Emerging data from chimeric antigen receptor (CAR) T-cell trials in B-cell malignancies demonstrate that a common mechanism of resistance to this novel class of therapeutics is the emergence of tumors with loss or downregulation of the target antigen. Antigen loss or antigen-low escape is likely to emerge as an even greater barrier to success in solid tumors, which manifest greater heterogeneity in target antigen expression. Potential approaches to overcome this challenge include engineering CAR T cells to achieve multispecificity and to respond to lower levels of target antigen and more efficient induction of natural antitumor immune responses as a result of CAR-induced inflammation. In this article, we review the evidence to date for antigen escape and downregulation and discuss approaches currently under study to overcome these obstacles.Significance: Antigen escape and downregulation have emerged as major issues impacting the durability of CAR T-cell therapy. Here, we explore their incidence and ways to overcome these obstacles in order to improve clinical outcomes. Cancer Discov; 8(10); 1219-26. ©2018 AACR.

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Tumor Antigen Escape from CAR T-cell Therapy.

Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours' aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.

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Clinical update on head and neck cancer: molecular biology and ongoing challenges.

Triple negative breast cancer (TNBC), which is typically lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), represents the most aggressive and mortal subtype of breast cancer. Currently, only a few treatment options are available for TNBC due to the absence of molecular targets, which underscores the need for developing novel therapeutic and preventive approaches for this disease. Recent evidence from clinical trials and preclinical studies has demonstrated a pivotal role of signal transducer and activator of transcription 3 (STAT3) in the initiation, progression, metastasis, and immune evasion of TNBC. STAT3 is overexpressed and constitutively activated in TNBC cells and contributes to cell survival, proliferation, cell cycle progression, anti-apoptosis, migration, invasion, angiogenesis, chemoresistance, immunosuppression, and stem cells self-renewal and differentiation by regulating the expression of its downstream target genes. STAT3 small molecule inhibitors have been developed and shown excellent anticancer activities in in vitro and in vivo models of TNBC. This review discusses the recent advances in the understanding of STAT3, with a focus on STAT3’s oncogenic role in TNBC. The current targeting strategies and representative small molecule inhibitors of STAT3 are highlighted. We also propose potential strategies that can be further examined for developing more specific and effective inhibitors for TNBC prevention and therapy.

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STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review

The role of STAT3 in leading the crosstalk between human cancers and the immune system

The potential and controversy of targeting STAT family members in cancer

Acinar cell carcinoma (ACC) is a relatively rare pancreatic neoplasm with poorly defined prognosis. This study aimed to investigate this rare pancreatic neoplasm through comparing patients with ACC to pancreatic ductal cell adenocarcinoma (DCA). Tianjin Medical University Cancer Institute and Hospital pathology database was reviewed from 1995 to 2015, and 19 patients with pathologically confirmed ACC were enrolled while 19 conventional DCA patients assigned randomly as control. Retrospective review and follow-up were performed for each patient. Regression methods were used to identify differences between ACC and DCA. In our study, most patients suffered from abdominal or back pain, and no lipase hypersecretion syndrome was observed. For ACC, resected cases had better survival than those without resection, and earlier staging was related to longer survival. Resection with postoperative adjuvant therapy had a better outcome than surgery alone. Twelve cases developed recurrence. Compared to DCA, ACC had earlier staging and better survival. The overall 1-, 2-, and 5-year survival rates for patients with ACC were 73.7, 26.3, and 5 %, respectively. ACC carries a better prognosis than DCA and a similarly high recurrence rate, while surgical resection proved the best first-line approach for it. A well-planned neoadjuvant or adjuvant chemoradiotherapy indeed benefit the patients with ACC.

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Acinar cell carcinoma: a report of 19 cases with a brief review of the literature

Signal transducer and activator of transcription 3 (STAT3) is involved in the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) and is therefore a target with therapeutic potential. In this study, we show that HJC0152, a recently developed anticancer agent and a STAT3 signaling inhibitor, exhibits promising antitumor effects against HNSCC both in vitro and in vivo via inactivating STAT3 and downstream miR-21/β-catenin axis. HJC0152 treatment efficiently suppressed HNSCC cell proliferation, arrested the cell cycle at the G0-G1 phase, induced apoptosis, and reduced cell invasion in both SCC25 and CAL27 cell lines. Moreover, HJC0152 inhibited nuclear translocation of phosphorylated STAT3 at Tyr705 and decreased VHL/β-catenin signaling activity via regulation of miR-21. Loss of function of VHL remarkably compromised the antitumor effect of HJC0152 in both cell lines. In our SCC25-derived orthotopic mouse models, HJC0152 treatment significantly abrogated STAT3/β-catenin expression in vivo, leading to a global decrease of tumor growth and invasion. With its favorable aqueous solubility and oral bioavailability, HJC0152 holds the potential to be translated into the clinic as a promising therapeutic strategy for patients with HNSCC. Mol Cancer Ther; 16(4); 578-90. ©2017 AACR.

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Suppression of the growth and invasion of human head and neck squamous cell carcinomas via regulating STAT3 signaling and the miR-21/β-catenin axis with HJC0152

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of human malignancy. For decades, research into HNSCC invasion and metastasis has been dedicated to the study of protein-coding genes. Along with whole-genome and transcriptome sequencing development, long non-coding RNA (lncRNA) has attracted greater attention. Compelling evidence has proven the critical role of lncRNAs in the occurrence and development of HNSCC by means of epigenetic modifications, regulation of gene transcription, and post-transcription level. More importantly, crosstalk between lncRNAs and microRNAs was recently proven to regulate HNSCC metastasis through EMT modification. Based on these, this review summarizes the critical roles of lncRNAs in HNSCC metastasis and the crosstalk between lncRNAs and microRNAs as well as the detailed regulatory mechanism of the interaction. Thus, a deeper understanding of the lncRNA network in cancer metastasis is finally uncovered in order to provide a rationale and innovative concepts toward new therapeutic strategies for the highly metastatic HNSCC.

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The Role of lncRNA Crosstalk in Leading Cancer Metastasis of Head and Neck Squamous Cell Carcinoma

Abstract 9: Suppression of the invasion and growth of human head and neck squamous cell carcinomas via regulating STAT3 signaling and miR-21/β-catenin axis with HJC0152

Sinan Wang

Papers

The role of STAT3 in leading the crosstalk between human cancers and the immune system

Acinar cell carcinoma: a report of 19 cases with a brief review of the literature

Suppression of the growth and invasion of human head and neck squamous cell carcinomas via regulating STAT3 signaling and the miR-21/β-catenin axis with HJC0152

The Role of lncRNA Crosstalk in Leading Cancer Metastasis of Head and Neck Squamous Cell Carcinoma

Abstract 9: Suppression of the invasion and growth of human head and neck squamous cell carcinomas via regulating STAT3 signaling and miR-21/β-catenin axis with HJC0152