Oral Cancer Treatment Side Effect Prevented by New Drug

A synthetically-manufactured enzyme can prevent the occurrence of a side effect called severe oral mucositis in cancer patients undergoing radiation therapy. Severe oral mucositis or SOM is a painful and debilitating side effect of radiation and chemotherapy given to patients suffering from head, neck, nasal and oral cancers. Almost 70 – 80 % of cancer patients receiving chemoradiotherapy end up with a grade 3 or 4 of the condition. Some drugs are available that can treat the disease at early stages but none to prevent.

In this situation, a company called Galera Therapeutics has created a "breakthrough therapy," according to the U.S. Food and Drug Administration, by developing a new drug named GC4419 that can prevent the occurrence of SOM.

"It is exciting to publicly report on the structure and synthesis of GC4419 for the first time," says Dennis P. Riley, Ph.D., 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 3 trial with GC4419 in head and neck cancer patients this year."

The researchers will present their results at the 256th National Meeting & Exposition of the American Chemical Society (ACS).

The “Superoxide” Free Radical

Free radicals are produced in the body by several means – either through normal metabolic processes in the human body or external sources like exposure to cigarette smoking, the ozone layer, X-rays, environmental pollutants, and radiation.

One harmful free radical is the superoxide radical ((O2-)) which is produced as a byproduct of oxygen metabolism. It can cause cell damage and especially attack the cell’s mitochondria.

If there is an imbalance between the production of free radicals and the body’s ability to defend or detoxify their harmful effects through antioxidants, physiological functions are affected, and the body undergoes oxidative stress.

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The most powerful antioxidant produced by the body is the superoxide dismutase (SOD) which is an enzyme found in almost all living cells. SOD facilitates the conversion of superoxide to molecular oxygen (O2) and hydrogen peroxide (H2O2). Although (H2O2) is also damaging, it is more so towards cancer cells and less towards normal cells.

The elevated levels of the superoxide radical are responsible for most of the side effects of radiation therapy, including oral mucositis. It causes OM by destroying the epithelial cells lining the mouth. The newly designed synthetic enzyme GC4419 mimics the function of the naturally occurring superoxide dismutase.

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Riley, who is with Galera Therapeutics, says "Hydrogen peroxide produced from superoxide 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."

GC4419

The synthetic superoxide dismutase was a complex molecule design to create and took the research team around two decades before settling down on the final structure of the desired molecule GC4419 with more than 99.5 percent chemical purity.

GC4419 has completed Phase 1 and 2 clinical trials and has shown safety and efficacy in preventing SOM in head and neck cancer patients undergoing radiation therapy.

If further clinical trials are successful and GC4419 gets FDA approval, Riley says, "there's no reason it could not be used to prevent side effects from radiation treatment of other cancers. You can think of pancreatic cancer, for example, in which you might want to use high-dose radiation for locally advanced disease, but the pancreas is too close to other organs that cannot handle the side effects of radiation. We are currently studying GC4419's anti-tumor effect in a Phase 1/2 clinical trial in pancreatic cancer at MD Anderson Cancer Center. 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."

Oral Mucositis

Oral mucositis (OM) is probably the most common, and problematic complication of cancer treatments. It occurs when cancer treatments, especially radiation therapy, breaks down the rapidly dividing epithelial cells that line the entire gastrointestinal tract (GIT). This leaves the mucosal tissue (mucosa or mucous membrane) that lines the GIT open to ulceration and infection. The oral mucosal part that covers the mouth is one of the most sensitive parts of the body and is particularly vulnerable to radiation and chemotherapy, thereby making the oral cavity the most common location for mucositis.

The symptoms of mucositis are severe pain, swollen mouth and gums - inflammation, sores in the mouth, gums or tongue – ulceration, and blood in the mouth - bleeding. Mucositis usually starts developing 5-10 days beginning chemotherapy and can last from one week to six weeks or more.

In the most severe cases, it can lead to severe problems like pain, inability to swallow or consume liquids or solid food, often leading to the use of feeding tubes and narcotic analgesics. It can also lead to an increased risk of infections due to the open sores.

References:

1. New drug could prevent debilitating side effect of cancer treatment
(https://phys.org/news/2018-08-drug-debilitating-side-effect-cancer.html)
2. Mucositis
(https://oralcancerfoundation.org/complications/mucositis/)
3. The Health Benefits of Superoxide Dismutase
(https://jonbarron.org/herbal-library/nutraceuticals/superoxide-dismutase)

Source-Medindia