Clinical efficacy and biomarker analysis of neoadjuvant camrelizumab plus chemotherapy for early-stage triple-negative breast cancer: a experimental single-arm phase II clinical trial pilot study.

BACKGROUND: Triple-negative breast cancer (TNBC) is associated with a dismal prognosis. Immune checkpoint inhibitors have shown promising antitumor activity in neoadjuvant settings. This single-arm, phase II trial aimed to evaluate the efficacy and safety of camrelizumab plus chemotherapy as the neoadjuvant therapy (NAT) in early TNBC. METHODS: Patients received eight cycles of camrelizumab plus nonplatinum-based chemotherapy. The primary endpoint was total pathological complete response (pCR). Secondary endpoints included the breast pathological complete response (bpCR), adverse events (AEs). Multiomics biomarkers were assessed as exploratory objective. RESULTS: Twenty of 23 TNBC patients receiving NAT underwent surgery, with the total pCR rate of 65% (13/20) and bpCR rate of 70% (14/20). Grade ≥3 treatment-related AEs were observed in 14 (60.9%) patients, with the most common AE being neutropenia (65.2%). Tumor immune microenvironment was analyzed between pCR and non-pCR samples before and after the NAT. Gene expression profiling showed a higher immune infiltration in pCR patients than non-pCR patients in pre-NAT samples. Through establishment of a predictive model for the NAT efficacy, TAP1 and IRF4 were identified as the potential predictive biomarkers for response to the NAT. Gene set enrichment analysis revealed the glycolysis and hypoxia pathways were significantly activated in non-pCR patients before the NAT, and this hypoxia was aggravated after the NAT. CONCLUSION: Camrelizumab plus nonplatinum-based chemotherapy shows a promising pCR rate in early-stage TNBC, with an acceptable safety profile. TAP1 and IRF4 may serve as potential predictive biomarkers for response to the NAT. Aggravated hypoxia and activated glycolysis after the NAT may be associated with the treatment resistance.

Clinical application of molecular residual disease detection by circulation tumor DNA in solid cancers and a comparison of technologies: review article.

Molecular residual disease (MRD), detected by circulating tumor DNA (ctDNA) can be involved in the entire process of solid tumor management, including recurrence prediction, efficacy evaluation, and risk stratification. Currently, the detection technologies are divided into two main categories, as follows: tumor-agnostic and tumor informed. Tumor-informed assay obtains mutation information by sequencing tumor tissue samples before blood MRD monitoring, followed by formulation of a personalized MRD panel. Tumor-agnostic assays are carried out using a fixed panel without the mutation information from primary tumor tissue. The choice of testing strategy may depend on the level of evidence from ongoing randomized clinical trials, investigator preference, cost-effectiveness, patient economics, and availability of tumor tissue. The review describes the difference between tumor informed and tumor agnostic detection. In addition, the clinical application of ctDNA MRD in solid tumors was introduced, with emphasis on lung cancer, colorectal cancer, Urinary system cancer, and breast cancer.

Vascular endothelial-derived Von Willebrand factor inhibits lung cancer progression through the αvß3/ERK1/2 axis.

Lung cancer remains a common malignant tumor causing death due to the rapid industrialization and serious pollution of the environment. The Von Willebrand Factor (vWF) protein is an endothelial marker and is widely used to diagnose cancer and other inflammations, however its exact mechanism of action remains largely unexplored. In particular, how it plays two opposing roles in tumor development is not clear. Our study aimed to the impact of endothelial-derived vWF on tumor development by co-culturing human umbilical vein endothelial cells (HUVECs) with lung cancer cells (95D and A549). A knockdown of endothelial-derived vWF assisted lung cancer cell in proliferation, migration and inhibited apoptosis in vitro, while overexpression of endothelial-derived vWF inhibited the proliferation, migration and induced apoptosis of lung cancer cells. The results of further experiments indicated that the vWF secreted by endothelial cells could affect lung cancer cell migration and apoptosis via its binding to integrin αvß3 on the surface of lung cancer cells. Furthermore, a novel finding was the fact that endothelial-derived vWF inhibited lung cancer cell apoptosis by phosphorylating ERK1/2. At the same time, we established experimental lung metastasis model and xenograft model in normal mice and vWF-/- mice, and found that knockout of vWF in mice significantly promoted lung cancer growth and metastasis. In conclusion, our research found that endothelial-derived vWF could directly combine to αvß3 on the exterior of A549 and 95D, thereby mediating lung cancer proliferation, migration and apoptosis and inhibiting the development of lung cancer.

The joint detection of CEA and ctDNA in cerebrospinal fluid: an auxiliary tool for the diagnosis of leptomeningeal metastases in cancer.

BACKGROUND: Leptomeningeal metastases (LMs) are highly invasive which leads to poor prognosis, but the accurate diagnosis of LM is challenging. It is necessary to investigate more advanced diagnostic methods to realize precision medicine. The main purpose of this study was to select a more effective method for the auxiliary diagnosis of LM by comparing various detection methods. The secondary purpose was to explore the value of cerebrospinal fluid (CSF) tumor markers (TMs) and circulating tumor DNA (ctDNA) testing in guiding clinical treatment. METHODS: TMs in serum and CSF of patients were detected by chemiluminescence. The ctDNA of CSF and plasma were detected by the next-generation sequencing (NGS) technology. RESULTS: In total, 54 tumor patients participated in this study, in which 39 with LM and 15 without LM (8 with parenchymal tumor and 7 without brain metastasis). The results showed that the sensitivity and accuracy of CSF cytology isolated during the first lumbar puncture were 0.31 (95% CI 0.17-0.48) and 0.50 (95% CI 0.36-0.64), respectively. The sensitivity and accuracy of CSF_CEA were 0.71 (95% CI 0.54-0.85) and 0.78 (95% CI 0.64-0.89), which were better than those of CSF_NSE and CSF_CFRA-211. The sensitivity and accuracy of CSF_ctDNA were 0.92 (95% CI 0.79-0.98) and 0.91 (95% CI 0.80-0.97), significantly higher than that of CSF cytology (P < 0.01). The sensitivity and accuracy of CSF_CEA combined with CSF_ctDNA were 0.97 (95% CI, 0.87-1.00) and 0.94 (95% CI 0.85-0.99), which were significantly higher than the traditional methods CSF cytology (P < 0.01). For LM patients with hydrocephalus, the sensitivity of CSF ctDNA even achieved 100% (14/14). CONCLUSION: CSF_CEA combined with CSF_ctDNA could be used to accurately distinguish patients with LM from those with no brain metastasis and from those with parenchymal tumors. CSF_ctDNA testing reveals a unique mutation profile for patients with LM. Dynamic detection of CSF TM and ctDNA can better predict the efficacy and reveal the cause of drug resistance to guide subsequent treatment. CLINICAL TRIAL REGISTRATION: Clinical trial registration number: NCT03029065.

Age-dependent genomic characteristics and their impact on immunotherapy in lung adenocarcinoma.

BACKGROUND: The incidence of lung cancer tends to be younger, and adenocarcinoma is the main histological type. Even patients with the same tumor type may have significant differences in clinical features, tumor microenvironment and genomic background at different ages. Immune checkpoint inhibitors (ICIs) have been shown to improve clinical outcomes in patients with lung adenocarcinoma (LUAD). However, differences in ICI efficacy between older and younger patients are unknown. Our study aimed to explore the relationship between age and immunotherapy in LUAD. METHODS: In our study, 1313 resected LUAD patients in our hospital were divided into young (age ≤ 50) and old groups (age > 50), and the clinical characteristic differences between them were analyzed. Of these, next-generation sequencing (NGS) was performed on the 311 cases. In addition, immune-related signatures of 508 LUAD patients were analyzed by TCGA RNA expression data. Then, we validated genomic and clinical information of 270 LUAD samples in the MSKCC cohort. RESULTS: ERBB2 and EGFR gene mutations were significantly different between the two groups, and the gene mutation number in the old group was significantly higher than that in the young group. In addition, immune-related signatures of LUAD patients were analyzed by TCGA RNA expression data, which indicated that the patients in the old group might have a better immune microenvironment. Then, we validated the MSKCC cohort and found that the TMB of the old group was significantly higher than that of the young group, and the OS of immunotherapy was longer in the old group. CONCLUSION: Our study was the first to analyze the differences in the genomic landscape and immune-related biomarkers between the young and old groups of LUAD patients and found that the old group had a better efficacy of immunotherapy, providing a reference for the study design and treatment of patients with LUAD.

Hypoxia promotes the expression of Von Willebrand factor in breast cancer cells by up-regulating the transcription factor YY1 and down-regulating the hsa-miR-424.

Von Willebrand factor (VWF), a large glycoprotein with hemostatic properties, is mainly synthesized by megakaryocytes and endothelial cells (ECs). In recent years, studies have found that tumor cells also can produce VWF de novo. Tumor growth is usually accompanied by hypoxic environment, and whether hypoxia will influence von Willebrand factor production in tumor cells is still unknown. In this research, we demonstrated that hypoxia could induce the production of VWF in breast cancer cells (MCF-7 and MDA-MB-231 cell lines), and promoted cell migration as well as angiogenesis. Notably, VWF is a key factor for hypoxia to promote breast cancer cell migration and angiogenesis, and knocking down VWF can attenuate the effects of hypoxia. Further study was conducted on the molecular mechanism to clarify why hypoxia can promote VWF synthesis in breast cancer cells. We found that Yin-Yang 1 (YY1, a transcription factor) had a binding site to the promoter region of VWF, and acted as a transcriptional activator of VWF. Meanwhile, hsa-miR-424 inhibited VWF production by associating with the 3'-UTR of VWF mRNA. Here, we proved that hypoxia up-regulated the transcription factor YY1 and down-regulated hsa-miR-424 to increase the expression level of VWF. Additionally, knockdown of transcription factor YY1 and transfection of hsa-miR-424 mimics had a synergistic effect in reducing hypoxia-induced VWF production of breast cancer cells, cell migration and angiogenesis in vitro.

Transformation of invasive lung adenocarcinoma with ALK rearrangement into pulmonary sarcomatoid carcinoma.

BACKGROUND: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) improve outcomes for non-small-cell lung cancer (NSCLC) patients with ALK fusions. Nevertheless, ALK TKI resistance will inevitably occur. Histological transformation is one of the causes of TKI resistance in NSCLC. Reports of ALK-rearranged adenocarcinoma with histological transformation are limited. CASE PRESENTATION: A case of an invasive lung adenocarcinoma patient with ALK rearrangement who experienced histological transformation into sarcomatoid carcinoma after ALK TKI resistance is reported, and ALK fusion, MET amplification and TP53 mutation were detected after transformation. CONCLUSIONS: This case first reported a patient with invasive lung adenocarcinoma harboring ALK rearrangement who underwent histological transformation into sarcomatoid carcinoma after ALK TKI resistance, and MET amplification might represent the cause. After transformation, the patient benefited from targeted therapy combined with chemotherapy, which represents a promising option for patients with sarcomatoid carcinoma transformation.

Effective treatment in lung adenocarcinoma patient with brain metastases harboring novel CLHC1/RNT4 intergenic region- ALK fusion: A case report.

RATIONALE: Anaplastic lymphoma kinase (ALK) fusion, an important oncogenic mutation, occurs in 3% to 7% of non-small cell lung cancer (NSCLC) cases, and EML4 is the most common partner gene. With the widespread application of next-generation sequencing (NGS), more gene breakpoint fusions have been discovered and functional fusion transcripts can provide targeted clinical benefits. PATIENT CONCERNS AND DIAGNOSIS: A 40-year-old woman was diagnosed with lung adenocarcinoma with brain metastases. A novel CLHC1/RNT4 intergenic region, ALK (Exon20-29) (abundance 39.97%), was identified using lung puncture tissue by NGS analysis (Simceredx), and results of immunohistochemistry and fluorescence in situ hybridization confirmed ALK fusion. INTERVENTIONS AND OUTCOMES: The patient was administered oral crizotinib (250 mg bid) combined with endostar (30 mg d1-7) for 12 cycles from June 18, 2020. The patient's condition was controlled, and the curative effect was evaluated as stable disease (SD). Unfortunately, brain magnetic resonance images showed multiple nodules in the left cerebellar hemisphere, and chest computed tomography showed no significant changes in the progression of the disease. Subsequently, alectinib (600 mg bid) was administered on April 1, 2021. Brain lesions were significantly reduced and partial remission (PR) was achieved. No significant changes were observed in the lung lesions. LESSONS: ALK fusion is a risk factor for brain metastasis (BM) in patients with advanced non-small NSCLC patients. In our case, a novel CLHC1/RNT4 intergenic region, ALK fusion, was identified for the first time in a lung adenocarcinoma patient with BM, who benefited from crizotinib and endostar sequential alectinib. Our case highlights the advantages of NGS for fusion detection and provides promising treatment options for NSCLC patients with BM harboring ALK fusions.

Afatinib, an effective treatment for patient with lung squamous cell carcinoma harboring uncommon EGFR G719A and R776C co-mutations.

BACKGROUND: Epidermal growth factor receptor (EGFR) is a crucial driven gene in non-small cell lung cancer (NSCLC), and the EGFR mutation rate in lung squamous cell carcinoma (SCC) is only 3 ~ 6.92%. Uncommon EGFR mutations, such as S768I, L861Q and G719X, accounting for approximately 15% of NSCLC harboring EGFR mutation. Afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), has been approved for NSCLC harboring uncommon mutations by the FDA in 2018. In our report, the lung SCC patient harboring uncommon compound EGFR mutation (G719A and R776C) benefited from afatinib. CASE PRESENTATION: A case of a lung SCC patient harboring uncommon compound EGFR mutation (G719A and R776C) benefited from afatinib, and new MYC amplification was detected by next-generation sequencing (NGS) after disease progression. CONCLUSIONS: This case first identified a patient with lung squamous cell carcinoma harboring uncommon compound EGFR mutation (G719A and R776C) benefited from afatinib and achieved 11 months of progression-free survival (PFS). Then, new MYC amplification was detected after disease progression, indicating that MYC amplification may be one of the reasons for afatinib resistance.

Lung adenocarcinoma-derived vWF promotes tumor metastasis by regulating PHKG1-mediated glycogen metabolism.

Tumor metastasis is a series of complicated biological events. Hematogenous metastasis mediated by von Willebrand factor (vWF) is critical in tumor metastasis. However, the source of vWF and its role in tumor metastasis are controversial, and the further mechanism involved in mediating tumor metastasis is still unclear. In this study, we first demonstrated that lung adenocarcinoma cells could express vWF de novo and promotes tumor metastasis. Through the analysis of transcriptome sequencing, the metastasis promotion effect of vWF may be related to phosphorylase kinase subunit G1 (PHKG1), a catalytic subtype of phosphorylase kinase (PhK). PHKG1 was highly expressed in lung adenocarcinoma patients and led to poor prognosis. Further experiments found that lung adenocarcinoma-derived vWF induced the upregulation of PHKG1 through the PI3K/AKT pathway to promote glycogenolysis. Glycogen was funneled into glycolysis, leading to increased metastasis. Tumor metastasis assayed in vitro and in vivo showed that knockdown of PHKG1 or synergistic injection of phosphorylase inhibition based on the overexpression of vWF could inhibit metastasis. In summary, our research proved that lung adenocarcinoma-derived vWF may mediate tumor metastasis by regulating PHKG1 to promote glycogen metabolism and suggested potential targets for inhibition of lung adenocarcinoma metastasis.

Breast cancer cells-derived Von Willebrand Factor promotes VEGF-A-related angiogenesis through PI3K/Akt-miR-205-5p signaling pathway.

The metastasis and angiogenesis of breast cancer has always been a difficult problem for treatment. It has recently been discovered that Von Willebrand Factor (vWF), in addition to hemostasis, also plays a role in tumor metastasis and angiogenesis. We noticed that besides endothelial cells, breast cancer cells (MDA-MB-231 and MCF-7) could also express vWF. In vitro experiments showed that knocking down vWF inhibited breast cancer cell metastasis. And we found that overexpression of vWF significantly promoted VEGF-A-dependent vascular proliferation in vitro by activating the PI3K/Akt signaling pathway. Further studies indicated that inhibition of PI3K/Akt signaling pathway up-regulated the expression of miR-205-5p, and miR-205-5p could bind to the 3'UTR region of VEGF-A to hinder the production of VEGF-A. Furthermore, when a spontaneous lung metastasis model was established in Balb/c female mice, knockdown of vWF in 4 T1 cells resulted in a decrease in tumor blood vessel density and effectively inhibited lung metastasis, accompanied by a decrease in the expression level of VEGF-A and an increase in the expression level of miR-205-5p. In summary, our findings provide experimental evidence that overexpression of vWF in breast cancer cells down-regulates the expression of miR-205-5p and up-regulates the expression of VEGF-A through the PI3K/Akt signaling pathway, thereby promoting tumor angiogenesis and metastasis.

Erlotinib combined with bevacizumab and chemotherapy in first line osimertinib-resistant NSCLC patient with leptomeningeal metastasis: A case report.

RATIONALE: Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small cell lung cancer (NSCLC) with a poor prognosis. Osimertinib is a promising option for NSCLC with LM harboring epidermal growth factor receptor (EGFR) mutation. However, therapeutic approaches remain a challenge for osimertinib resistant NSCLCs with LM. Although studies have reported that the first/second-generation EGFR-tyrosine kinase inhibitors were active against osimertinib-resistant NSCLC with EGFR C797S and sensitive mutation (SM), the resistance inevitably occurred due to the development of the EGFR SM/C797S/T790M triple mutations. PATIENT CONCERNS: A 48-year-old woman was diagnosed with stage IV lung adenocarcinoma harboring the EGFR mutation in the combination of chest computed tomography, biopsy and amplification refractory mutation system-polymerase chain. One year and a half after oral administration of osimertinib, the patient progressed to extensive LM. DIAGNOSES: Magnetic resonance images of the brain showed extensive LM. Exfoliated tumor cells from cerebrospinal fluid (CSF) were positive detected by lumbar puncture and the cytology examination. EGFR mutations (exon19 E746_T751delinsI and exon20 C797S) in CSF circulating tumor DNA were detected by next-generation sequencing (NGS). INTERVENTIONS: Pemetrexed (800 mg day 1), cis-platinum (40 mg day 1-3) combined with bevacizumab (400 mg day 1) every 3 weeks were administered to the patient. After 1 cycle, due to optic nerve invasion, erlotinib was applied 150 mg/d combined with previous regimen. The patient continued erlotinib monotherapy after 6 cycles. OUTCOMES: After LM, erlotinib combined with pemetrexed, cis-platinum and bevacizumab were administered to the patient for 4.25 months based on the CSF NGS. Then, the patient continued erlotinib monotherapy and appeared disease progression after 10 months. The overall survival is 35 months. LESSONS: LM is a fatal complication of advanced NSCLC with a poor prognosis. NGS profiling of CSF circulating tumor DNA is important in NSCLC patients with LM and erotinib plus bevacizumab and chemotherapy is a promising option for patients with LM harboring EGFR C797S/SM.

Non-alkylator anti-glioblastoma agents induced cell cycle G2/M arrest and apoptosis: Design, in silico physicochemical and SAR studies of 2-aminoquinoline-3-carboxamides.

Malignant gliomas are the most common brain tumors, with generally dismal prognosis, early clinical deterioration and high mortality. Recently, 2-aminoquinoline scaffold derivatives have shown pronounced activity in central nervous system disorders. We herein reported a series of 2-aminoquinoline-3-carboxamides as novel non-alkylator anti-glioblastoma agents. The synthesized compounds showed comparable activity to cisplatin against glioblastoma cell line U87 MG in vitro. Among them, we found that 6a displayed good inhibitory activity against A172 and U118 MG glioblastoma cell lines and induced cell cycle arrest in the G2/M phase and apoptosis in U87 MG by flow cytometry analysis. Additionally, 6a displayed low cytotoxicity to several normal human cell lines. In silico study showed 6a had promising physicochemical properties and was predicted to cross the blood-brain barrier. Moreover, preliminary structure-activity relationships are also investigated, shedding light on further modifications towards more potent agents on this series of compounds. Our results suggest this compound has a promising potential as an anti-glioblastoma agent with a differential effect between tumor and non-malignant cells.

Helicobacter pylori infection as a potential favorable factor for immune checkpoint inhibitor therapy for gastric cancer.

Gastric cancer (GC) has the third highest rate of cancer incidence and mortality worldwide. First-line immune checkpoint inhibitor (ICI) therapy for advanced GC led to landmark breakthroughs, but which GC patients are most likely to benefit from ICI therapy needs to be investigated in depth and identified via valuable biomarkers. In this letter, we describe superior outcomes in Asian patients than in North American and European patients treated with ICI therapy, and we speculate that positive H. pylori status may be a beneficial prognostic factor for ICI therapy in patients with GC. Many studies have revealed that H. pylori-activated immune responses improve prognosis in patients with GC via increased PD-L1 expression and CD3+ T cells. We propose that H. pylori status should be emphasized in ongoing or forthcoming ICI therapy trials to maximize the benefits of treatment for patients with advanced GC. Further research is required to better understand the mechanisms of inflammation and cancer progression.

ADAM28 from both endothelium and gastric cancer cleaves von Willebrand Factor to eliminate von Willebrand Factor-induced apoptosis of gastric cancer cells.

Disintegrin and metalloproteinase 28 (ADAM28) is a member of the disintegrin and metalloprotease domain (ADAM) family. It is associated with the growth and metastasis of various malignancies in vivo, but its role in gastric cancer remains unclear. The purpose of this study was to investigate the effect of ADAM28 derived from gastric cancer and endothelium on gastric cancer cells and its related mechanisms. In this study, Western blot analysis and q-PCR results showed that ADAM28 was up-regulated in gastric cancer cell lines. The TCGA database showed that patients with high ADAM28 expression had significantly shorter overall survival than those with low ADAM28 expression. By MTT analysis, wound healing assay, and flow cytometry, we found that overexpression/knockdown of ADAM28 expression in gastric cancer cells can regulate cell proliferation, apoptosis and migration in vitro. In addition, overexpression/knockdown of ADAM28 in human umbilical vein endothelial cells (HUVECs) in the upper ventricle can regulate the apoptosis of lower ventricular gastric cancer cells in the co-culture system. Furthermore, ELISA demonstrated that knockdown of ADAM28 from endothelial cells increased the expression of von Willebrand Factor (vWF) in the supernatant. We found that ADAM28 both from gastric cancer cells and HUVECs eliminated vWF-induced apoptosis of gastric cancer cells by cleaving vWF, and the addition of the vWF knockdown plasmid eliminated the increase of integrin ß3, p-TP53 and c-Casp3 caused by ADAM28 knockdown. In conclusion, ADAM28 from endothelium and gastric cancer may cleave vWF to eliminate vWF-induced apoptosis of gastric cancer cells and play an pro-metastasis effect.

Separation of Five Flavonoids from Aerial Parts of Salvia Miltiorrhiza Bunge Using HSCCC and Their Antioxidant Activities.

The aerial parts of Salvia miltiorrhiza Bunge, as the non-medicinal parts, are always discarded during harvesting, resulting in a huge waste of resources and environmental pressure. Due to the high flavonoid content and their antioxidant activities characteristics, the aerial parts of S. miltiorrhiza can be developed into natural antioxidants and used in foods. A high-speed counter-current chromatography (HSCCC) method, using a two-phase solvent system composed of tert-butyl methyl ether/n-butanol/acetonitrile/water (3:1:1:20, v/v), was the first to successfully isolate five flavonoids from the aerial parts of S. miltiorrhiza in one attempt, and separately categorized as rutin (1), isoquercitrin (2), kaempferol-3-O-α-l-rhamnopyranosyl-(1→6)-ß-d-glucopyranoside (3), kaempferol-3-O-ß-d-glucopyranoside (4) and apigenin-7-O-ß-d-glucopyranoside (5) after identification. The purities of these plant isolates were 97.3%, 99.5%, 92.8%, 98.1% and 98.7%, respectively. All the flavonoids were identified by HR-ESI-MS, 1D and 2D NMR. Compounds 3 and 5 were firstly isolated from the plant of S. miltiorrhiza. Results from antioxidant assays showed that rutin (1) and isoquercitrin (2) had higher antioxidant capacities compared to L-ascorbic acid as the positive control.

Novel antibodies against GPIbα inhibit pulmonary metastasis by affecting vWF-GPIbα interaction.

BACKGROUND: Platelet glycoprotein Ibα (GPIbα) extracellular domain, which is part of the receptor complex GPIb-IX-V, plays an important role in tumor metastasis. However, the mechanism through which GPIbα participates in the metastatic process remains unclear. In addition, potential bleeding complication remains an obstacle for the clinical use of anti-platelet agents in cancer therapy. METHODS: We established a series of screening models and obtained rat anti-mouse GPIbα monoclonal antibodies (mAb) 1D12 and 2B4 that demonstrated potential value in suppressing cancer metastasis. To validate our findings, we further obtained mouse anti-human GPIbα monoclonal antibody YQ3 through the same approach. RESULTS: 1D12 and 2B4 affected the von Willebrand factor (vWF)-GPIbα interaction via binding to GPIbα aa 41-50 and aa 277-290 respectively, which markedly inhibited the interaction among platelets, tumor cells, and endothelial cells in vitro, and reduced the mean number of surface nodules in the experimental and spontaneous metastasis models in vivo. As expected, YQ3 inhibited lung cancer adhesion and demonstrated similar value in metastasis. More importantly, for all three mAbs in our study, none of their Fabs induced thrombocytopenia. CONCLUSION: Our results therefore supported the hypothesis that GPIbα contributes to tumor metastasis and suggested potential value of using anti-GPIbα mAb to suppress cancer metastasis.