The P2X7 receptor for ATP as a therapeutic target in the prevention of radiation-induced salivary gland dysfunction

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Summary Despite technological advancements in head and neck squamous cell carcinoma (HNSCC) radiotherapies, collateral damage to surrounding normal tissues such as salivary glands following ionizing radiation (IR) remains a significant problem for these patients and severely diminishes their quality of life. It is estimated that >95% of HNSCC patients exhibit xerostomia and salivary gland hypofunction following the irradiation regimen and >73% of these patients continue to suffer for months to years after completion of radiotherapy. The lack of treatment options to prevent IR-induced xerostomia or recover salivary function is compounded by a limited understanding of the underlying mechanisms that mediate chronic IR-induced salivary dysfunction. Our previous studies demonstrate the action of extracellular ATP (eATP), a key “alarmin” molecule in damaged tissue that contributes to IR-induced salivary dysfunction, can be inhibited by pharmacological or genetic blockade of P2X7Rs for eATP, thereby conferring significant radioprotection to salivary glands. In addition, our studies show that radioprotection from P2X7R antagonism maintains normal salivary output through day 30 post-IR, although longer time periods relevant to the treatment of IR-induced chronic xerostomia and salivary dysfunction have not been investigated. Our ultimate goal is to use P2X7R antagonists as radioprotective agents to retain salivary gland function in head and neck cancer patients undergoing radiotherapy, although there is little information available on whether P2X7R antagonists will interfere with tumor regression achieved by radiotherapy, and proposed studies will address this gap in knowledge. The overall goal of this proposal is to develop an approach using P2X7R antagonism to prevent IR-induced salivary dysfunction in head and neck cancer patients receiving radiotherapy without inhibiting the IR-induced regression of HNSCC tumors. Successful completion of this proposal will greatly accelerate translation of this novel pharmacological approach to human patients undergoing IR therapies for head and neck cancer. The following specific aims will be pursued: Specific Aim 1 will develop a radioprotective approach using P2X7R antagonism in an irradiated syngeneic mouse model of HNSCC that preserves salivary gland function and anti-tumor responses. Specific Aim 2 will investigate the durability of the radioprotective effects of P2X7R antagonism towards developing an approach for chronic salivary dysfunction that occurs in HNSCC patients following radiotherapy. Specific Aim 3 will evaluate the contribution of eATP release and purinomic signaling downstream of P2X7R activation to IR-induced salivary gland dysfunction in mouse and human salivary gland organotypic cultures towards identifying alternative radioprotective targets and translating findings in mice to humans.