Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

Ricci, Angela Dalia; Rizzo, Alessandro; Llimpe, F. L. Rojas; Fabio, Francesca Di; Biase, Dario de; Rihawi, Karim

doi:10.3390/cancers13071664

Cited by 68 publications

(52 citation statements)

References 47 publications

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“…Members of the NF-κB signaling pathways have not been explored so far for molecular targeted therapy in GC. At present, molecular therapy of GC is restricted to targeting the human epidermal growth factor receptor 2 (HER2) by trastuzumab [ 179 , 180 ].…”

Section: Therapeutic Targeting Of Nf-κb In Gastric Cancermentioning

confidence: 99%

NF-κB in Gastric Cancer Development and Therapy

et al. 2021

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Gastric cancer is considered one of the most common causes of cancer-related death worldwide and, thus, a major health problem. A variety of environmental factors including physical and chemical noxae, as well as pathogen infections could contribute to the development of gastric cancer. The transcription factor nuclear factor kappa B (NF-κB) and its dysregulation has a major impact on gastric carcinogenesis due to the regulation of cytokines/chemokines, growth factors, anti-apoptotic factors, cell cycle regulators, and metalloproteinases. Changes in NF-κB signaling are directed by genetic alterations in the transcription factors themselves, but also in NF-κB signaling molecules. NF-κB actively participates in the crosstalk of the cells in the tumor micromilieu with divergent effects on the heterogeneous tumor cell and immune cell populations. Thus, the benefits/consequences of therapeutic targeting of NF-κB have to be carefully evaluated. In this review, we address recent knowledge about the mechanisms and consequences of NF-κB dysregulation in gastric cancer development and therapy.

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Section: Therapeutic Targeting Of Nf-κb In Gastric Cancermentioning

confidence: 99%

NF-κB in Gastric Cancer Development and Therapy

et al. 2021

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“…ErbB immunization strategies are an attractive option because of ease of administration, low toxicity, affordability, limited clinic visits, and potential clinical effectiveness. Anti-tumor antibodies also enhance the efficacy of conventional chemotherapies, radiation therapy, and checkpoint inhibitors [15] , [16] , [17] , [18] . Finally, relatively few effective immunotherapeutic options exist for the treatment of highly metastatic malignancies in the dog [19] .…”

Section: Introductionmentioning

confidence: 99%

Vaccine-induced ErbB (EGFR/HER2)-specific immunity in spontaneous canine cancer

Doyle

Gee

Masters

et al. 2021

Translational Oncology

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Highlights Spontaneous dog cancers closely resemble human cancer. Dogs with EGFR associated tumors were immunized with an EGFR/HER2 peptide vaccine. EGFR peptide vaccinated dogs developed anti-EGFR/HER2 antibodies. Vaccinated dogs have anti-EGFR antibody and T cells infiltrating tumors. Vaccinated dogs with osteosarcoma had tumor regression and increased survival.

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“…The amplification and overexpression of HER2 were first discovered in breast cancer and are well-known to be significantly correlated with a worse prognosis [ 18 ]. HER2 targeted therapy has recently been introduced for the treatment of advanced gastric cancer [ 19 ]. As such, determination of the HER2 status is critical to select patients who will benefit from this treatment.…”

Section: Introductionmentioning

confidence: 99%

Disruption of Her2-Induced PD-L1 Inhibits Tumor Cell Immune Evasion in Patient-Derived Gastric Cancer Organoids

Chakrabarti

Koh

Steele

et al. 2021

Cancers

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(1) Background: The expression of programmed death-ligand 1 (PD-L1), which interacts with programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTLs), enables tumors to escape immunosurveillance. The PD-1/PD-L1 interaction results in the inhibition of CTL proliferation, and effector function, thus promoting tumor cell evasion from immunosurveillance and cancer persistence. Despite 40% of gastric cancer patients exhibiting PD-L1 expression, only a small subset of patients responds to immunotherapy. Human epidermal growth factor receptor2 (HER2) is one of the critical regulators of several solid tumors, including metastatic gastric cancer. Although half of PD-L1-positive gastric tumors co-express HER2, crosstalk between HER2 and PD-1/PD-L1 in gastric cancer remains undetermined. (2) Methods: Human gastric cancer organoids (huTGOs) were generated from biopsied or resected tissues and co-cultured with CTLs and myeloid-derived suppressor cells (MDSCs). Digital Spatial Profiling (DSP) was performed on FFPE tissue microarrays of numerous gastric cancer patients to examine the protein expression of immune markers. (3) Results: Knockdown of HER2 in PD-L1/HER2-positive huTGOs led to a concomitant decrease in PD-L1 expression. Similarly, in huTGOs/immune cell co-cultures, PD-L1 expression decreased in huTGOs and was correlated with an increase in CTL proliferation which enhanced huTGO death. Treatment with Nivolumab exhibited similar effects. However, a combinatorial treatment with Mubritinib and Nivolumab was unable to inhibit HER2 expression in co-cultures containing MDSCs. (4) Conclusions: Our study suggested that co-expression of HER2 and PD-L1 may contribute to tumor cell immune evasion. In addition, autologous organoid/immune cell co-cultures can be exploited to effectively screen responses to a combination of anti-HER2 and immunotherapy to tailor treatment for gastric cancer patients.

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Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

Cited by 68 publications

References 47 publications

NF-κB in Gastric Cancer Development and Therapy

NF-κB in Gastric Cancer Development and Therapy

Vaccine-induced ErbB (EGFR/HER2)-specific immunity in spontaneous canine cancer

Disruption of Her2-Induced PD-L1 Inhibits Tumor Cell Immune Evasion in Patient-Derived Gastric Cancer Organoids

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