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Single administration of low dose cyclophosphamide (CTX) was previously reported to enhance the antitumor efficacy of immunotherapies. To investigate the possible mechanisms for this effect, we examined whether a single administration of low dose CTX could augment the immunogenicity of dendritic cell (DC) vaccines. Fifty milligrams per kilogram body weight dose of CTX was administrated intraperitoneally to mice after B16 melanoma or C26 colon carcinoma tumor models were established, DC vaccine generated from mouse bone marrow and pulsed with B16 or C26 tumor cells lysates were vaccinated 4 days later. CTX treatment potentiated the antitumor effects of the DC vaccine, and increased the proportion of IFN-gamma secreting lymphocytes in spleens. Furthermore, a significantly reduced proportion of CD4+CD25+FoxP3+ regulatory T (Treg) cells was detected by flow cytometry in spleen lymphocytes from tumor-bearing mice treated with CTX. Thus, a single administration of low dose CTX could augment antitumor immune responses of DC vaccine by reducing the proportion of CD4+CD25+FoxP3+ Treg cells in tumor-bearing mice. Our results suggested a possible mechanism of CTX-induced immunopotentiation and provided a strategy of immunotherapy combining a low dose CTX with DC vaccine.

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Pancreatic cancer (PC) is one of the most fatal diseases with a very high rate of metastasis and low rate of survival. Despite the advances in understanding this devastating disease, PC still accounts for 3% of all cancers and causes almost 7% of death of cancer patients. Recent studies have demonstrated that the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its key negative regulator Kelch-like ECH-associated protein 1 (Keap1) are dysregulated in PC and the Keap1-Nrf2 pathway is an emerging target for PC prevention and therapy. Indeed, Nrf2 plays an either tumor-suppressive or promoting function in PC, which depends on the developmental stages of the disease and the cellular context. Several natural-product Nrf2 activators have been developed to prevent pancreatic carcinogenesis, while the Nrf2 inhibitors have been examined for their efficacy in inhibiting PC growth and metastasis and reversing chemoresistance. However, further preclinical and clinical studies for determining the effectiveness and safety of targeting the Keap1-Nrf2 pathway for PC prevention and therapy are warranted. In this review, we comprehensively discuss the dual roles of the Keap1-Nrf2 signaling pathway in PC as well as the current targeting strategies and known activators and inhibitors of Nrf2. We also propose new strategies that may be used to address the current issues and develop more specific and more effective Nrf2 activator/inhibitors for PC prevention and therapy.

The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitinproteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various biological processes, including proliferation, metastasis, angiogenesis, immune response, and chemoresistance. In normal cells, STAT3 is tightly regulated to maintain a transiently active state, while persistent STAT3 activation occurs frequently in cancers, associating with a poor prognosis and tumor progression. Targeting the STAT3 protein is a potentially promising therapeutic strategy for tumors. Although none of the STAT3 inhibitors has been marketed yet, a few of them have succeeded in entering clinical trials. This Review aims to systematically summarize the progress of the last 5 years in the discovery of directive STAT3 small-molecule inhibitors and degraders, focusing primarily on their structural features, design strategies, and bioactivities. We hope this Review will shed light on future drug design and inhibitor optimization to accelerate the discovery process of STAT3 inhibitors or degraders.

Trastuzumab has been approved for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction cancers (GC and GJC) in combination with chemotherapy. The aim of this HER2 early/advanced gastric epidemiology (HER-EAGLE) study was to evaluate the frequency of HER2 over-expression and to evaluate agreement on HER2 status assessment in GC and GJC patients in local laboratories versus a central laboratory in China. Tumor samples from 734 GC or GJC patients who were enrolled at 11 different hospitals in China were examined. HER2 status was assessed by immunohistochemistry (IHC), and followed by dual-color silver-enhanced in Situ hybridization (DSISH) in IHC 2+ cases. Clinicopathologic characteristics were collected from all of the patients. HER2-positive tumors were identified in 12.0% (88/734) of the GC and GJC cases. There were significantly higher rates of HER2 positivity in patients with GJC (GJC: 18.1%, GC: 9.7%, P=0.002), and intestinal-type cancers using the Lauren classification (intestinal: 23.6%, diffuse/mixed: 4.3%, P<0.0001). No significant difference in HER2 positivity was identified between resection and biopsy samples, or between early and advanced disease stages. The agreement between local laboratories and the central laboratory on HER2 status scoring was good (kappa=0.86). The main reason of HER2 status discordance between local and the central laboratories was IHC result mis-interpretation in local laboratories. These results suggest that IHC followed by DSISH testing is an accurate and cost-effective procedure in China.