Effect of Sorafenib or Regorafenib on P63 Expression and Keratinocyte Differentiation in Human Skin

Skin toxicity is a frequently observed side effect in the era of "molecularly targeted therapies". Skin toxicity following administration of protein kinase inhibitors such as sorafenib, regorafenib, lapatinib, sunitinib, and others can be debilitating to the patient, resulting in dose reduction and discontinuation of treatment. The mechanisms of skin toxicity induced by targeted chemotherapy, such as sorafenib or regorafenib, are poorly understood. Further research is warranted to better understand the pathophysiology of drug-related skin toxicity in this setting and develop correction strategies. This study tests the hypothesis that sorafenib and regorafenib interfere with p63 expression and keratinocyte differentiation and skin remodeling. Eligible study participants will be evaluated clinically for evidence of skin toxicity during their visits to the outpatient Oncology clinics. Study participants will undergo skin biopsies before sorafenib or regorafenib treatment is initiated and once rash develops or 12 weeks into treatment with sorafenib or regorafenib. Skin biopsies will be performed in Oncology clinics by the study investigators and clinic support staff. Study participants will undergo both skin biopsies regardless of whether they develop a rash. In patients who develop a rash the most representative lesion will be biopsied. A normal appearing area of skin will be biopsied in participants who do not develop a rash.在分子靶向治疗（molecularly targeted therapies）时代，皮肤毒性是一类十分常见的不良反应。患者接受索拉非尼、瑞戈非尼、拉帕替尼、舒尼替尼等蛋白激酶抑制剂（protein kinase inhibitors）治疗后出现的皮肤毒性，可显著损害患者健康，甚至导致治疗减量乃至中断。但目前针对索拉非尼、瑞戈非尼等靶向化疗药物诱发皮肤毒性的具体机制仍知之甚少，亟需开展进一步研究以阐明此类药物相关性皮肤毒性的病理生理学（pathophysiology）机制，并制定针对性的干预策略。本研究旨在验证下述假说：索拉非尼与瑞戈非尼可干扰p63基因表达、角质形成细胞（keratinocyte）分化及皮肤重塑过程。 符合入组标准的研究受试者在前往肿瘤门诊（outpatient Oncology clinics）复诊时，将接受临床评估以排查皮肤毒性征象。所有受试者均需在索拉非尼或瑞戈非尼治疗开始前接受皮肤活检，并在出现皮疹时或启动治疗满12周时再次接受皮肤活检。皮肤活检将由研究人员及门诊医护团队在肿瘤门诊内完成。 无论受试者是否出现皮疹，均需完成两次皮肤活检。若受试者出现皮疹，则选取最具代表性的皮损部位进行活检；若未出现皮疹，则选取外观正常的皮肤区域进行活检。