Esophageal Carcinoma: Towards Targeted Therapies

Overview

Journal Cell Oncol (Dordr)

Publisher Springer

Date 2019 Dec 19

PMID 31848929

Citations 74

Authors

Ali Fatehi Hassanabad

Rania Chehade

Daniel Breadner

Jacques Raphael

Affiliations

Soon will be listed here.

Abstract

Background: Patients with esophageal cancer are confronted with high mortality rates. Whether it is esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EAC), patients usually present at advanced stages, with treatment options traditionally involving chemotherapy in metastatic settings. With the comprehensive genomic characterization of esophageal cancers, targeted therapies are gaining interest and agents such as ramucirumab, trastuzumab and pembrolizumab are already being used for the treatment of EAC.

Conclusions: Pembrolizumab has recently been FDA-approved for PD-L1 positive, locally advanced or metastatic ESCC. Despite comprehensive molecular characterization, however, available targed therapies for ESCC are still lagging behind. Herein, we discuss current trends towards more targeted therapies in esophageal cancers, taking into consideration unique features of ESCCs and EACs. Patients progressing on standard therapies should be subjected to genomic profiling and considered for clinical trials aimed at testing targeted therapies. Future targeted therapies may include CDK4/6 inhibitors, PARP inhibitors and inhibitors targeting the NRF2 and Wnt signaling pathways. Ultimately, optimized biomarker assays and next generation sequencing platforms may allow for the identification of subcategories of ESCC and EAC patients that will benefit from selective targeted therapies and/or combinations thereof.

Citing Articles

A nomogram for predicting cancer-specific survival in patients with locally advanced unresectable esophageal cancer: development and validation study.

Xie L, Zhang Y, Niu X, Jiang X, Kang Y, Diao X Front Immunol. 2025; 16:1524439.

PMID: 40028339 PMC: 11868048. DOI: 10.3389/fimmu.2025.1524439.

ZCCHC4 regulates esophageal cancer progression and cisplatin resistance through ROS/c-myc axis.

Yao L, Wu P, Yao F, Huang B, Zhong F, Wang X Sci Rep. 2025; 15(1):5149.

PMID: 39934309 PMC: 11814405. DOI: 10.1038/s41598-025-89628-3.

SPC25 upregulates CCND1 to promote the progression of esophageal squamous cell carcinoma by inhibiting MDM2-mediated E2F1 ubiquitination.

Jiang H, Jin X, Gu H, Li B, Li Z, Sun Y Transl Oncol. 2025; 53:102300.

PMID: 39919356 PMC: 11849203. DOI: 10.1016/j.tranon.2025.102300.

PYGO2 promotes resistance to chemotherapy via reducing apoptosis and G2/M cell cycle arrest in esophageal carcinoma cells.

Ardalan Moghadam Al F, Forghanifard M, Zarrinpour V Med Oncol. 2025; 42(2):45.

PMID: 39808374 DOI: 10.1007/s12032-024-02590-4.

Prediction of Early Mortality in Esophageal Cancer Patients with Liver Metastasis Using Machine Learning Approaches.

Sheng Y, Zhang L, Hu Z, Peng B Life (Basel). 2024; 14(11).

PMID: 39598235 PMC: 11595315. DOI: 10.3390/life14111437.

References

Polioudaki H, Chantziou A, Kalyvianaki K, Malamos P, Notas G, Mavroudis D . Nuclear localization of PD-L1: artifact or reality?. Cell Oncol (Dordr). 2019; 42(2):237-242. DOI: 10.1007/s13402-018-00419-7. View

Dai J, Wang X, Buas M, Zhang C, Ma J, Wei B . Whole-genome sequencing of esophageal adenocarcinoma in Chinese patients reveals distinct mutational signatures and genomic alterations. Commun Biol. 2018; 1:174. PMC: 6200836. DOI: 10.1038/s42003-018-0182-8. View

Shibata T, Kokubu A, Saito S, Narisawa-Saito M, Sasaki H, Aoyagi K . NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer. Neoplasia. 2011; 13(9):864-73. PMC: 3182278. DOI: 10.1593/neo.11750. View

Wilke H, Muro K, Van Cutsem E, Oh S, Bodoky G, Shimada Y . Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15(11):1224-35. DOI: 10.1016/S1470-2045(14)70420-6. View

Bang Y, Cho J, Kim Y, Kim J, Di Bartolomeo M, Ajani J . Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer. Clin Cancer Res. 2017; 23(19):5671-5678. DOI: 10.1158/1078-0432.CCR-17-0025. View

Bang Y, Van Cutsem E, Feyereislova A, Chung H, Shen L, Sawaki A . Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376(9742):687-97. DOI: 10.1016/S0140-6736(10)61121-X. View

Hecht J, Bang Y, Qin S, Chung H, Xu J, Park J . Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial. J Clin Oncol. 2015; 34(5):443-51. DOI: 10.1200/JCO.2015.62.6598. View

Thuss-Patience P, Shah M, Ohtsu A, Van Cutsem E, Ajani J, Castro H . Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017; 18(5):640-653. DOI: 10.1016/S1470-2045(17)30111-0. View

Luchini C, Bibeau F, Ligtenberg M, Singh N, Nottegar A, Bosse T . ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019; 30(8):1232-1243. DOI: 10.1093/annonc/mdz116. View

10.

Dulak A, Stojanov P, Peng S, Lawrence M, Fox C, Stewart C . Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet. 2013; 45(5):478-86. PMC: 3678719. DOI: 10.1038/ng.2591. View

11.

Lagergren J, Smyth E, Cunningham D, Lagergren P . Oesophageal cancer. Lancet. 2017; 390(10110):2383-2396. DOI: 10.1016/S0140-6736(17)31462-9. View

12.

Seervi M, Sumi S, Chandrasekharan A, Sharma A, Santhoshkumar T . Molecular profiling of anastatic cancer cells: potential role of the nuclear export pathway. Cell Oncol (Dordr). 2019; 42(5):645-661. DOI: 10.1007/s13402-019-00451-1. View

13.

Deng J, Chen H, Zhou D, Zhang J, Chen Y, Liu Q . Comparative genomic analysis of esophageal squamous cell carcinoma between Asian and Caucasian patient populations. Nat Commun. 2017; 8(1):1533. PMC: 5688099. DOI: 10.1038/s41467-017-01730-x. View

14.

Clement G, Jablons D, Benhattar J . Targeting the Wnt signaling pathway to treat Barrett's esophagus. Expert Opin Ther Targets. 2007; 11(3):375-89. DOI: 10.1517/14728222.11.3.375. View

15.

Kasper S, Schuler M . Targeted therapies in gastroesophageal cancer. Eur J Cancer. 2014; 50(7):1247-58. DOI: 10.1016/j.ejca.2014.01.009. View

16.

Long A, Giroux V, Whelan K, Hamilton K, Tetreault M, Tanaka K . WNT10A promotes an invasive and self-renewing phenotype in esophageal squamous cell carcinoma. Carcinogenesis. 2015; 36(5):598-606. PMC: 4498148. DOI: 10.1093/carcin/bgv025. View

17.

Gorrini C, Baniasadi P, Harris I, Silvester J, Inoue S, Snow B . BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J Exp Med. 2013; 210(8):1529-44. PMC: 3727320. DOI: 10.1084/jem.20121337. View

18.

Kawasaki Y, Okumura H, Uchikado Y, Kita Y, Sasaki K, Owaki T . Nrf2 is useful for predicting the effect of chemoradiation therapy on esophageal squamous cell carcinoma. Ann Surg Oncol. 2014; 21(7):2347-52. DOI: 10.1245/s10434-014-3600-2. View

19.

. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017; 541(7636):169-175. PMC: 5651175. DOI: 10.1038/nature20805. View

20.

Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S . Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet. 2003; 35(3):238-45. DOI: 10.1038/ng1248. View