23 August 2018; MA, USA)