scholarly journals Anti-Metastatic Activity of an Anti-EGFR Monoclonal Antibody against Metastatic Colorectal Cancer with KRAS p.G13D Mutation

2020 ◽  
Vol 21 (17) ◽  
pp. 6037
Author(s):  
Tomokazu Ohishi ◽  
Yukinari Kato ◽  
Mika K. Kaneko ◽  
Shun-ichi Ohba ◽  
Hiroyuki Inoue ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
High Sensitivity ◽  
Kras Mutations ◽  
Cytotoxicity Activities ◽  
Hct 116 Cells

The now clinically-used anti-epidermal growth factor receptor (EGFR) monoclonal antibodies have demonstrated significant efficacy only in patients with metastatic colorectal cancer (mCRC), with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS). However, no effective treatments for patients with mCRC with KRAS mutated tumors have been approved yet. Therefore, a new strategy for targeting mCRC with KRAS mutated tumors is desired. In the present study, we examined the anti-tumor activities of a novel anti-EGFR monoclonal antibody, EMab-17 (mouse IgG2a, kappa), in colorectal cancer (CRC) cells with the KRAS p.G13D mutation. This antibody recognized endogenous EGRF in CRC cells with or without KRAS mutations, and showed a high sensitivity for CRC cells in flow cytometry, indicating that EMab-17 possesses a high binding affinity to the endogenous EGFR. In vitro experiments showed that EMab-17 exhibited antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity activities against CRC cells. In vivo analysis revealed that EMab-17 inhibited the metastases of HCT-15 and HCT-116 cells in the livers of nude mouse metastatic models, unlike the anti-EGFR monoclonal antibody EMab-51 of subtype mouse IgG1. In conclusion, EMab-17 may be useful in an antibody-based therapy against mCRC with the KRAS p.G13D mutation.

The efficacy of antiepidermal growth factor receptor monoclonal antibodies for patients with KRAS G13D mutations and chemorefractory metastatic colorectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 527-527
Author(s):  
Kohei Akiyoshi ◽  
Yasuhide Yamada ◽  
Naoki Takahashi ◽  
Yoshitaka Honma ◽  
Satoru Iwasa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Cancer Center ◽  
Wild Type ◽  
Duration Of Treatment ◽  
Kras Mutations

527 Background: The treatment benefits of epidermal growth factor receptor (EGFR) monoclonal antibodies for patients with KRAS mutations have not been demonstrated. However, some studies have suggested that all KRAS mutations are not equivalent, and that KRAS G13D mutations might have some survival benefit. Methods: We retrospectively analyzed the efficacy and toxicity of treatment with EGFR monoclonal antibody in 8 patients with KRAS G13D mutations and 5-FU/oxaliplatin/irinotecan (CPT) refractory metastatic colorectal cancer compared with 94 KRAS wild type patients at the National Cancer Center Hospital. Results: Eight patients with KRAS G13D mutations were treated with anti-EGFR monoclonal antibodies between July, 2009 and July, 2011. The median age was 66 (42-70); male/female 6/2; PS was 0/1/2, 2/5/1; treatment regimen was cetuximab/ cetuximab+CPT/ panitumumab+CPT, 2/5/1. Response rate (RR) was 12.5% and disease control rate (DCR) was 50.0% with 1 PR, 3 SD, and 4 PD. The PR case treated with cetuximab+CPT showed marked regression of tumor and long duration of treatment (9 months). The progression free survival (PFS) of 2 SD cases was 4.2 and 3.9 months. The other SD case is now on treatment. The median PFS of the 8 patients was 2.1 months (95% confidence interval [CI]: 0.0-5.2). The median overall survival (OS) has not been reached. Grade 3/4 toxicities included 1 hypomagnesemia G4 and 1 rash acneiform G3. Meanwhile, 94 KRAS wild type patients treated with anti EGFR monoclonal antibodies had an RR of 22.3% and DCR was 66.0% with 21 PR, 41 SD, 30 PD, and 2 NE. PFS was 5.6 months (95% CI: 4.9-6.3) and OS was 8.6 months (95% CI: 6.5-10.7). Conclusions: In this analysis, we identified one PR to anti-EGFR monoclonal antibody in a patient with KRAS G13D mutation and chemo-refractory metastatic colorectal cancer. However, we were unable to demonstrate equivalent efficacy in patients with KRAS G13D mutations and KRAS wild type patients. Further studies are needed to evaluate the efficacy and prognosis for this treatment.

scholarly journals Defucosylated Mouse–Dog Chimeric Anti-EGFR Antibody Exerts Antitumor Activities in Mouse Xenograft Models of Canine Tumors

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3599
Author(s):  
Guanjie Li ◽  
Tomokazu Ohishi ◽  
Mika K. Kaneko ◽  
Junko Takei ◽  
Takuya Mizuno ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Line ◽  
Growth Factor Receptor ◽  
High Sensitivity ◽  
Osteosarcoma Cell ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Vitro Analysis

The epidermal growth factor receptor (EGFR) contributes to tumor malignancy via gene amplification and protein overexpression. Previously, we developed an anti-human EGFR (hEGFR) monoclonal antibody, namely EMab-134, which detects hEGFR and dog EGFR (dEGFR) with high sensitivity and specificity. In this study, we produced a defucosylated mouse–dog chimeric anti-EGFR monoclonal antibody, namely E134Bf. In vitro analysis revealed that E134Bf highly exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against a canine osteosarcoma cell line (D-17) and a canine fibroblastic cell line (A-72), both of which express endogenous dEGFR. Moreover, in vivo administration of E134Bf significantly suppressed the development of D-17 and A-72 compared with the control dog IgG in mouse xenografts. These results indicate that E134Bf exerts antitumor effects against dEGFR-expressing canine cancers and could be valuable as part of an antibody treatment regimen for dogs.

scholarly journals The roles and prognostic significance of ABI1-TSV-11 expression in patients with left-sided colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Zhang ◽  
Zhaohui Zhong ◽  
Mei Li ◽  
Jingyi Chen ◽  
Tingru Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Significance ◽  
Growth Factor Receptor ◽  
The Cancer Genome Atlas ◽  
Actin Dynamics ◽  
Elevated Expression ◽  
Sw480 Cells ◽  
And Migration

AbstractAbnormally expressed and/or phosphorylated Abelson interactor 1 (ABI1) participates in the metastasis and progression of colorectal cancer (CRC). ABI1 presents as at least 12 transcript variants (TSVs) by mRNA alternative splicing, but it is unknown which of them is involved in CRC metastasis and prognosis. Here, we firstly identified ABI1-TSV-11 as a key TSV affecting the metastasis and prognosis of left-sided colorectal cancer (LsCC) and its elevated expression is related to lymph node metastasis and shorter overall survival (OS) in LsCC by analyzing data from The Cancer Genome Atlas and TSVdb. Secondly, ABI1-TSV-11 overexpression promoted LoVo and SW480 cells adhesion and migration in vitro, and accelerated LoVo and SW480 cells lung metastasis in vivo. Finally, mechanism investigations revealed that ABI1-isoform-11 interacted with epidermal growth factor receptor pathway substrate 8 (ESP8) and regulated actin dynamics to affect LoVo and SW480 cells biological behaviors. Taken together, our data demonstrated that ABI1-TSV-11 plays an oncogenic role in LsCC, it is an independent risk factor of prognosis and may be a potential molecular marker and therapeutic target in LsCC.

scholarly journals Cerenkov luminescence imaging is an effective preclinical tool for assessing colorectal cancer PD-L1 levels in vivo

2020 ◽  
Author(s):  
Sheng Zhao ◽  
Wen-Bin Pan ◽  
Hui-Jie Jiang ◽  
Rong-Jun Zhang ◽  
Hao Jiang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Competitive Inhibition ◽  
Specific Binding ◽  
Luminescence Imaging ◽  
Tumor Bearing ◽  
Cerenkov Luminescence Imaging ◽  
The Status

Abstract Background : Preclinical and clinical studies have demonstrated that immunotherapy has effectively delayed tumor progression, and the clinical outcomes of anti-PD-1/PD-L1 therapy were related to PD-L1 expression level in the tumors. A 131 I-labeled anti-PD-L1 monoclonal antibody tracer, 131 I-PD-L1-Mab, was developed to study the target ability of non-invasive Cerenkov luminescence imaging in colorectal cancer xenograft mice.Method: Anti-PD-L1 monoclonal antibody labeled with 131 I( 131 I-PD-L1-Mab), and in vitro binding assays were used to evaluate the affinity of 131 I-PD-L1-Mab to PD-L1 and their binding level to different colorectal cancer cells, and compared with flow cytometry, western blot analysis, and immunofluorescence staining. The clinical application value of 131 I-PD-L1-Mab was evaluated through biodistribution and Cerenkov luminescence imaging, and different tumor-bearing models expressing PD-L1 were evaluated.Results: 131 I-PD-L1-Mab showed high affinity to PD-L1, and the equilibrium dissociation constant was 1.069×10 -9 M. The competitive inhibition assay further confirmed the specific binding ability of 131 I-PD-L1-Mab. In four different tumor-bearing models with different PD-L1 expression, the biodistribution and Cerenkov luminescence imaging showed that the RKO tumors demonstrated the highest uptake of the tracer 131 I-PD-L1-Mab, with a maximum uptake of 1.613 ± 0.738% ID/g at 120 h.Conclusions: There is a great potential for 131 I-PD-L1-Mab noninvasive Cerenkov luminescence imaging to assess the status of tumor PD-L1 expression and select patients for anti-PD-L1 targeted therapy.

scholarly journals BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy

2020 ◽  
Vol 8 (3) ◽  
pp. 192-205 ◽  
Author(s):  
Zi-Nan Li ◽  
Lin Zhao ◽  
Li-Feng Yu ◽  
Min-Jie Wei
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Survival Rate ◽  
Metastatic Colorectal Cancer ◽  
Early Stage ◽  
Unmet Need ◽  
Growth Factor Receptor ◽  
Kras Mutations ◽  
Viral Oncogene ◽  
Viral Oncogene Homolog

Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and 30% of patients with CRC experience metastasis. Patients with metastatic colorectal cancer (mCRC) have a 5-year overall survival rate of <10%. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and V-Ki-ras2 Kirsten ratsarcoma viral oncogene homolog (KRAS) mutations are mostly studied in mCRC, as clinical trials found that first-line chemotherapy with anti-epidermal growth factor receptor agent confers limited efficacy for mCRC. Treatment decisions for early-stage mCRC do not consider BRAF or KRAS mutations, given the dramatically poor prognosis conferred by these mutations in clinical trials. Thus, it is necessary to identify patients with mCRC harboring BRAF or KRAS mutations to formulate rational therapeutic strategies to improve prognosis and survival. BRAF and KRAS mutations occur in ∼10% and ∼44% of patients with mCRC, respectively. Although the survival rate of patients with mCRC has improved in recent years, the response and prognosis of patients with the aforementioned mutations are still poor. There is a substantial unmet need for prospective personalized therapies for patients with BRAF- or KRAS-mutant mCRC. In this review, we focus on BRAF and KRAS mutations to understand the mechanisms underlying resistance and improving the response rate, outcomes, and prognosis of patients with mCRC bearing these mutations and to discuss prospective personalized therapies for BRAF- and KRAS-mutant mCRC.

Phase 2 study of pembrolizumab in combination with azacitidine in subjects with metastatic colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3054-3054 ◽  
Author(s):  
James J. Lee ◽  
Weijing Sun ◽  
Nathan Bahary ◽  
James Ohr ◽  
John C. Rhee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Metastatic Colorectal Cancer ◽  
Tumor Progression ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Anti Tumor Activity ◽  
Study Therapy

3054 Background: Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) has relatively poor tumoral infiltration of CD8+ T cells and is resistant to pembrolizumab (Pembro) when compared to MSI-H mCRC. DNA hypomethylating agent induces epigenetic expression of multiple genes including cancer-testis antigens in CRC, which are recognized by cytotoxic CD8+ T cells in vitro and in vivo. This trial tested whether concurrent treatment with azacitidine (Aza) could enhance the anti-tumor activity of Pembro. Methods: This is a phase 2 trial to evaluate anti-tumor activity and safety of Pembro plus Aza in patients (pts) with previously treated mCRC without any further standard chemotherapy option. Pts received Pembro 200 mg IV on day 1 of each cycle Q3W and Aza 100 mg daily SQ injection on days 1-5 of each cycle Q3W. Primary endpoint was response rate (ORR) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Tumor tissues were collected for correlative studies. Results: Thirty-one pts were enrolled [median age, 61 years (range, 30-79); 17 M/14 F; ECOG PS 0/1 (58%/42%); 30 pts with MSS mCRC]. Pts received at least 2 lines of prior systemic chemotherapy for mCRC (median, 3; range, 1-5). Thirty pts received at least one dose of study therapy (median, 3 cycles; range, 1-8). Ten pts could not complete the first 3 cycles due to rapid symptomatic tumor progression. One pt with MSS mCRC achieved PR and 3 pts had SD as best response. The ORR was 3% (1/30; 95% CI, 0.1-17%). Seven pts with PD at the end of cycle 3 continued on study therapy, and 2 pts had stabilization of tumor progression. Median PFS was 2.1 months (95% CI, 1.8-2.8), and median OS was 6.2 months (95% CI, 3.5-8.7). While treatment-related adverse events (TRAEs) were reported in 63% of pts, most of the TRAEs were Gr 1/2 (96%). Frequent TRAEs possibly related to Aza were anemia (n = 5), constipation (n = 5), and leukopenia (n = 4); and possibly related to both Aza and Pembro were nausea (n = 5) and fatigue (n = 5). Gr 3 TRAEs included anemia (n = 1), ALT elevation (n = 1), and alkaline phosphatase elevation (n = 1). Conclusions: Pembro plus Aza is feasible with a tolerable safety profile but appears to have minimal anti-tumor effect for MSS mCRC. Clinical trial information: NCT02260440.

scholarly journals Exosome-Derived ADAM17 Promotes Liver Metastasis in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinbing Sun ◽  
Zhihua Lu ◽  
Wei Fu ◽  
Kuangyi Lu ◽  
Xiuwen Gu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Metastatic Niche ◽  
Colorectal Cancer Cells ◽  
Niche Formation ◽  
Underlying Mechanisms

Exosomes derived from cancer cells are deemed important drivers of pre-metastatic niche formation at distant organs, but the underlying mechanisms of their effects remain largely unknow. Although the role of ADAM17 in cancer cells has been well studied, the secreted ADAM17 effects transported via exosomes are less understood. Herein, we show that the level of exosome-derived ADAM17 is elevated in the serum of patients with metastatic colorectal cancer as well as in metastatic colorectal cancer cells. Furthermore, exosomal ADAM17 was shown to promote the migratory ability of colorectal cancer cells by cleaving the E-cadherin junction. Moreover, exosomal ADAM17 overexpression as well as RNA interference results highlighted its function as a tumor metastasis-promoting factor in colorectal cancer in vitro and in vivo. Taken together, our current work suggests that exosomal ADAM17 is involved in pre-metastatic niche formation and may be utilized as a blood-based biomarker of colorectal cancer metastasis.

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