Biology subjects

Nagalo, B. M.

Publications and source records attributed to Nagalo, B. M..

2 recordsLinked to original sources

bioRxiv2020

Transcriptional Landscape of Hepatocellular Carcinoma Reveals that Patient Ethnic-Origin Influences Patterns of Expression

The global incidence of hepatocellular carcinoma (HCC) has increased threefold in the last 30 years. In the United States, individuals with ancestry from Asia, Africa and Latin America have a significantly higher risk of developing HCC. However, the molecular mechanisms by which HCC disparities occur remain mostly understudied. Herein, we employed advanced bioinformatics analysis tools to identify genomic drivers that could explain the differences seen among HCC patients of distinct ethnicities (geographic origins). Data from TCGA and open-source software tools HiSTAT, StringTie, and Ballgown were used to map next-generation sequencing (NGS) reads from DNA and RNA, assemble transcripts, and quantify gene abundance. Differential genes/transcripts were mapped to known biomarkers and targets of systemic HCC therapeutics. Four overlapping transcripts were identified between each ethnicity group: FCN2, FCN3, COLEC10, and GDF2. However, we also found that multiple genes are expressed in an ethnicity-specific manner. Our models also revealed that both current and emerging biomarkers fail to capture heterogeneity between patients of different ethnicities. Finally, we have determined that first-line treatment, such as Sorafenib, may be better suited for Asian patients, while Lenvatinib may exhibit better efficacy for Caucasian patients. In conclusion, we have outlined that the pathways involved in early hepatocarcinogenesis may occur in an ethnicity-specific manner and that these distinct phenotypes should be taken into account for biomarker and therapeutic development.

cancer biology↗

bioRxiv2020

Synergistic Combination of Cytotoxic Chemotherapy and Cyclin Dependent Kinase 4/6 Inhibitors in Biliary Tract Cancers

Biliary tract cancers (BTCs) are uncommon but highly lethal gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care (SOC) systemic therapy, but has a modest impact on survival and harbor toxicities including myelosuppression, nephropathy, neuropathy and ototoxicity. While BTCs are characterized by aberrations activating the cyclinD1-CDK4/6-CDKN2A-RB pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident pre-clinical efficacy and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the anti-tumor efficacy of CDK4/6 inhibitors by combination with chemotherapy-regimens but their mechanism of action remains elusive. Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy due to autophagy induced resistance. Notably, triplettherapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated RRM1 reduction, resulting in sensitization to gemcitabine. Conclusions: As such, these data provide robust pre-clinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors, and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

cancer biology↗