Early-Phase Interventional Trials in Oral Cancer Prevention

Abstract

The increasing breadth of molecular targets, promise of immune-targeted therapies and repurposed agents have heightened interest in cancer prevention. While, to date, testing of oral cancer chemoprevention strategies has failed to deliver therapeutic agents for routine clinical practice, there remains an urgent need for further clinical research to overcome this hurdle. Patients at the greatest risk of disease stand to benefit the most from inclusion in clinical trials; therefore, there is a need to carefully define this population using validated clinical and molecular markers. Safety, tolerability and the efficacy of interventions is assessed through carefully selected endpoints. These endpoints may include pharmacodynamic, clinical, histological and on-target molecular modifications as an individual or as a composite endpoint. Early-phase trials provide an area of opportunity to explore novel and repurposed agents in the setting of oral cancer chemoprevention, eventually leading to phase III trials with clinical endpoints such as transformation and clinical outcome; these studies are large, lengthy and expensive and should be reserved for the most promising of agents. This paper will explore current evidence in oral cancer chemoprevention, drug repurposing, selection of appropriate endpoints for early-phase trials and novel therapeutic angles in oral cancer chemoprevention.

Alcohol and Head and Neck Cancer: Updates on the Role of Oxidative Stress, Genetic, Epigenetics, Oral Microbiota, Antioxidants, and Alkylating Agents

“…The tumorigenesis of HNC represents an intricate sequential process that, while progressing from squamous hyperplasia through graded dysplasia to invasive carcinoma, implicates a gradual acquisition of genetic and epigenetic alterations, with genetic damage and repair and chromosomal loss and gain targeting the critical components of crucial genetic pathways regulating cell growth, motility, and stromal interactions [ 91 , 92 ]. The accumulation of alterations in crucial tumor suppressor genes (such as TP53 and CDKN2A) or signaling pathways (such as PI3K–AKT–mTOR and RAS–MAPK) is associated with the onset, progression, and poor prognosis of HPV-negative HNCs [ 93 ].…”

Transcriptional analysis highlights three distinct immune profiles of high-risk oral epithelial dysplasia

“…Others, such as TP53, EGFR-family members and cell cycle regulators commonly found in OSCC, have also been documented in OPMD (10). Unfortunately, these molecular alterations have yet to be translated into clinical utility because their effectiveness as biomarkers of malignant transformation and/or chemopreventive targets is limited (11).…”

Dietary Carotenoids in Head and Neck Cancer—Molecular and Clinical Implications

“…Therefore, it seems important to accurately identify these cases using validated and proven clinical and molecular markers. The safety, tolerability, and the efficacy of chemopreventive agents can be assessed by identifying selected individual or composite endpoints, taking also into account the pharmacodynamics of these substances as well as clinical, histological, and molecular target changes in research systems [ 38 , 155 ]. Novel agents are explored as potential chemopreventive factors in early phase research, and these can eventually lead to the last clinical phase of the trials with endpoints such as cancer onset, progression, and patient prognosis.…”