OPTIMIZATION OF DOSING REGIMENS OF SULINDAC IN COMBINATION WITH ERLOTINIB FOR SMALL INTESTINAL AND COLON CANCER PREVENTION

家族性腺瘤性息肉病（FAP）是一种常染色体显性遗传疾病，由APC（大肠腺瘤性息肉病）基因的种系突变引起。FAP的特征是多个同步和异时性结直肠腺瘤，其发展为结直肠癌（CRC）的风险为70%至100%。研究表明，APC失活和表皮生长因子受体（EGFR）信号通路促进COX-2的表达和肠道肿瘤的后续发展。在最近的一项双盲、安慰剂对照、随机试验（NCT01187901）中，与安慰剂相比，非甾体抗炎药（NSAID）舒林酸（sulindac）与EGFR抑制剂厄洛替尼（erlotinib）联合使用可有效减少FAP患者的总息肉负担和数量。治疗6个月后，这种效果显著，在经典和减毒FAP参与者中都观察到。然而，不良事件的发生率很高。最显著的是治疗组中87%的参与者出现痤疮样皮疹，39%的参与者出现口腔黏膜炎。在试验期间，54%接受治疗的患者在研究期间的某一时刻减少了舒林达的剂量。11例患者因胃肠道出血、谷丙转氨酶水平升高、血压升高、眼痛或视力改变、扁桃体炎而暂时停药。虽然所有参与者在试验开始时都服用了两种研究药物的固定标准剂量，但由于不耐受而导致的剂量调整导致了剂量范围的变化。尽管如此，在所使用的厄洛替尼剂量范围内观察到引起息肉消退的效果相同，这表明可以在保持疗效的同时降低厄洛替尼剂量。虽然舒林酸的剂量是基于先前的研究，但厄洛替尼的剂量是根据癌症治疗和肺癌化疗试验估计的。该研究的其他局限性包括：没有长期随访数据，sulindac和erlotinib作用的持久性未知，对任何一种药物产生耐药性的可能性，以及患者是否最终接受更少的内窥镜检查/手术或发生更少的癌症的问题。此外，舒林他和厄洛替尼都可能分别伴有罕见和严重的不良反应，如心脏毒性和间质性肺疾病。因此，需要进行剂量范围的研究，以确定较低和/或较低剂量的舒林酸和厄洛替尼是否可以减少这些不良反应，但保持疗效。

Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disorder caused by germline mutations in the APC (adenomatous polyposis coli) gene. FAP is characterized by multiple synchronous and metachronous colorectal adenomas with a 70% to 100% risk of developing colorectal cancer (CRC). Studies have suggested that APC inactivation and epidermal growth factor receptor (EGFR) signaling promote COX-2 expression and the subsequent development of intestinal neoplasia. In a recent double-blind, placebo-controlled, randomized trial (NCT01187901), a non-steroidal anti-inflammatory drug (NSAID), sulindac, in combination with an EGFR inhibitor, erlotinib, effectively reduced the total polyp burden and number in participants with FAP compared with placebo. This effect was significant after 6 months of therapy and was observed in both classic and attenuated FAP participants. However, there was a high rate of adverse events. The most notable were an acneiform rash in 87% of participants and oral mucositis in 39% of participants in the treatment group. During the trial, 54% of patients taking treatment had sulindac-dose reduction at some point during the study. There were 11 patients for whom study drugs were temporarily discontinued due to concern for gastrointestinal bleeding, elevated alanine aminotransferase level, elevated blood pressure, ocular pain or change in vision, and tonsillitis. Though all participants started the trial taking fixed standard doses of the 2 study medications, dose modifications due to intolerance led to a range of doses. Nonetheless, equal efficacy in causing polyp regression was observed across the resulting range of erlotinib doses used, suggesting the erlotinib dose could be lowered while maintaining efficacy. Although the dosing of sulindac was based on prior studies, the dosing of erlotinib was estimated from cancer treatment and lung cancer chemotherapy trials. Other limitations of this study include: no long-term follow-up data, unknown durability of the effect of sulindac and erlotinib, the potential to develop resistance to either drug, and the question as to whether patients ultimately undergo fewer surveillance endoscopies/surgery or develop fewer cancers. Also, both sulindac and erlotinib can be associated with rare and serious adverse effects such as cardiotoxicity and interstitial lung disease respectively. Hence dose-ranging studies are needed to determine if lower and/or less-frequent dosing of sulindac and erlotinib could diminish these adverse effects but retain efficacy. The polyposis in rat colon (Pirc) model has a significant advantage over ApcMin/+ and other Apc mutant mouse models of FAP and CRC, because of its relatively high colon tumor burden, and a lifespan suitable for prevention studies that require an assessment of preventive efficacies and toxicities as well as the development of resistance following long term exposure to chemopreventive agents. In addition, the Pirc model mimics the tumor distribution in FAP patients; the rats develop both small intestinal and colonic tumors, the latter of which can be tracked in individual Pirc rats by periodic endoscopic examinations without sacrificing animals. This model allows an assessment of the effects of chemopreventive agents on both small intestinal and colon tumor types, which have clinically exhibited different transcriptional alterations and sensitivities to agents. However, the toxicity of the two drugs (sulindac and erlotinib) in combination may not allow long term treatment necessary in a prevention setting. Using the Pirc model of small intestinal and colon cancer, the overarching goal of this study is to identify optimal dosing and/or scheduling of sulindac and erlotinib combination regimen that would exhibit lower toxicity while maintaining efficacy in preventing tumor development. A secondary goal is to assess the efficacy of the agents on small intestinal tumors compared to colonic tumors and to develop clinically relevant biomarkers of agent efficacy.