LncRNA SNHG3 is activated by E2F1 and promotes proliferation and migration of non-small-cell lung cancer cells through activating TGF-ß pathway and IL-6/JAK2/STAT3 pathway.

Recently, long noncoding RNAs (lncRNAs) have been widely reported to play pivotal roles in the regulation of human cancers. Although the oncogenic property of lncRNA small nucleolar RNA host gene 3 (SNHG3) has been revealed in a variety of cancers, functions and regulatory mechanism of SNHG3 in non-small-cell lung cancer (NSCLC) remain to be investigated. In this study, we detected the upregulated expression of SNHG3 in NSCLC tissues as well as cells through quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. Using Kaplan-Meier analysis, we determined that a high-level of SNHG3 was associated with a low overall survival rate of patients with NSCLC. Through gain and loss of function experiments, we demonstrated that SNHG3 had a significantly positive effect on NSCLC cell proliferation and migration. Mechanistic investigations revealed that SNHG3 was a predicted direct transcriptional target of E2F1. We observed that the transcriptional activation of SNHG3 could be induced by E2F1. To explore the mechanism, rescue experiments were carried out, which revealed that the cotreatment with SB-431542, JSI-124, or JSI-124 + SB-431542 rescued the effects brought by the overexpression of SNHG3 on NSCLC cell proliferation, migration, and epithelial-mesenchymal transition process. Our results suggested that E2F1 activated SNHG3 and promoted cell proliferation and migration in NSCLC via transforming growth factor-ß pathway and interleukin-6/janus-activated kinase 2/signal transducer and activator of transcription 3 pathway, which implied that SNHG3 may be a biomarker for the treatment of patients with NSCLC.

Low levels of TSC22 enhance tumorigenesis by inducing cell proliferation in colorectal cancer.

Transforming growth factor ß-stimulated clone 22 domain 1 (TSC22) has been identified as a cancer suppressor gene in various kinds of cancers. The purpose of this study was to explore the expression of TSC22 in colorectal cancer (CRC) tissues and cell lines. 24 matched CRC and normal tissue samples by qPCR along with 18 pairs of them by Western blot demonstrated TSC22 level was decreased in CRC compared with normal tissue. The protein expression of TSC22 was examined in 310 CRC specimens. Results showed low expression of TSC22 was significantly correlated with tumor size (P = 0.048) and tumor infiltration (P = 0.016). Kaplan-Meier method suggested low expression of TSC22 was inversely associated with OS for 276 samples (P < 0.01). Multivariate Cox regression analysis confirmed TSC22 expression as independent predictors of the OS in CRC patients. Furthermore, we found TSC22 could suppress tumor by inhibiting cell proliferation in CRC cell lines.

NNK-induced DNA methyltransferase 1 in lung tumorigenesis in A/J mice and inhibitory effects of (-)-epigallocatechin-3-gallate.

DNA methyltransferase 1 (DNMT1), a key enzyme mediating DNA methylation, is known to be elevated in various cancers, including the mouse lung tumors induced by the tobacco-specific carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). However, it is not known whether DNMT1 expression is induced right after NNK treatment and how DNMT1 expression varies throughout lung tumorigenesis. In the present study, we found that administration of NNK to A/J mice caused elevation of DNMT1 in bronchial epithelial cells at Days 1, 3, and 14 after NNK treatment. DNMT1 elevation at Day 1 was accompanied by an increase in phospho-histone H2AX (γ-H2AX) and phospho-AKT (p-AKT). At Weeks 5 to 20, NNK-induced DNMT1 in lung tissues was in lower levels than the early stages, but was highly elevated in lung tumors at Week 20. In addition, the early induction of p-AKT and γ-H2AX as well as cleaved caspase-3 in NNK-treated lung tissues was not detected at Weeks 5 to 20 but was elevated in lung tumors. In concordance with DNMT1 elevation, promoter hypermethylation of tumor suppressor genes Cdh13, Prdm2, and Runx3 was observed in lung tissues at Day 3 and in lung tumors. Treatment by EGCG attenuated DNMT1, p-AKT, and γ-H2AX inductions at Days 1 and 3 and inhibited lung tumorigenesis.

A pancancer analysis of the clinical and genomic characteristics of multiple primary cancers.

Multiple primary cancer (MPC) denotes individuals with two or more malignant tumors occurring simultaneously or successively. Herein, a total of 11,000 pancancer patients in TCGA database (1993-2013) were divided into MPC or non-MPC groups based on their history of other malignant tumors. The incidence of MPC has risen to 8.5-13.1% since 2000. Elderly individuals, males, early-stage cancer patients, and African Americans and Caucasians are identified as independent risk factors (p < 0.0001). Non-MPC patients exhibit significantly longer overall survival (OS) and disease-free survival (DFS) (p = 0.0038 and p = 0.0014). Age (p < 0.001) and tumor staging at initial diagnosis (p < 0.001) contribute to this difference. In our center, MPC was identified in 380 out of 801 tumor events based on SEER criteria. The peak occurrence of secondary primary was about 1-5 years after the first primary tumor, with a second small peak around 10-15 years. Multiple tumors commonly occur in the same organ (e.g., breast and lung), constituting 12.6%. Certain cancer types, notably skin cutaneous melanoma (SKCM), exhibit significantly higher tumor mutational burden (TMB) in the MPC group (17.31 vs. 6.55 mutations/MB, p < 0.001), with high TMB associated with improved survival (p < 0.001). High TMB in MPC may serve as a predictor for potential immunotherapy application.

Significant response from fruquintinib plus anti-PD-1 immunotherapy for microsatellite stable metastatic colorectal cancer with liver and lung metastasis in the third line: case report.

Background: There are limited treatment options available for patients with metastatic colorectal cancer (mCRC). About 95% of CRC patients have mismatch repair proficient/microsatellite stable (pMMR/MSS) tumors are virtually unresponsive to programmed cell death protein 1 (PD-1) antibody treatment. This report shows that a patient with pMMR/MSS mCRC achieved significant response and the longest progression-free survival (PFS) of 28 months currently reported from tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) family (VEGFR-1,2,3) (fruquintinib) plus anti-PD-1 immunotherapy in the third line, providing a new and promising treatment option for some MSS mCRC patients. Case Description: This case details a 65-year-old male with CRC who was diagnosed with pT4aN2bM0, IIIC, and pMMR/MSS after curative surgery in August 2018. Subsequently, he received adjuvant chemotherapy [FOLFOX (folinic acid, fluorouracil, and oxaliplatin) for 5 cycles], first-line treatment (pelvic radiation plus capecitabine), and second-line treatment [TOMIRI (raltitrexed and irinotecan) plus cetuximab for 2 cycles]. Lung, liver, and pelvic cavity metastases worsened in October 2019. He began receiving the fruquintinib plus PD-1 inhibitor (FP) regimen as third-line treatment and after 3 cycles, the size of the lung lesions was significantly reduced and evaluated as partial response (PR), whereas the liver and pelvic cavity lesions remained stable. As of December 2021, he had received a total of 33 courses of FP regimen. In February 2022, liver metastases progressed. In brief, he achieved a long PFS of 28 months and an overall survival (OS) of 40 months from the third-line treatment. Additionally, the patient only experienced mild proteinuria after the combined treatment and tolerated well. Conclusions: Fruquintinib combined with immunotherapy could exert good therapeutic effects with safety in MSS mCRC patients. And patients with lung metastasis may be the principal beneficiaries.

Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer.

Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-ß pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC.

Successes and failures of immunotherapy for gastric cancer.

Many exploratory clinical studies have been conducted on immune checkpoint inhibitors (ICIs) as new therapeutic approaches for the first-line treatment of patients with advanced gastric cancer. Despite varying interpretations of the successes and failures of this clinical research, most analyses have focused on the results from the perspective of exploring the superiority of immunotherapy. Consequently, the role of chemotherapy as an important partner of immunotherapy in first-line combination therapy regimens for gastric cancer has attracted less attention. Here, we explore and analyze first-line immunotherapies for gastric cancer from the perspective of chemotherapy, to understand reasons for the failure of studies and to indicate directions for future clinical research.

Fruquintinib Enhances the Antitumor Immune Responses of Anti-Programmed Death Receptor-1 in Colorectal Cancer.

Background: Programmed death receptor-1 (PD-1) blockade shows little benefit in patients with microsatellite-stable colorectal cancer (MSS-CRC). Fruquintinib is a China-made anti-angiogenic drug which is approved for the third line therapy in mCRC. This study investigates the effect of the combination of fruquintinib and PD-1 blockade on MSS-CRC and its relative mechanisms. Methods: The mouse allograft tumor models that represent MSS and microsatellite instability (MSI) CRC were established using murine CT26 and MC38 colon cancer cells, respectively, to assess the treatment efficacy. The percentages of immune cells were detected in the peripheral blood, spleen and tumor tissues in the tumor-bearing mice by flow cytometry analysis. Angiogenesis in tumor tissues was detected by immunofluorescence. The safety of drug treatment was evaluated by histopathology analysis in murine main organs. The efficacy of the combination of fruquintinib and sintilimab were verified in the treatment of MSS-CRC patients. Results: Our results showed that the combination of fruquintinib and sintilimab exhibited the strongest inhibition of tumor growth and achieved the longest survival time in mice bearing MC38 or CT26 xenograft tumors, compared to fruquintinib and sintilimab alone. Mechanistically, the combination of fruquintinib and sintilimab reduced angiogenesis, reprogramed the vascular structure, enhanced the infiltration of CD8+T cells (p<0.05), CD8+TNFα+ (p<0.05) T cells and CD8+IFNγ+ (p<0.05) T cells and reduced the ratios of MDSCs and macrophages in mice. There was no obvious toxicity observed in the main organs of the tumor-bearing mice with the combined treatment. Moreover, the treatment using the combination of fruquintinib and sintilimab achieved effective response in five patients with refractory advanced MSS CRC. Conclusion: Our results show that the combination of fruquintinib and sintilimab greatly inhibits CRC growth by altering tumor immune microenvironment. This study provides the rational for using the combination of fruquintinib and anti-PD-1 antibody for the treatment of advanced CRC.

Targeting depletion of myeloid-derived suppressor cells potentiates PD-L1 blockade efficacy in gastric and colon cancers.

Myeloid-derived suppressor cells (MDSCs) have been demonstrated to suppress antitumor immunity and induce resistance to PD-1/PD-L1 blockade immunotherapy in gastric and colon cancer patients. Herein, we found that MDSCs accumulate in mice bearing syngeneic gastric cancer and colon cancer. Death receptor 5 (DR5), a receptor of TNF-related apoptosis-inducing ligand (TRAIL), was highly expressed on MDSCs and cancer cells; targeting DR5 using agonistic anti-DR5 antibody (MD5-1) specifically depleted MDSCs and induced enrichment of CD8+ T lymphocytes in tumors and exhibited stronger tumor inhibition efficacy in immune-competent mice than in T-cell-deficient nude mice. Importantly, the combination of MD5-1 and anti-PD-L1 antibody showed synergistic antitumor effects in gastric and colon tumor-bearing mice, resulting in significantly suppressed tumor growth and extended mice survival, whereas single-agent treatment had limited effect. Moreover, the combination therapy induced sustained memory immunity in mice that exhibited complete tumor regression. The enhanced antitumor effect was associated with increased intratumoral CD8+ T-cell infiltration and activation, and a more vigorous tumor-inhibiting microenvironment. In summary, our findings highlight the therapeutic potential of combining PD-L1 blockade therapy with agonistic anti-DR5 antibody that targets MDSCs in gastric and colon cancers.

The Efficacy and Safety of Sintilimab Combined With Nab-Paclitaxel as a Second-Line Treatment for Advanced or Metastatic Gastric Cancer and Gastroesophageal Junction Cancer.

Background: Unresectable advanced or recurrent gastric cancer patients have a poor prognosis. PD-1 monotherapy regimen and PD-1 combined chemotherapy regimen have become the standard third- and first-line treatment for advanced gastric cancer, respectively. However, the status of immune checkpoint inhibitors in the second-line treatment for advanced gastric cancer has not been established. The combination of chemotherapy and anti-PD-1 antibody has been demonstrated to have a synergistic effect. In this study, we aimed to evaluate the efficacy and safety of sintilimab combined with nab-paclitaxel in the second-line treatment for advanced gastric cancer (GC)/gastroesophageal junction (GEJ) cancer patients. Patients and Methods: We retrospectively analyzed patients with advanced GC/GEJ cancer that progressed after first-line systemic therapies with sintilimab combined with nab-paclitaxel from April 1, 2019 to December 31, 2021. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: Thirty-nine patients were enrolled and eligible for response assessment. Complete response (CR) was not observed, 15 patients achieved partial response (PR), 16 patients had stable disease (SD) and 9 patients had progressive disease (PD). The ORR and DCR were 15 (38.5%) and 31 (79.5%), respectively. Median PFS was 5.4 months (95%CI: 3.072-7.728). PFSs between different subgroups were analyzed. The results showed that gender, age, Human epidermal growth factor receptors 2 (HER2) status, PD-L1 expression, primary tumor site and chemotherapy cycles had no significant effect on PFS. Most of the adverse events (AEs) were of grade 1-2 and manageable. The common treatment-related adverse events of grade 3 or 4 included anemia (12.8%), neutropenia (12.8%), leukopenia (10.3%), hand-foot syndrome (7.7%), thrombocytopenia (7.7%). The potential immune-related adverse events (irAEs) were grade 1 pneumonia (1 pts [2.6%]) and grade 4 hepatitis (1 pts [2.6%]). There were no treatment-related deaths. Conclusion: These results indicate that sintilimab combined with nab-paclitaxel exhibits good anti-tumor activity and an acceptable safety profile as a second-line treatment for advanced or metastatic gastric cancer. These results warrant further investigation and evaluation to identify patients who can benefit more from the combined treatment strategy.

Personalized Treatment of Advanced Gastric Cancer Guided by the MiniPDX Model.

BACKGROUND: The morbidity and mortality of gastric cancer are high in China. There are challenges to develop precise and individualized drug regimens for patients with gastric cancer after a standard treatment. Choosing the most appropriate anticancer drug after a patient developing drug resistance is very important to improve the patient's prognosis. MiniPDX has been widely used as a new and reliable preclinical research model to predict the sensitivity of anticancer drugs. METHODS: The OncoVee® MiniPDX system developed by Shanghai LIDE Biotech Co., Ltd. was used to establish the MiniPDX models using specimens of patients with gastric cancer. The cancer tissues were biopsied under endoscopy, and then, the tumor cell suspension was prepared for a drug sensitivity test by subcutaneously implanting into Balb/c-nude mice. The selected optimal regimen obtained from the MiniPDX assay was used to treat patients with drug-resistant gastric cancer. RESULTS: We successfully established an individualized and sensitive drug screening system for four patients from January 2021 to July 2021. MiniPDX models identified potentially effective drugs for these four patients, with partial remission in two of the patients after treatment and disease progression in the remaining of two patients. Severe side effects from chemotherapy or targeted therapy were not observed in all patients. CONCLUSION: Establishing a personalized drug screening system for patients with drug-resistant gastric cancer can guide the selection of clinical drugs, improve the clinical benefit of patients, and avoid ineffective treatments. It can be an effective supplement for treatment options.

Retrospective Study on the Efficacy and Safety of Pyrotinib-Based Therapy for HER2-Positive Nonbreast Advanced Solid Tumors.

Background: Human epidermal growth factor receptor 2 (HER2) is a member of the large ErbB family and an important oncogene in many solid tumors. Pyrotinib has been approved for the treatment of HER2-positive, recurrent, or metastatic breast cancer. However, there are very few clinical studies on pyrotinib in other HER2-positive solid tumors. Therefore, more evidence of clinical research is impendently needed to shepherd pyrotinib-based therapy in HER2-positive nonbreast advanced solid tumors. Patients and Methods. We performed a retrospective analysis of HER2-positive nonbreast advanced solid tumors patients with HER2 amplification or mutations who were administered with pyrotinib-based therapy in Henan Cancer Hospital between July 1, 2019, and December 2, 2021. In our research, 25 eligible patients were included with 16 patients with lung cancer, 6 patients with gastric cancer, 2 patients with colorectal cancer, and 1 patient with cholangiocarcinoma. Progression-free survival (PFS) is our main research end point. Results: The median PFS was 188 days (95% CI: 83-not reached (NR)), and overall survival (OS) was 250 days (95% CI: 188-NR), respectively. 16 patients with lung cancer had a median PFS of 204 days (95% CI: 55-NR) and 6 patients with gastric cancer had PFS of 142 days (95% CI: 83-NR), respectively. The median OS was 366 days (95% CI: 248-NR) in patients with lung cancer and 179 days (95% CI: 90-NR) in patients with gastric cancer. The median PFS and OS of patients receiving >3 line treatment were lower than those receiving ≤3 line treatment (PFS: 188 days vs 204 days, p = 0.92; OS: 188 days vs 366 days, p = 0.43). All 25 patients can be evaluated. The objective response rate (ORR) was 24%, and the disease control rate (DCR) was 68%. Lung cancer ORR was 25%, and gastric cancer ORR was 16.7%. In addition, the DCR of lung cancer was 62.5% and that of gastric cancer was 66.7%. In addition, the ORR and DCR of patients receiving treatment ≤3 lines were higher than those receiving treatment >3 lines (ORR: 35.7% vs 9.1%, p = 0.18; DCR: 71.4% vs 63.6%, p > 0.99). The most common treatment-related adverse events (TRAEs) were diarrhea (84%), but only 3 patients (12%) reported grade 3 diarrhea with good control. Conclusion: These results show that in HER2-positive nonbreast advanced solid tumors, the treatment based on pyrotinib regimen has good antitumor activity and acceptable safety. This retrospective study aims to promote larger clinical studies to further clarify the efficacy and safety of pyrotinib in the treatment of nonbreast solid tumors.

XIAP-associated factor 1 interacts with and attenuates the trans-activity of four and a Half LIM protein 2.

XIAP-associated factor 1(XAF1) is a tumor suppressor with its functional mechanisms not fully understood. The zinc-finger cluster located at the N-terminus is the only domain structure. Four and a half LIM domain protein 2 (FHL2) also contains a tandem zinc finger structure, and its protein functions as an important adaptor and modifier in protein-protein interactions. Both of their structures are relatively simple, while the association between them is still unclear. In this study, we detected the interaction between XAF1 and FHL2 by using the yeast two-hybrid system. We identified FHL2 as a XAF1 binding protein. Furthermore, both XAF1 and FHL2 localized to the cytoplasm, mitochondria, and nucleus of gastric cancer cells. Over-expression of XAF1 excluded FHL2 from the nucleus and suppressed the trans-activity of FHL2 in stimulating the transcriptional activities of ß-catenin and AP-1. In conclusion, our findings unraveled an antagonistic mechanism between a tumor suppressor and an oncoprotein in cancer cells.

Serum interleukin-33 levels in patients with gastric cancer.

BACKGROUND: Interleukin-33 (IL-33) is a novel member of the IL-1 family of cytokines, and it is closely related to IL-18, one of the best characterized members of the IL-1 family. It's been demonstrated that elevated levels of IL-18 are involved in a wide variety of tumors, especially in gastric cancer. AIMS: The purpose of this study was to determine the correlations between serum IL-33 levels and the clinicopathologic features in gastric cancer patients. METHODS: Serum samples were collected from 68 patients with gastric cancer and 57 controls. Serum IL-33 levels were measured by ELISA. Classical tumor markers of CEA and CA19-9 levels were routinely detected by chemiluminescence immunoassay. Western blot analysis was used to detect IL-33 expression in gastric cancer tissue samples and cell lines. The relationship between serum levels of IL-33 and clinical characteristics in patients was analyzed. RESULTS: IL-33 levels in the serum of gastric cancer patients were significantly elevated in comparison with that of healthy volunteers. Furthermore, higher serum levels of IL-33 in gastric cancer patients were found to correlate with several poor prognostic factors like depth of invasion, distant metastasis and advanced stage (stage III/IV). On the other hand, serum IL-33 levels did not correlate with CEA and CA19-9. The expression of IL-33 protein was upregulated in carcinoma tissues in comparison with matched normal tissues, and no statistically significant difference was found between the four gastric cancer cell lines and human gastric epithelial cell line GES-1. CONCLUSIONS: Serum IL-33 may be a useful biomarker for predicting the prognosis of gastric cancer.

Current status and future perspective of immune checkpoint inhibitors in colorectal cancer.

Immune checkpoint inhibitors (ICIs), as a subverter of immunotherapy in oncology, are changing all aspects of therapy for malignant tumors, especially their remarkable effects on melanoma and non-small cell lung cancer (NSCLC). For colorectal cancer (CRC), only a small number of patients with high immunogenicity (microsatellite instability-high/mismatch-repair deficient (MSI-H/dMMR)) benefit greatly from ICIs treatment, and most CRC patients with low immunogenicity (microsatellite instability-low/mismatch-repair proficient (MSI-L/pMMR)) do not. Currently, numerous clinical trials are ongoing to improve CRC patients' response to ICIs immunotherapy through better patient selection and novel combination strategies. Thus, this review discusses the current status and latest progress of ICIs treatment in CRC. We expect that these studies can change the pattern of CRC immunotherapy in the future.

Antibody-activated trans-endothelial delivery of mesoporous organosilica nanomedicine augments tumor extravasation and anti-cancer immunotherapy.

Tumor vasculature constitutes a formidable hurdle for the efficient delivery of cancer nanomedicine into tumors. The leverage of passive pathway through inter-endothelial gaps in tumor blood vessels might account for limited extravasation of nanomedicine into tumor microenvironment (TME). Herein, Annexin A1 antibody-installed mesoporous organosilica nanoplatforms carrying immunotherapeutics of anti-PD-L1 antibody (aPD-L1) and Indoximod are developed to target at caveolar Annexin-A1 protein of luminal endothelial cells and to trigger the active trans-endothelial transcytosis of nanomedicine mediated by caveolae. Such strategy enables rapid nanomedicine extravasation across tumor endothelium and relatively extensive accumulation in tumor interstitium. aPD-L1 and Indoximod release from aPD/IND@MON-aANN in a reduction-responsive manner and synergistically facilitate the intratumoral infiltration of cytotoxic T lymphocytes and reverse the immunosuppressive TME, thus demonstrating substantial anti-tumor efficacy in subcutaneous 4T1 breast tumors and remarkable anti-metastatic capacity to extend the survival of 4T1 tumor metastasis model. Moreover, aPD/IND@MON-aANN nanomedicine also exhibits distinct superiority over the combination therapy of free drugs to potently attenuate the progression of urethane-induced orthotopic lung cancers. Collectively, aPD/IND@MON-aANN nanoplatforms with boosted delivery efficiency via antibody-activated trans-endothelial pathway and enhanced immunotherapeutic efficacy provides perspectives for the development of cancer nanomedicines.

A PD-1 Inhibitor Induces Complete Response of Advanced Bladder Urothelial Carcinoma: A Case Report.

The prognosis of patients with advanced urothelial carcinoma is dismal. Platinum-based chemotherapy is still the main first-line treatment for advanced urothelial carcinoma, while immunotherapy can be used as a first-line treatment option for people who cannot tolerate platinum. Immunotherapy is preferred in the second-line treatment of bladder urothelial carcinoma. PD-1 inhibitors (Pembrolizumab, nivolumab and atezolizumab) and PD-L1 inhibitors (Ddurvalumab and avelumab) have not been approved for the treatment of advanced urothelial cancer in China. We describe a patient with advanced urothelial carcinoma experienced disease progression after gemcitabine chemotherapy. Following a treatment of domestic PD-1 inhibitor (sintilimab), the patient achieved a durable complete response with mild toxicity. This case indicates that PD-1 inhibitor sintilimab might be a second-line treatment choice for advanced urothelial carcinoma.

Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway.

Utidelone (UTD1), a novel microtubule stabilizing agent, is an epothilone B analogue which was produced by genetic engineering. UTD1 has exhibited broad antitumor activity in multiple solid tumors. However, its activity and mechanism in colorectal cancer (CRC) remain to be studied. In this study, UTD1 dramatically inhibited CRC cell proliferation (with 0.38 µg/ml, 0.77 µg/ml IC50 in RKO and HCT116, respectively) in vitro. Immunofluorescence staining showed that UTD1 induced the formation of microtubule bundling and asters in RKO cells. Flow cytometry analysis demonstrated that UTD1 induced cell cycle to arrest in G2/M phase, subsequent apoptosis. Significantly, UTD1 exhibited stronger effect on inducing apoptosis than paclitaxel and 5-FU, especially in HCT15 cells which is ABCB1 high-expression. UTD1 exposure cleaved caspase-3 and poly ADP-ribose polymerase (PARP), decreased mitochondrial membrane potential, released cytochrome c, increased the production of active oxygen and activated c-Jun N-terminal kinase (JNK), suggesting ROS/JNK pathway was involved in this process. Moreover, UTD1 inhibited tumor growth and was more effective and safer compared with paclitaxel and 5-FU in RKO xenograft in nude mice. Taken together, our findings first indicate that UDT1 inhibits tumor growth in CRC xenograft model and may be a promising agent for CRC treatment.

Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors.

Cancer-associated fibroblasts (CAFs) has been recognized as one cause of tumor resistance to immune checkpoint blockade therapy, but the underlying mechanisms still remain elusive. In the present study, a bone marrow-derived CAF (BMF) -rich tumor model is successfully established by subcutaneously mixed inoculation of BMFs and tumor cells into mice and the BMF-mixed tumor xenografts are demonstrated to be resistant to anti-PD-L1 antibody immunotherapy compared to the mere tumor xenografts. In vitro assays via the co-culture system of BMFs and tumor cells indicate that the co-cultured BMFs are induced to overexpress PD-L1, while there is no such a phenomenon in the co-cultured cancer cells. The further knock-out of PD-L1 in BMFs rescues the sensitivity of BMF-mixed tumor xenografts to PD-L1 blockade therapy. Mechanistically, via the microarray assay, we identify that the upregulation of PD-L1 in BMFs stimulated by cancer cells is medicated by the activation of the Wnt/ß-catenin signaling pathway in BMFs. Moreover, the administration of Wnt/ß-catenin signaling inhibitors, including XAV-939 and Wnt-C59, distinctly inhibits the upregulation of PD-L1 expression in the co-cultured BMFs. The further combination administration of XAV-939 significantly potentiates the therapeutic outcome of PD-L1 blockade therapy in BMF-mixed tumors. In summary, our study demonstrates that Wnt inhibition augments PD-L1 blockade efficacy by overcoming BMF-mediated immunotherapy resistance.

Combination of Anlotinib and Celecoxib for the Treatment of Abdominal Desmoid Tumor: A Case Report and Literature Review.

Desmoid tumor is a rare disease, which is histologically characterized by local invasion, monoclonality, and fibroblast proliferation; and clinically characterized by a variable and often unpredictable course. The treatment of desmoid tumor is mainly surgical resection, but the recurrence rate is high. In recent years, a variety of treatment methods, including endocrine therapy, surgery, radiotherapy, chemotherapy, non-steroidal anti-inflammatory drugs, targeted drugs, interferon and more, have been used and achieved certain curative effects. In addition, in view of the inertia characteristics of desmoid tumor, observation is also a first-line scheme recommended by multiple guidelines. In the past, the research progress of targeted therapy for desmoid tumor is relatively slow and the curative effect is limited. Thus, targeted therapy is usually used as a remedial treatment after the failure of other conventional treatment methods. However, in recent years, with the rapid progress in the basic research of targeted therapy, some new targeted drugs are increasingly used for the clinical treatment of desmoid tumor and have achieved good results. Herein, we described a patient with aggressive fibromatosis in the abdominal cavity. Following a combined treatment using anlotinib and celecoxib, the patient achieved a partial response with mild toxicity. Simultaneously, the patient's pain symptoms completely disappeared. This case indicates that the combination of anlotinib and NSAIDs could be an effective treatment for desmoid tumor.