Discovery of indazole inhibitors for heat shock protein 90 as anti-cancer agents.

A series of indazole analogs, derived from the B,C-ring-truncated scaffold of deguelin, were designed to function as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antitumor agents against HER2-positive breast cancer. Among the synthesized compounds, compound 12d exhibited substantial inhibitory effects in trastuzumab-sensitive (BT474) and trastuzumab-resistant (JIMT-1) breast cancer cells, with IC50 values of 6.86 and 4.42 µM, respectively. Notably, compound 12d exhibited no cytotoxicity in normal cells. Compound 12d markedly downregulated the expression of the major HSP90 client proteins in both cell types, attributing its cytotoxicity to the destabilization and inactivation of HSP90 client proteins. Molecular docking studies using the homology model of an HSP90 homodimer demonstrated that inhibitor 12d fit nicely into the C-terminal domain, boasting a higher electrostatic complementary score than ATP. In vivo pharmacokinetic study indicated the high oral bioavailability of compound 12 d at F = 66.9 %, while toxicological studies indicated its negligible impact on hERG channels and CYP isozymes. Genotoxicity tests further confirmed its safety profile. The findings collectively position compound 12d as a promising candidate for further development as an antitumor agent against HER2-positive breast cancer.

Intralesional Methotrexate Injection for the Treatment of Epithelial Crateriform Tumor.

BACKGROUND: Intralesional methotrexate injection (IL-MTX) is an appropriate strategy for treating epithelial crateriform tumors (ECTs) when surgical excision can result in functional or cosmetic defects; however, not all ECTs are responsive to this treatment. OBJECTIVE: This study aimed to evaluate the effectiveness of IL-MTX for ECTs and to determine the differences in clinical response according to the pathological features. METHODS: The medical records of patients treated with IL-MTX for their ECTs were retrospectively reviewed. Effectiveness was evaluated in terms of size reduction and flattening. RESULTS: Twenty-five cases of ECTs with biopsy were included in this study. Eight cases of keratoacanthoma (KA) and 15 cases of squamous cell carcinoma (SCC) were identified, but 2 cases could not be clearly distinguished. Seventeen patients (68%) showed a response after injection, and response rate in KA and SCC were 75% (6/8) and 60% (9/15), respectively. Nine patients showed complete resolution with IL-MTX. Patients received 3 injections, and regression was observed in 7.56 weeks after the first injection. According to histopathological results, patients with KA and SCC received 2 and 3.33 injections, respectively, and complete resolution was observed after 7 and 7.67 weeks, respectively. CONCLUSION: IL-MTX is safe and effective, and could be considered as a useful non-surgical treatment option for ECTs. Both KA and crateriform SCC showed good response; However, KA showed a better response.

Efficacy of Bleomycin Intralesional Injection for Treating Digital Mucous Cysts: A Comparative Study of Corticosteroid Intralesional Injection and Surgical Excision.

BACKGROUND: Sclerotherapy has shown superior efficacy among the nonsurgical options for managing digital mucous cysts (DMC). Notably, previous research has indicated that bleomycin offers a more favorable side-effect profile and similar efficacy to conventional sclerosing agents. OBJECTIVE: This study aimed to assess the efficacy and safety of bleomycin intralesional injection (ILI) for treating DMC through a comparative analysis of corticosteroid ILI and surgical excision. METHODS: We retrospectively reviewed electronic medical records and clinical photographs. Telephone interviews were conducted to further investigate long-term treatment efficacy, safety, and overall treatment satisfaction. RESULTS: Ten patients underwent surgical excision, and 13 and 15 patients received bleomycin and corticosteroid ILI, respectively. Both surgical excision and bleomycin ILI demonstrated superior treatment efficacy compared to corticosteroid ILI. No statistically significant difference in the treatment effectiveness between surgical excision and bleomycin ILI was observed. No significant adverse effects were observed. In the survey, the level of satisfaction was the highest for bleomycin ILI, followed by surgical excision and corticosteroid ILI. CONCLUSION: This study revealed that bleomycin ILI exhibits a treatment efficacy higher than that of corticosteroid ILI and slightly lower than that of surgical excision, without any side effects. Therefore, bleomycin ILI is a safe and effective therapeutic option for the treatment of DMC.

The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer.

Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients. Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval for clinical use, primarily due to issues such as induction of the heat shock response (HSR), off-target effects, and unfavorable toxicity profiles. We sought to examine the effects of HVH-2930, a novel C-terminal HSP90 inhibitor, in overcoming trastuzumab resistance. Methods: The effect of HVH-2930 on trastuzumab-sensitive and -resistant cell lines in vitro was evaluated in terms of cell viability, expression of HSP90 client proteins, and impact on cancer stem cells. An in vivo model with trastuzumab-resistant JIMT-1 cells was used to examine the efficacy and toxicity of HVH-2930. Results: HVH-2930 was rationally designed to fit into the ATP-binding pocket interface cavity of the hHSP90 homodimer in the C-terminal domain of HSP90, stabilizing its open conformation and hindering ATP binding. HVH-2930 induces apoptosis without inducing the HSR but by specifically suppressing the HER2 signaling pathway. This occurs with the downregulation of HER2/p95HER2 and disruption of HER2 family member heterodimerization. Attenuation of cancer stem cell (CSC)-like properties was associated with the downregulation of stemness factors such as ALDH1, CD44, Nanog and Oct4. Furthermore, HVH-2930 administration inhibited angiogenesis and tumor growth in trastuzumab-resistant xenograft mice. A synergistic effect was observed when combining HVH-2930 and paclitaxel in JIMT-1 xenografts. Conclusion: Our findings highlight the potent efficacy of HVH-2930 in overcoming trastuzumab resistance in HER2-positive breast cancer. Further investigation is warranted to fully establish its therapeutic potential.

Gastro-BaseNet: A Specialized Pre-Trained Model for Enhanced Gastroscopic Data Classification and Diagnosis of Gastric Cancer and Ulcer.

Most of the development of gastric disease prediction models has utilized pre-trained models from natural data, such as ImageNet, which lack knowledge of medical domains. This study proposes Gastro-BaseNet, a classification model trained using gastroscopic image data for abnormal gastric lesions. To prove performance, we compared transfer-learning based on two pre-trained models (Gastro-BaseNet and ImageNet) and two training methods (freeze and fine-tune modes). The effectiveness was verified in terms of classification at the image-level and patient-level, as well as the localization performance of lesions. The development of Gastro-BaseNet had demonstrated superior transfer learning performance compared to random weight settings in ImageNet. When developing a model for predicting the diagnosis of gastric cancer and gastric ulcers, the transfer-learned model based on Gastro-BaseNet outperformed that based on ImageNet. Furthermore, the model's performance was highest when fine-tuning the entire layer in the fine-tune mode. Additionally, the trained model was based on Gastro-BaseNet, which showed higher localization performance, which confirmed its accurate detection and classification of lesions in specific locations. This study represents a notable advancement in the development of image analysis models within the medical field, resulting in improved diagnostic predictive accuracy and aiding in making more informed clinical decisions in gastrointestinal endoscopy.