golotimod and Stomatitis

Gamma-D-glutamyl-L-tryptophan (SCV-07) demonstrated an overall efficacy signal in ameliorating oral mucositis (OM) in a clinical trial of head and neck cancer patients. However, not all SCV-07-treated subjects responded positively. Here we determined if specific gene clusters could discriminate between subjects who responded to SCV-07 and those who did not. Microarrays were done using peripheral blood RNA obtained at screening and on the last day of radiation from 28 subjects enrolled in the SCV-07 trial. An analytical technique was applied that relied on learned Bayesian networks to identify gene clusters which discriminated between individuals who received SCV-07 and those who received placebo, and which differentiated subjects for whom SCV-07 was an effective OM intervention from those for whom it was not. We identified 107 genes that discriminated SCV-07 responders from non-responders using four models and applied Akaike Information Criteria (AIC) and Bayes Factor (BF) analysis to evaluate predictive accuracy. AIC were superior to BF: the accuracy of predicting placebo vs. treatment was 78% using BF, but 91% using the AIC score. Our ability to differentiate responders from non-responders using the AIC score was dramatic and ranged from 93% to 100% depending on the dataset that was evaluated. Predictive Bayesian networks were identified and functional cluster analyses were performed. A specific 10 gene cluster was a critical contributor to the predictability of the dataset. Our results demonstrate proof of concept in which the application of a genomics-based analytical paradigm was capable of discriminating responders and non-responders for an OM intervention.

Topics: Adult; Aged; Aged, 80 and over; Bayes Theorem; Chemoradiotherapy; Dipeptides; Female; Genomics; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mouth Mucosa; Multigene Family; Precision Medicine; Predictive Value of Tests; Radiation Injuries; Stomatitis; Treatment Outcome

To evaluate the efficacy of a novel immunomodulating peptide (SCV-07) in attenuating the course of radiation-induced mucositis in an established animal model of oral mucositis (OM).. In three separate experiments, golden Syrian hamsters received either an acute radiation challenge to the buccal mucosa of eight fractionated doses of 7.5 Gy of radiation over a 2-week-period, or a combination of acute radiation and cisplatin. In each experiment, animals were treated with varying doses or schedules of SCV-07 or placebo. OM was scored in a blinded fashion using digital images obtained during the experimental period.. We found that SCV-07 reduced the severity and duration of both acute and fractionated radiation-induced OM. Similarly, when radiation and chemotherapy were used to induce OM, treatment with SCV-07 significantly reduced the duration of ulcerative OM. The therapeutic benefit was dependent on both dose and schedule of administration.. Taken together, we found SCV-07 was able to modify the duration and severity of oral mucositis and was dependent on schedule and dose.

Topics: Animals; Antineoplastic Agents; Cisplatin; Cricetinae; Dipeptides; Disease Models, Animal; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Gingivitis, Necrotizing Ulcerative; Immunologic Factors; Male; Mesocricetus; Mouth Mucosa; Oral Ulcer; Placebos; Radiotherapy; Single-Blind Method; Stomatitis; Time Factors