食管癌靶向治疗新进展.pdf

Oncotarget1348 Oncotarget, Vol. 6, No.3 Advances in targeted therapies and new promising targets in esophageal cancer Abbes Belkhiri1, Wael El-Rifai1,2 1Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA 2Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee 37212, USA Correspondence to: Wael El-Rifai, e-mail: wael.el-rifai@vanderbilt.edu Abbes Belkhiri, e-mail: abbes.belkhiri@vanderbilt.edu Keywords: adenocarcinoma, esophageal, gastric, cancer, targeted therapy Received: September 19, 2014 Accepted: November 15, 2014 Published: January 16, 2015 ABSTRACT Esophageal cancer, comprising squamous carcinoma and adenocarcinoma, is a leading cause of cancer-related death in the world. Notably, the incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world. Unfortunately, the standard first-line chemo-radiotherapeutic approaches are toxic and of limited efficacy in the treatment of a significant number of cancer patients. The molecular analysis of cancer cells has uncovered key genetic and epigenetic alterations underlying the development and progression of tumors. These discoveries have paved the way for the emergence of targeted therapy approaches. This review will highlight recent progress in the development of targeted therapies in esophageal cancer. This will include a review of drugs targeting receptor tyrosine kinases and other kinases in esophageal cancer. Additional studies will be required to develop a rational integration of these targeted agents with respect to histologic types of esophageal cancer and the optimal selection of cancer patients who would most likely benefit from targeted therapy. Identification of AURKA and AXL as key molecular players in esophageal tumorigenesis and drug resistance strongly justifies the evaluation of the available drugs against these targets in clinical trials. INTRODUCTION The increasing incidence and poor prognosis of esophageal cancer represent a major public health problem worldwide. In 2013, it was estimated that 17,990 new cases of esophageal cancer will be diagnosed and only 15% of patients will survive their disease in the United States [1]. This malignancy comprises two major histologic types, esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinoma (AC)—together they account for the sixth leading cause of death in the world [2]. Although in the last few decades SCC cases have steadily decreased, the incidence of AC has increased at an alarming rate ( 6-fold) in the Western world [3]. SCC and AC differ substantially in their underlying etiology factors and tumorigenesis. While smoking and alcohol [4], prior head and neck cancer [5], and human papilloma virus infection [6] are risk factors in SCC; gastro-esophageal reflux disease (GERD) and obesity have been associated with increased risk of AC [7]. SCC develops from a premalignant dysplastic lesion that originates from the native squamous epithelium, whereas the development of AC is initiated from an intestinal metaplastic lesion (Barrett’s esophagus, BE) that occurs in response to GERD [8]. In addition to surgical resection, the current standard of care for patients with either SCC or AC is chemotherapy with cisplatin and 5-fluorouracil (5-FU) [9], and in combination with other agents such as oxaliplatin [10] and irinotecan [11]. Unfortunately, the majority of patients at advanced stages of the disease fail to benefit from these treatments as the 5-year survival rate remains 15% [12], underscoring the critical need for more effective therapies. Hence, there is an urgent necessity to identify the underlying molecular alterations of SCC and AC, and characterize molecular signatures to distinguish the two types of esophageal cancer. Genomic, proteomic, and molecular epidemiologic studies have greatly helped identify potential therapeutic targets that could eventually overcome the shortcomings of the current Oncotarget1349 standard therapies of esophageal cancer. As part of the International Cancer Genome Consortium project, Song and colleagues [13] conducted a comprehensive genomic analysis of SCC samples and identified several significantly mutated genes, among which ADAM29 and FAM135B. These two genes have not been previously described in SCC. Of note, FAM135B has been characterized as a novel cancer gene that promotes malignancy of SCC cells [13]. A recent similar study on AC samples revealed many new significantly mutated genes including DOCK2 and ELMO1 [14]. Functional analysis indicated that mutations in ELMO1, found in EAC, significantly enhanced cellular invasion; this suggests the potential contribution of RAC1 signaling to Barrett’s tumorigenesis [14]. These studies provide a foundation for further investigations to characterize subsets of esophageal cancer that may be clinical。