Pazopanib Sensitivity in a Patient With Breast Cancer and FGFR1 Amplification.

Treatment options for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer and resistance to endocrine therapy remain limited. An interesting therapeutic target in these patients is fibroblast growth factor receptor 1 (FGFR1). FGFR1 is amplified in approximately 11% of patients with breast cancer, especially those with HR+ disease. This report presents a patient with metastatic HR+ HER2- breast cancer harboring an FGFR1 amplification who was resistant to endocrine therapy but responded to pazopanib, a multi-tyrosine kinase inhibitor with FGFR-inhibiting activity. Upon pazopanib treatment, the patient's brain lesions nearly disappeared, and she experienced therapeutic changes in the lung and an improvement of liver function. This case suggests that pazopanib may be a promising agent for the treatment of patients with breast cancer and FGFR1 amplifications.

Durable response to olaparib combined low-dose cisplatin in advanced hepatocellular carcinoma with FANCA mutation: A case report.

RATIONALE: To date, there is no actionable gene has been discovered in hepatocellular carcinoma (HCC). Tumor cells with DNA damage response and repair (DDR) gene loss-of-function mutation is sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors and platinum chemotherapy in ovarian, prostate and pancreatic cancers. There is a case report demonstrated the efficacy of PARP inhibitor for BRCA2 mutation that belongs to DDR gene in HCC, which suggested the potential role of PARP inhibitor for HCC with DDR gene mutation. PATIENT CONCERNS: We reported a 44-year-old woman with non-viral HCC who was refractory to multiple treatment including target therapy, immunotherapy, and chemotherapy. The tumor tissue was submitted to next-generation sequencing using the commercially available ACTOnco®+ (ACT Genomics, Taiwan) assay that interrogates 440 and 31 cancer-related genes and fusion genes, respectively. DIAGNOSIS: A truncating mutation FANCA p.Q1307fs was also observed. The tumor was microsatellite stable and had low tumor mutational burden of 4.5 muts/Mb. INTERVENTIONS AND OUTCOMES: Given FANCA belongs to DDR genes, the inactivation evoked the idea of using PARP inhibitor and cisplatin. Therefore, the patient started to use olaparib combined with low-dose cisplatin (30 mg/m2, every 4 weeks) therapy in December 2019. Significant reduction in the tumor marker level in 1 month (PIVKA-II from 17,395 to 411 ng/dL) and follow-up CT scan showed stable disease. Her tumor did not progress until December 2020 with a progression-free survival of 12 months. LESSONS: We report the first case of FANCA-mutated HCC that responded well to olaparib and low-dose cisplatin. This addressed the potential therapeutic role of DDR gene mutation in HCC and the possible synergistic effect of PARP inhibitor and cisplatin. These findings highlight areas where further investigation and effort are needed.

Valproic Acid Enhances Radiosensitization via DNA Double-strand Breaks for Boronophenylalanine-mediated Neutron Capture Therapy in Melanoma Cells.

BACKGROUND: Boron neutron capture therapy (BNCT) is a radiotherapeutic approach that can destroy cancer cells while sparing the surrounding normal cells. Currently, boronophenylalanine (BPA) is the most common boron delivery agent used in BNCT for treating recurrent cancers of the head and neck, gliomas, and melanomas. On the other hand, valproic acid (VPA) is one of the representative class I histone deacetylase inhibitors (HDACi), which is a promising sensitizer for cancer therapies. In this study, we aimed to verify whether VPA could induce an enhanced effect in destroying melanoma cells in concurrence with BNCT and to explore the underlying mechanism of VPA-BNCT action in killing these cells. MATERIALS AND METHODS: Murine melanoma B16-F10 cells were pre-treated with VPA and irradiated with neutron during BPA-BNCT. We explored the clonogenic assay and the expression of phosphorylated H2AX (γH2AX) for cell survival and DNA double-strand breaks (DSBs), respectively. We also examined the expression levels of DNA damage responses-associated proteins and performed a cell cycle analysis. RESULTS: Our data indicated that the combination treatment of VPA and BNCT could significantly inhibit the growth of melanoma cells. Furthermore, VPA-BNCT treatment could exacerbate and perturb DNA DSBs in B16-F10 cells. In addition, pre-treatment of VPA abolished the G2/M arrest checkpoint caused by BNCT. CONCLUSION: Our results demonstrate that VPA has the potential to serve as a radiosensitizer of BPA-mediated BNCT for melanoma. These findings could improve BNCT treatments for melanoma.

A genetic algorithm-based Boolean delay model of intracellular signal transduction in inflammation.

BACKGROUND: Signal transduction is the major mechanism through which cells transmit external stimuli to evoke intracellular biochemical responses. Understanding relationship between external stimuli and corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach to integrate experimental data and qualitative knowledge to identify the physiological consequences of environmental stimuli is needed. RESULTS: In present study, we employed a genetic algorithm-based Boolean model to represent NF-κB signaling pathway. We were able to capture feedback and crosstalk characteristics to enhance our understanding on the acute and chronic inflammatory response. Key network components affecting the response dynamics were identified. CONCLUSIONS: We designed an effective algorithm to elucidate the process of immune response using comprehensive knowledge about network structure and limited experimental data on dynamic responses. This approach can potentially be implemented for large-scale analysis on cellular processes and organism behaviors.

Computational modeling with forward and reverse engineering links signaling network and genomic regulatory responses: NF-kappaB signaling-induced gene expression responses in inflammation.

BACKGROUND: Signal transduction is the major mechanism through which cells transmit external stimuli to evoke intracellular biochemical responses. Diverse cellular stimuli create a wide variety of transcription factor activities through signal transduction pathways, resulting in different gene expression patterns. Understanding the relationship between external stimuli and the corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach is needed to integrate experimental data and theoretical hypotheses to identify the physiological consequences of environmental stimuli. RESULTS: We proposed a systematic approach that combines forward and reverse engineering to link the signal transduction cascade with the gene responses. To demonstrate the feasibility of our strategy, we focused on linking the NF-kappaB signaling pathway with the inflammatory gene regulatory responses because NF-kappaB has long been recognized to play a crucial role in inflammation. We first utilized forward engineering (Hybrid Functional Petri Nets) to construct the NF-kappaB signaling pathway and reverse engineering (Network Components Analysis) to build a gene regulatory network (GRN). Then, we demonstrated that the corresponding IKK profiles can be identified in the GRN and are consistent with the experimental validation of the IKK kinase assay. We found that the time-lapse gene expression of several cytokines and chemokines (TNF-alpha, IL-1, IL-6, CXCL1, CXCL2 and CCL3) is concordant with the NF-kappaB activity profile, and these genes have stronger influence strength within the GRN. Such regulatory effects have highlighted the crucial roles of NF-kappaB signaling in the acute inflammatory response and enhance our understanding of the systemic inflammatory response syndrome. CONCLUSION: We successfully identified and distinguished the corresponding signaling profiles among three microarray datasets with different stimuli strengths. In our model, the crucial genes of the NF-kappaB regulatory network were also identified to reflect the biological consequences of inflammation. With the experimental validation, our strategy is thus an effective solution to decipher cross-talk effects when attempting to integrate new kinetic parameters from other signal transduction pathways. The strategy also provides new insight for systems biology modeling to link any signal transduction pathways with the responses of downstream genes of interest.

Zebrafish as a model host for Candida albicans infection.

In this work, the zebrafish model organism was developed to obtain a minivertebrate host system for a Candida albicans infection study. We demonstrated that C. albicans can colonize and invade zebrafish at multiple anatomical sites and kill the fish in a dose-dependent manner. Inside zebrafish, we monitored the progression of the C. albicans yeast-to-hypha transition by tracking morphogenesis, and we monitored the corresponding gene expression of the pathogen and the early host immune response. We performed a zebrafish survival assay with different C. albicans strains (SC5314, ATCC 10231, an hgc1 mutant, and a cph1/efg1 double mutant) to determine each strain's virulence, and the results were similar to findings reported in previous mouse model studies. Finally, using zebrafish embryos, we monitored C. albicans infection and visualized the interaction between pathogen and host myelomonocytic cells in vivo. Taken together, the results of this work demonstrate that zebrafish can be a useful host model to study C. albicans pathogenesis, and they highlight the advantages of using the zebrafish model in future invasive fungal research.