Biology subjects

Farkkila, A.

Publications and source records attributed to Farkkila, A..

3 recordsLinked to original sources

bioRxiv2021

Optimized detection of somatic allelic imbalances specific for homologous recombination deficiency improves the prediction of clinical outcomes in ovarian cancer

Homologous recombination DNA-repair deficiency (HRD) is a common driver of genomic instability and confers a therapeutic vulnerability in cancer. The accurate detection of somatic allelic imbalances (AIs) has been limited by methods focused on BRCA1/2 mutations and using mixtures of cancer types. Using pan-cancer data, we revealed distinct patterns of AIs in high-grade serous ovarian cancer (HGSC). We used machine learning and statistics to generate improved criteria to identify HRD in HGSC (ovaHRDscar). ovaHRDscar significantly predicted clinical outcomes in three independent patient cohorts with higher precision than previous methods. Characterization of 98 spatiotemporally distinct metastatic samples revealed low intra-patient variation and indicated the primary tumor as the preferred site for clinical sampling in HGSC. Further, our approach improved the prediction of clinical outcomes in triple-negative breast cancer (tnbcHRDscar), validated in two independent patient cohorts. In conclusion, our tumor-specific, systematic approach has the potential to improve patient selection for HR-targeted therapies.

cancer biology↗

bioRxiv2020

Agile workflow for interactive analysis of mass cytometry data

MotivationSingle-cell proteomics technologies, such as mass cytometry, have enabled characterization of cell-to-cell variation and cell populations at a single cell resolution. These large amounts of data, however, require dedicated, interactive tools for translating the data into knowledge. ResultsWe present a comprehensive, interactive method called Cyto to streamline analysis of large-scale cytometry data. Cyto is a workflow-based open-source solution that automatizes the use of of state-of-the-art single-cell analysis methods with interactive visualization. We show the utility of Cyto by applying it to mass cytometry data from peripheral blood and high-grade serous ovarian cancer (HGSOC) samples. Our results show that Cyto is able to reliably capture the immune cell sub-populations from peripheral blood as well as cellular compositions of unique immune- and cancer cell subpopulations in HGSOC tumor and ascites samples. AvailabilityThe method is available as a Docker container at https://hub.docker.com/r/anduril/cyto and the user guide and source code are available at https://bitbucket.org/anduril-dev/cyto Contactsampsa.hautaniemi@helsinki.fi Supplementary informationSupplementary material is available and FCS files are hosted at flowrepository.org/id/FR-FCM-Z2LW

bioinformatics↗

bioRxiv2020

Polymerase Theta Inhibition Kills Homologous Recombination Deficient Tumors

PARP inhibitors (PARPi) have become a new line of therapy for Homologous Recombination (HR)-deficient cancers. However, resistance to PARPi has emerged as a major clinical problem. DNA polymerase theta (POL{theta}) is synthetic lethal with HR and a druggable target in HR-deficient cancers. Here, we identified the antibiotic Novobiocin (NVB) as a specific POL{theta} inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POL{theta} ATPase domain, inhibits its ATPase activity, and phenocopies POL{theta} depletion. BRCA-deficient tumor cells and those with acquired PARPi resistance are sensitive to NVB in vitro and in vivo. Increased POL{theta} expression levels predict NVB sensitivity. The mechanism of NVB-mediated cell death in PARPi resistant cells is the accumulation of toxic RAD51 foci, which also provides a pharmacodynamic biomarker for NVB response. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. One Sentence SummaryWe identified Novobiocin as a specific POL{theta} inhibitor that selectively kills naive and PARPi resistance HR-deficient tumors in vitro and in vivo.

cancer biology↗