Current Cancer Drug Targets - Volume 25, Issue 1, 2025

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally. Despite advancements in immunotherapy, the prognosis for patients with HCC continues to be poor. As oxidative stress plays a significant role in the onset and progression of various diseases, including metabolism-related HCC, comprehending its mechanism in HCC is critical for effective diagnosis and treatment.

This study utilized the TCGA dataset and a collection of oxidative stress genes to identify the expression of oxidative stress-related genes in HCC and their association with overall survival using diverse bioinformatics methods. A novel prognostic risk model was developed, and the TCGA cohort was divided into high-risk and low-risk groups based on each tumor sample's risk score. Levels of immune cell infiltration and the expression of immune checkpoint-related genes in different risk subgroups were analyzed to investigate the potential link between tumor immunity and oxidative stress-related features. The expression of model genes in actual samples was validated through immunohistochemistry, and their mRNA and protein expression levels were measured in cell cultures.

Four oxidative stress-related genes (EZH2, ANKZF1, G6PD, and HMOX1) were identified and utilized to create a predictive risk model for HCC patient overall survival, which was subsequently validated in an independent cohort. A correlation was found between the expression of these prognostic genes and the infiltration of tumor immune cells. Elevated expression of EZH2, ANKZF1, G6PD, and HMOX1 was observed in both HCC tissues and cell lines.

The combined assessment of EZH2, ANKZF1, G6PD, and HMOX1 gene expression can serve as an oxidative stress risk model for assessing HCC prognosis. Furthermore, there is a correlation between the expression of these risk model genes and tumor immunity.

Emerging evidence identified sex as a variable regulating immune system functions and modulating response to immunotherapy in cancer patients.

This retrospective study analysed sex-related differences in immunotherapy outcomes in a real-world population of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs).

We retrospectively investigated clinical data of 99 patients with advanced NSCLC and treated with single-agent nivolumab and pembrolizumab at Medical Oncology Unit, Careggi University Hospital, Florence (Italy), between April 2014 to August 2019. Main clinical characteristics and clinical outcomes were analysed.

Our study showed that the efficacy of ICI treatment differed according to gender. A trend for better median progression-free survival (mPFS) was reported in males (mPFS 5.0 months, 95% Confidence Interval [CI] 4.0-11.0) than females (mPFS 4.5 months, 95% CI 2.0-9.0) (p=0.133), while no significant difference for overall survival (OS) between the two sex groups was observed (p=0.622). In the nivolumab cohort, we showed a statistically significant difference for a longer PFS in men compared to women (log-rank p=0.054), HR for PFS in females versus males was 1.81 (95% CI 0.97-3.37, p=0.062). Disease control rate (DCR) was achieved in 55.7% and 45.7% of men and women, respectively, while disease progression was registered in 44.3% of males and 54.3% of females (p=0.386).

Gender is a variable that should be taken into account in the choice of immunotherapy. Future prospective randomized trials testing tailored sex-based immunotherapy strategies are required to validate our findings before integrating into clinical practice.

DOCK1 has been reported to be involved in tumor progression and resistance.1-(2-(30-(trifluoromethyl)-[1,10-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl2(1H)- pyridone (TBOPP) is a selective DOCK1 inhibitor; however, the role and molecular mechanisms of DOCK1 and its inhibition in breast cancer (BC) resistance remain poorly understood. Objective: This study aims toinvestigate the underlying mechanisms of DOCK1 in BC resistance.

DOCK1 or Twist siRNA and Twist plasmid were used to explore the function of DOCK1 in vitro experiments. A mouse xenograft model was used for in vivo experiments.

In the present study, we demonstrated that DOCK1 siRNA promoted cisplatin sensitivity in BC cells. Moreover, TBOPP also enhances the therapeutic effect of cisplatin both in vitro and in vivo. Mechanistically, DOCK1 siRNA inhibited EMT. Twist 1 is one of the EMT-inducing transcription factors and is known to induce EMT. To further reveal the effect of DOCK in BC cells, we co-transfected with DOCK1 and Twist1 siRNA to BC cells and found that co-transfection with DOCK1 and Twist siRNA could not further enhance the cisplatin sensitivity of BC cells. Moreover, DOCK1 siRNA failed to reverse the effect of Twist 1 up-regulation.

Taken together, these results demonstrate that DOCK1 may function as a potential therapeutic target in BC and that combining cisplatin with TBOPP may provide a promising therapeutic strategy for cisplatin-resistant BC patients.

Thyroid metastasis arising from primary breast cancer is a rare phenomenon, with only a handful of cases documented in both national and international literature. The management approach and prognosis of this occurrence have sparked debates and uncertainties.

Herein, we report the case of a 55-year-old woman with breast cancer. She previously underwent extensive excision of the breast lesion with adjuvant chemotherapy and endocrine therapy. After 9 years, she presented with neck discomfort and examination suggested right thyroid metastasis and lymph node metastasis in the neck. Imaging showed pulmonary and bone metastases. Furthermore, the patient received endocrine therapy. After 7 months of follow-up, the patient survived without any new distant metastases. Thyroid metastases originating from breast cancer often unfold with a subtle, intricate nature, making early detection challenging. They tend to emerge inconspicuously, intertwining with widespread systemic metastases, hinting at a less favorable prognosis.

Given the unusual clinical indicators, identifying heterochronic thyroid metastases in patients with tumors poses a distinct challenge, requiring clinicians to navigate the follow-up process with heightened sensitivity. The key lies in timely detection and early intervention, factors that can significantly enhance the overall quality of life for patients.

Trastuzumab deruxtecan (T-DXd) has shown promising outcomes as a second or subsequent-line treatment for human epidermal growth factor-2 (HER2)-positive advanced gastric or gastroesophageal junction cancer.

We reported a 49-year-old male patient with stage IV HER2-amplified gastric cancer. Despite extensive pretreatments, including first-line trastuzumab plus FOLFOX, second-line trastuzumab plus FOLFOX, followed by traditional Chinese medicine, third-line nivolumab plus trastuzumab, fourth-line pyrotinib plus paclitaxel and five hepatic arterial chemoembolization procedures, and fifth-line pembrolizumab plus nab-paclitaxel and thoracic radiotherapy, the patient experienced disease progression. In April 2021, T-DXd was initiated as the sixth-line therapy in combination with radiotherapy for brain metastases. After one treatment cycle, the patient achieved a partial response. T-DXd was discontinued in August 2022 due to recurrent anemia attributed to cardiac stenosis-related bleeding.

The condition of the patient remained stable until May 2023, indicating a progression-free survival of over 24 months. This case suggests that T-DXd may offer long-term clinical benefits in patients with HER2-amplified advanced gastric cancer with brain metastases.