Radioprotectors: Defensive Weapons In The War On Cancer 

In 1971, President Richard Nixon declared a war on cancer (though with the Vietnam war still ongoing, he never actually used that phrase, calling for “the conquest of cancer”¹ instead). This metaphor has persisted and dominated to the present day², providing the impetus to dose anti-cancer agents as close as possible to the maximally-tolerated dose, or MTD, beyond which the toxicities are unbearable in a usually futile attempt to eradicate or break the back of the disease.

During the first Gulf War campaign, the term “shock and awe” was used to describe the hegemonic application of massive force on an enemy — a strategy which has found expression in the medical literature³ as a means to bring tumors rapidly to heel through the MTD use of anticancer agents such as radiation and chemotherapy.

One of the problems with “The War on Cancer” and, by extension, medical “shock and awe” metaphors is that they emphasize and encourage “taking the war to the enemy” with little (or less) consideration for the collateral damage that inevitably ensues from “friendly fire” to normal tissues and cells. Pharmaceutical agents, which defend or protect normal tissues and cells from the toxicities of radiation and chemotherapy are termed radioprotectors and chemoprotectors, respectively.

In the treatment of newly-diagnosed head and neck cancer, the two main causes of which are Human Papillomavirus (HPV) and tobacco abuse (smoking or chewing), where a combination of radiation and the chemotherapy agent, cisplatin, is used, one of the most common — and feared — side effects is oral mucositis (OM), or blistering of the mouth. The pain from OM during treatment of head and neck cancer is often so intense and severe that it interferes with eating, drinking, swallowing, and speech, putting patients at risk for malnutrition, dehydration, and depression.

A case in point is the poem below, a blistering howl of agony written by a patient with mucositis, which vividly and graphically communicates the horribly sadistic details of OM through the writer’s pain-distorted perceptions of teeth, touch, and taste:

A fish hook lodges in my throat.

Spittle, kindergarten paste, thickens everything – even vision.

Mouth, pocked with sores & blisters, swollen ulcerated tongue.

Topside, sandpapered with number 7 coarsest grade.

Taste buds, saliva glands, seared.

Cool water, corrosive acid now.

The tongue rests; teeth become enemies.

Coiled steel razored wire atop dentate prison walls.

Only moans escape my lips. I cannot eat or speak.

Inside a howl festers.

Pain lengthens time.

Anita Hart Balter (NEJM 1990)

The reason for the toxicity of radiation, in particular, to normal tissues is that it damages DNA directly and indirectly through the production of free radicals, highly reactive molecules that, like high-speed ball bearings, ricochet and careen into other molecules, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals. As new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can “neutralize” the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.

One of the agents in development as a radioprotector (and chemoprotector) is called RRx-001 (soon to be renamed MACRONAZ), which, ironically, akin to the biblical phrase that refers to “turning swords into plowshares,” is derived from an explosive. RRx-001⁴ behaves as an oxidant in tumors and an anti-oxidant in normal tissues, which explains how and why it is an anticancer agent that also protects against the side effects of radiation. A clinical trial called PREVLAR with RRx-001 is ongoing in head and neck cancer to protect against severe oral mucositis.

Another agent also in development as a radioprotector against severe oral mucositis in head and neck cancer is called GC4419, which blocks the formation of free radical and has shown good activity in clinical trials.

Over the course of their disease, 50% of all cancer patients, including those with head and neck cancer, are treated with radiotherapy⁵, which universally damages overlying normal tissues as well as tumors. Therefore, radioprotectors may revolutionize the anticancer arsenal available to oncologists, if only by permitting an increase in the radiation dose that is otherwise prevented by the occurrence of side effects.

The War on Cancer rages on unabated, but a subtle shift is perhaps underway with radioprotectors like RRx-001 and GC4419 that are used to reduce the risk of unintended damage to normal tissues without preventing and possibly increasing the anticancer effects of chemotherapy and radiation.

These findings are described in the article entitled A Review of Clinical Radioprotection and Chemoprotection for Oral Mucositis, recently published in the journal Translational Oncology. 

This work was conducted by Bryan Oronsky, Michelle Lybeck, Scott Caroen, and Erica Burbano from EpicentRx, Sharad Goyal from The George Washington University, Michelle M. Kim from the University of Michigan Health System, Pedro Cabrales from the University of California San Diego, Neil Oronsky from CFLS Data, Corey Carter from the Walter Reed National Military Medical Center, and Arnold Oronsky from InterWest Partners.

References:

1. Penson RT, Schapira L, Daniels KJ, et al. Cancer as metaphor. Oncologist 2004;9(6):708-16.
2. Oronsky B, Carter CA, Mackie V, et al. The War on Cancer: A Military Perspective. Frontiers in Oncology. 2014;4:387.
3. Riddell S. The emperor of all maladies: A biography of cancer. The Journal of Clinical Investigation. 2011;121(1):5. doi:10.1172/JCI45710.
4. Oronsky B, Scicinski J, Ning S, Peehl D, Oronsky A, Cabrales P, Bednarski M, Knox S. Rockets, radiosensitizers, and RRx-001: An origin story part I. Discov Med. 2016 Mar;21(115):173-80.
5. Baskar R, Lee KA, Yeo R, Yeoh K-W. Cancer and Radiation Therapy: Current Advances and Future Directions. International Journal of Medical Sciences. 2012;9(3):193-199.