Biology subjects

Kosiorek, H. E.

Publications and source records attributed to Kosiorek, H. E..

3 recordsLinked to original sources

bioRxiv2022

Type 1 interferon remodels normal and neoplastic hematopoiesis in human

Inflammation perturbs evolutionary dynamics of hematopoietic stem cell (HSC) clones in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasm (MPN) at baseline and following interferon- (IFN) treatment, the only MPN therapy to deplete clonal stem cells. We focused on essential thrombocythemia, an informative model of early-phase neoplastic hematopoiesis. We integrated somatic genotyping, transcriptomes, immunophenotyping, and chromatin accessibility across single cells. IFN simultaneously activated HSCs into two polarized states, a lymphoid progenitor expansion associated with an anti-inflammatory state and an IFN-specific inflammatory granulocytic progenitor (IGP) state derived directly from HSCs. The augmented lymphoid differentiation balanced the typical MPN-induced myeloid bias, associated with normalized blood counts. Clonal fitness upon IFN exposure was due to resistance of clonal stem cells to differentiate into IGPs. These results support a paradigm wherein inflammation perturbs clonal dynamics by HSC induction into the precipitous IGP differentiation program. One-Sentence SummaryInflammation accelerates clonal evolution by driving stem cell differentiation into an alternate interferon--induced progenitor state.

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↗

bioRxiv2018

Detection of residual disease after neoadjuvant therapy in breast cancer using personalized circulating tumor DNA analysis

Accurate detection of minimal residual disease (MRD) can guide individualized management of early stage cancer patients, but current diagnostic approaches lack adequate sensitivity. Circulating tumor DNA (ctDNA) analysis has shown promise for recurrence monitoring but MRD detection immediately after neoadjuvant therapy or surgical resection has remained challenging. We have developed TARgeted DIgital Sequencing (TARDIS) to simultaneously analyze multiple patient-specific cancer mutations in plasma and improve sensitivity for minute quantities of residual tumor DNA. In 77 reference samples at 0.03%-1% mutant allele fraction (AF), we observed 93.5% sensitivity. Using TARDIS, we analyzed ctDNA in 34 samples from 13 patients with stage II/III breast cancer treated with neoadjuvant therapy. Prior to treatment, we detected ctDNA in 12/12 patients at 0.002%-1.04% AF (0.040% median). After completion of neoadjuvant therapy, we detected ctDNA in 7/8 patients with residual disease observed at surgery and in 1/5 patients with pathological complete response (odds ratio, 18.5, Fishers exact p=0.032). These results demonstrate high accuracy for a personalized blood test to detect residual disease after neoadjuvant therapy. With additional clinical validation, TARDIS could identify patients with molecular complete response after neoadjuvant therapy who may be candidates for nonoperative management.\n\nOne Sentence SummaryA personalized ctDNA test achieves high accuracy for residual disease.

genomics↗