Current Cancer Drug Targets - Volume 14, Issue 6, 2014

Since bortezomib was approved by the US Food and Drug Administration as the first proteasome inhibitor for the treatment of multiple myeloma (MM) ten years ago, proteasome inhibition has been established as an effective MM treatment strategy. However, some limitations have been found with bortezomib-based therapies, including bortezomib resistance (both intrinsic and acquired), severe toxicities (such as peripheral neuropathy), and unsatisfied efficacy in the treatment of solid tumors. In order to overcome the shortcomings of bortezomib, researchers have investigated the involved molecular mechanisms and developed novel strategies to improve proteasome inhibitor-based therapies and patient cares. This mini hot issue will review the current advances in the status of bortezomib, clinically tested second generation proteasome inhibitors, and preclinically developed proteasome inhibitors, and summarize some cutting-edge strategies in this field, including selective targeting immunoproteasomes, 19S deubiquitinases or ubiquitin E3 ligases, and developing novel combinational therapies. While there are still many new challenges ahead, the great progress in proteasome inhibitor therapy will definitely help illuminate the bright future of MM and other cancer management.

Deubiquitinating enzymes (or DUBs) attack the ubiquitin-based isopeptide bond, thus counteracting ubiquitinprotein ligase activity in vivo. By disassembling ubiquitin-substrate and ubiquitin-ubiquitin covalent links, deubiquitinating enzymes exert a very powerful control of many signaling processes within the ubiquitin-proteasome system (UPS). Very active research in this field in the last decade shows that deubiquitinating enzymes play important regulatory roles in aspects relevant to cancer, such as proteasome activity, p53 stability, the regulation of fanconi anemia related proteins, tumor cell apoptosis induction, to mention a few. Thus, deubiquitinating enzymes have emerged as interesting drug targets in cancer research. Here, the pharmacological inhibition of DUBs and its potential effect in cancer treatment are reviewed.

Over the past ten years, proteasome inhibition has emerged as an effective therapeutic strategy for treating multiple myeloma (MM) and some lymphomas. In 2003, Bortezomib (BTZ) became the first proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA). BTZ-based therapies have become a staple for the treatment of MM at all stages of the disease. The survival rate of MM patients has improved significantly since clinical introduction of BTZ and other immunomodulatory drugs. However, BTZ has several limitations. Not all patients respond to BTZbased therapies and relapse occurs in many patients who initially responded. Solid tumors, in particular, are often resistant to BTZ. Furthermore, BTZ can induce dose-limiting peripheral neuropathy (PN). The second generation proteasome inhibitor Carfizomib (CFZ; U.S. FDA approved in August 2012) induces responses in a minority of MM patients relapsed from or refractory to BTZ. There is less PN compared to BTZ. Four other second-generation proteasome inhibitors (Ixazomib, Delanzomib, Oprozomib and Marizomib) with different pharmacologic properties and broader anticancer activities, have also shown some clinical activity in bortezomib-resistant cancers. While the mechanism of resistance to bortezomib in human cancers still remains to be fully understood, targeting the immunoproteasome, ubiquitin E3 ligases, the 19S proteasome and deubiquitinases in pre-clinical studies represents possible directions for future generation inhibitors of ubiquitin-proteasome system in the treatment of MM and other cancers.

Remarkable successes with the FDA-approved proteasome inhibitors bortezomib (Velcade®) and carfilzomib (Kyprolis®) have proved that the proteasome is an effective target for the treatment of multiple myeloma. In other hematological malignancies, however, clinical trials of proteasome-targeting drugs have shown generally disappointing results to date. Additionally, existing proteasome inhibitors have significant issues with toxicity, poor response rate, and the emergence of resistance for many patients. A new generation of small-molecule therapies specifically targeting the immunoproteasome may have the potential to overcome the drawbacks of bortezomib and carfilzomib in multiple myeloma and to bring significant benefits of proteasome inhibitor therapies to many more patients. In this article, we describe the potential of the immunoproteasome as a therapeutic target for hematological malignancies and the recent progress in the development of useful immunoproteasome inhibitors.

The Neuronally expressed developmentally downregulated 4 (NEDD4), functioning largely as an E3 ubiquitin ligase, has been demonstrated to play a critical role in the development and progression of human cancers. In this review, to understand the regulatory mechanism(s) of NEDD4 as well as the signaling pathways controlled by NEDD4, we briefly describe the NEDD4 upstream regulators and its downstream ubiquitin substrates. Moreover, we further discuss its oncogenic roles in human malignancies. Therefore, targeting NEDD4 could be a potential therapeutic strategy for treatment of human cancers.

Arsenic trioxide (As2O3) has been used in the clinic for the treatment of acute promyelocytic 1eukemia and some solid tumors. However, its effectiveness against lung cancer has not been well demonstrated, and the underlying mechanism(s) of action remain unclear. In the present study, we found that As2O3 significantly inhibited the growth of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) xenograft tumors. It was observed to have antiangiogenic effects in xenograft models and matrigel pellets. It also significantly inhibited the expression of VEGF-A, VEGFR-2, HIF-1α, Dll4 and Notch-1 in vivo. Moreover, As2O3 also inhibited the expression of HIF-1α, VEGFR-2, Dll4, and Notch-1 in lung cancer cell lines and human umbilical vein endothelial cells. These findings suggest that As2O3 has significant anti-lung cancer activity, which may occur as a result of the antiangiogenic effects caused by the downregulation of the VEGF and Dll4-Notch signaling pathways

Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the human PTPN11 gene, is a ubiquitously expressed protein tyrosine phosphatase (PTP) that consists of two tandem Src homology (SH2) domains (N-SH2 and C-SH2), a PTP catalytic domain, and a C-terminal tail with tyrosyl phosphorylation sites. It plays critical roles in numerous cellular processes through the regulation of various signaling pathways in PTP catalytic activity-dependent and -independent manners. Dysfunction of SHP2 resulting from pathogenic mutations and aberrant expression leads to the dysregulation of multiple signaling pathways, thus contributing to different human disorders. Germline and somatic mutations in PTPN11 are involved in Noonan syndrome (NS), LEOPARD syndrome (LS), and hematological malignancies, as well as several solid tumors. In this report, we provide an overview of the current knowledge of the structure and function of SHP2, and further discuss the molecular and pathogenic mechanism of SHP2 in human diseases, with a special focus on tumorigenesis. Furthermore, we summarize that SHP2 might itself represent a potential drug target for cancer prevention and treatment. Ongoing research and development of SHP2-specific inhibitors would enhance this potential.

Background: The present study was designed to evaluate the efficacy and safety of a combination of helical tomotherapy (HT) or intensity-modulated radiotherapy (IMRT) and EGFR (epidermal growth factor receptor) inhibitor (Cetuximab or Nimotuzumab) with or without chemotherapy in patients with locally advanced hypopharyngeal carcinoma. Patients and Methods: The retrospective study included forty-six patients (12 stage III and 34 stage IV) with locally advanced hypopharyngeal cancer. Among them, 20 were treated with induction chemotherapy with docetaxel and cisplatin (TP) followed by concurrent chemoradiotherapy with cisplatin and EGFR inhibitor, 13 received concurrent chemoradiotherapy with cisplatin and EGFR inhibitor, and 13 were treated with concurrent radiotherapy plus EGFR inhibitor. HT and IMRT were performed in 33 and 13 patients, respectively. Side effects were evaluated with the established CTCAE (Common Terminology Criteria for Adverse Events) 3.0 criteria. Results: The median follow-up time was 39.4 months (range 3-69 months). All patients completed the planned RT without any treatment breaks. The 3-year local control survival, disease-free survival, overall survival, and laryngeal preservation survival rates were 66.8%, 59.0%, 68.9%, and 86.7%, respectively. The most common grade 3 or higher side effect was oropharyngeal mucositis. One patient required dilatation of a pharyngeal stricture 18 months after treatment. No patient required percutaneous gastrostomy and tracheostomy tube. Conclusion: The treatment with EGFR inhibitor in combination with non-surgical combined modality in patients with hypopharyngeal carcinoma was well tolerated and resulted in encouraging laryngeal preservation survival rate. HT or IMRT, EGFR inhibitor, and effective management of severe oropharyngeal mucositis contributed to the positive outcomes.