EGFR Tyrosine Kinase Inhibition - Induced Cardiomyopathy

描述（由申请人提供）：流行病学研究证明，老年人经常发生低镁血症，他们也有很高的癌症发病率。抗癌药物（如顺铂、卡铂）可引起低镁血症和心血管并发症如心律失常。EGFR抑制抗体（西妥昔单抗）和TKI（厄洛替尼）药物是抗癌药物，众所周知前者会产生低镁血症。最近，FDA批准的厄洛替尼已被报道可引起小鼠低镁血症，并且临床上胃肠道（GI）副作用发生率较高。我们的初步研究显示，在接受TKI药物tyrphostin治疗的大鼠中，出现了显著的低镁血症和早期收缩功能障碍。我们先前的动物研究表明，饮食诱导的低镁血症可以触发P物质（SP）的显著产生/释放，从而导致肠（内毒素血症）毒性和心脏功能障碍（降低的% FS和LVEF）。因此，我们认为，在接受厄洛替尼治疗的某些患者中，由于低镁血症引起的SP诱导的炎症可能是GI副作用和潜在心血管毒性的关键介导因素。具体目标是：1）确定大鼠中慢性厄洛替尼治疗诱导的低镁血症和随后的肠和心脏炎症/功能障碍的程度;和2）评估是否可以通过临床使用的SP受体阻断剂阿瑞匹坦（Emend）减弱长期厄洛替尼诱导的肠和心脏毒性，以及它是否在厄洛替尼治疗的同时存在低镁血症的动物中有效（作为年龄或镁消耗性药物相关低镁血症的范例）。由于口服镁替代疗法可能被证明对长期低镁血症无效，特别是在有GI副作用的患者中，因此该项目的结果可能对EGFR/TKI药物治疗的癌症患者的GI和潜在心脏副作用的治疗具有直接的临床意义，特别是当与顺铂联合治疗时。

DESCRIPTION (provided by applicant): Epidemiology studies have documented frequent hypomagnesemia in the elderly who also have a high cancer incidence. Anticancer drugs (eg. cisplatin, caboplatin) may cause hypomagnesemia and cardiovascular complications such as arrhythmias. EGFR inhibiting antibody (cetuximab) and TKI (erlotinib) drugs are anticancer agents, and the former is well known to produce hypomagnesemia. Recently, FDA approved-erlotinib has been reported to cause hypomagnesemia in mice, and a higher clinical incidence of gastrointestinal (GI) side effects. Our pilot study has shown significant hypomagnesemia and early systolic dysfunction in rats treated with the TKI drug, tyrphostin. Our prior animal studies demonstrated that diet-induced hypomagnesemia can trigger a significant production/release of substance P (SP) with resultant intestinal (endotoxemia) toxicity and cardiac dysfunction (decreased % FS & LVEF). Therefore, we propose that SP- induced inflammation due to hypomagnesemia may be a key mediator of the GI side effects and potential cardiovascular toxicity in some patients treated with erlotinib. The specific aims are: 1) Determine the extent of chronic erlotinib treatment-induced hypomagnesemia and subsequent intestinal and cardiac inflammation/dysfunction in rats; and 2) Assess if long-term erlotinib-induced intestinal and cardiac toxicity can be attenuated by the clinically-used SP receptor blocker, aprepitant (Emend), and if it is effective in erlotinib-treated animals with co-existing hypomagnesemia (as a paradigm for age- or Mg-wasting drug-related hypomagnesemia). Since oral Mg replacement therapy may prove ineffective in prolonged hypomagnesemia, particularly in patients with GI side effects, the outcome of this project may have immediate clinical implications for treatment of GI and potential cardiac side effects in cancer patients treated with EGFR/TKI drugs, particularly when combined with cisplatin.