Cancer Research and Treatment

Identifying Anti-Cancer Effects and Exploring the Mechanism of an MPS1/TTK Inhibitor in Gastric Cancer: Eunseo Kim, Woo Sun Kwon, Tae Soo Kim, Jihyun Hwang, Sunghwan Kim, Sun Young Rha; Received August 14, 2024 Accepted December 10, 2024 Published online December 12, 2024; DOI: https://doi.org/10.4143/crt.2024.780 [Accepted]

Abstract PDF: Purpose
To identify the anti-cancer effect and investigate the underlying mechanism of MPS1/TTK (Monopolar spindle 1; also known as threonine tyrosine kinase) inhibitor in gastric cancer (GC) cell lines.
Materials and Methods
This study used compound-9, a highly selective MPS1/TTK inhibitor, to evaluate its anticancer effects on GC cell lines. Cell viability assay was performed to determine sensitivity to the inhibitor. Cell cycle analysis and apoptosis assays were performed using Flow cytometry to evaluate the effects of the inhibitor. Protein-expression levels were analyzed through western blotting after the inhibitor treatment.
Results
The EBV and MSI-H groups tended to be sensitive to the inhibitor, while the GS-likely group tended to be moderate-to-resistant. In contrast, the CIN-likely group was extremely sensitive or resistant. Within the CIN group, TP53^WT cell lines were sensitive, whereas TP53^MUT cell lines were sensitive or resistant. Upon treatment of the inhibitor, the TP53^WT-sensitive cell line underwent cell death more rapidly compared to the TP53^MUT-sensitive cell line. In contrast, the TP53^MUT-sensitive cell experienced higher levels of aneuploidy or polyploidy and underwent cell death at later time point than the TP53^WT-sensitive cell line. The TP53^MUT-resistant line can tolerate aneuploidy or polyploidy and exhibits drug resistance.
Conclusion
Our study explores the potential of an MPS1/TTK inhibitor, compound-9, as a targeted therapy in gastric cancer cells and investigates its mechanism of action.

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Gastrointestinal cancer

Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13): Dong-Hoe Koo, Minkyu Jung, Yeul Hong Kim, Hei-Cheul Jeung, Dae Young Zang, Woo Kyun Bae, Hyunki Kim, Hyo Song Kim, Choong-kun Lee, Woo Sun Kwon, Hyun Cheol Chung, Sun Young Rha; Cancer Res Treat. 2024;56(4):1136-1145. Published online April 29, 2024; DOI: https://doi.org/10.4143/crt.2023.1324

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Purpose
Varlitinib is a pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC).
Materials and Methods
Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity.
Results
RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median progression-free survival and overall survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D.
Conclusion
A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

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Unraveling the future: Innovative design strategies and emerging challenges in HER2-targeted tyrosine kinase inhibitors for cancer therapy
Sixiang Zheng, Ruixian Chen, Lele Zhang, Lun Tan, Lintao Li, Fangyi Long, Ting Wang
European Journal of Medicinal Chemistry.2024; 276: 116702. CrossRef

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First-in-Human Phase 1 Study of a B Cell– and Monocyte-Based Immunotherapeutic Vaccine against HER2-Positive Advanced Gastric Cancer: Minkyu Jung, Jii Bum Lee, Hyo Song Kim, Woo Sun Kwon, Hyun Ok Kim, Sinyoung Kim, Myunghwan Park, Wuhyun Kim, Ki-Young Choi, Taegwon Oh, Chang-Yuil Kang, Hyun Cheol Chung, Sun Young Rha; Cancer Res Treat. 2024;56(1):208-218. Published online June 28, 2023; DOI: https://doi.org/10.4143/crt.2022.1328

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Purpose
BVAC-B is an autologous B cell– and monocyte-based immunotherapeutic vaccine that contains cells transfected with a recombinant human epidermal growth factor receptor 2 (HER2) gene and loaded with the natural killer T cell ligand alpha-galactosylceramide. Here, we report the first BVAC-B study in patients with HER2-positive advanced gastric cancer.
Materials and Methods
Patients with advanced gastric cancer refractory to standard treatment with HER2+ immunohistochemistry ≥ 1 were eligible for treatment. Patients were administered low (2.5×10⁷ cells/dose), medium (5.0×10⁷ cells/dose), or high dose (1.0×10⁸ cells/dose) of BVAC-B intravenously four times every 4 weeks. Primary endpoints included safety and maximum tolerated BVAC-B dose. Secondary endpoints included preliminary clinical efficacy and BVAC-B-induced immune responses.
Results
Eight patients were treated with BVAC-B at low (n=1), medium (n=1), and high doses (n=6). No dose-limiting toxicity was observed, while treatment-related adverse events (TRAEs) were observed in patients treated with medium and high doses. The most common TRAEs were grade 1 (n=2) and grade 2 (n=2) fever. Out of the six patients treated with high-dose BVAC-B, three had stable disease with no response. Interferon gamma, tumor necrosis factor-α, and interleukin-6 increased after BVAC-B treatment in all patients with medium and high dose, and HER2-specific antibody was detected in some patients.
Conclusion
BVAC-B monotherapy had a safe toxicity profile with limited clinical activity; however, it activated immune cells in heavily pretreated patients with HER2-positive gastric cancer. Earlier treatment with BVAC-B and combination therapy is warranted for evaluation of clinical efficacy.

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HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments
Magdalena K. Scheck, Ralf D. Hofheinz, Sylvie Lorenzen
Cancers.2024; 16(7): 1336. CrossRef

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