Biology subjects

Holmen, S.

Publications and source records attributed to Holmen, S..

3 recordsLinked to original sources

bioRxiv2026

Ultrasound-Triggered Chemotherapy Extends Survival in a Genetically Engineered Glioblastoma Model

Glioblastoma (GBM) remains one of the most lethal primary brain tumors, in part because the blood-brain barrier (BBB), restricts delivery of most systemically administered chemotherapeutics. Although focused ultrasound (fUS) can transiently increase BBB permeability, therapeutic efficacy remains limited by reliance on systemic drug exposure and heterogeneous intratumoral distribution. Here, we report a pressure-gated ultrasound-triggered drug delivery strategy that enables localized intravascular release of chemotherapy at the site of sonication. Freebase doxorubicin and afatinib were encapsulated within ultrasound-sensitive mPEG-PDLLA/PFOB microdroplets and administered systemically to N-TVA::Ink4a/Arflox/lox;Ptenlox/lox mice bearing genetically engineered glioblastomas. Animals received repeated transcranial focused ultrasound over a 30-day treatment period. Ultrasound-triggered release of the dual-drug formulation significantly extended survival compared with untreated controls, with median survival increased by over two weeks - approximately a 30% improvement. Furthermore, this survival improvement was reflected in histological analysis, showing decreased tumor burden and severity. These improvements were not found in any control groups, demonstrating that spatially and temporally controlled intravascular drug release can substantially improve therapeutic efficacy in an aggressive immunocompetent glioblastoma model. These findings support pressure-gated ultrasound-triggered chemotherapy as a promising activation-based strategy for overcoming BBB-associated delivery limitations and improving outcomes in malignant brain tumors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/735435v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1518d39org.highwire.dtl.DTLVardef@10ed141org.highwire.dtl.DTLVardef@1cc04fforg.highwire.dtl.DTLVardef@15c0973_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPressure-gated focused ultrasound enables localized release of doxorubicin and afatinib in glioblastoma. C_LIO_LIUltrasound-triggered chemotherapy significantly extends survival in a genetically engineered immunocompetent GBM model. C_LIO_LILocal activation outperforms systemic administration of identical drug combinations. C_LIO_LIThis strategy shifts focused ultrasound therapy from general BBB opening to spatially controlled drug activation. C_LI

cancer biology↗

bioRxiv2025

The carnosinase dipeptidase CNDP1 is a novel metabolic vulnerability in brain metastasis

Brain metastatic cells undergo metabolic adaptations, such as increased reliance on oxidative phosphorylation. Integrating proteomic and transcriptomic profiling of patient samples revealed a consistent upregulation of the carnosine dipeptidase-1 (CNDP1) in brain versus extracranial metastases. Carnosine is an abundant metabolite in brain and muscle, known to exert anti-proliferative effects on cancer cells. Here, we demonstrate that CNDP1 inhibition suppresses both the establishment and maintenance of melanoma brain metastasis while its ectopic expression is sufficient to confer brain metastatic potential to poorly metastatic cells. CNDP1 suppression results in activation of the Integrated Stress Response via Heme-Regulated Inhibitor Kinase and reprogrammed translation towards preferential expression of mitochondrial and survival transcripts. We further show that CNDP1 upregulation supports mitochondrial activity by limiting the levels of its substrate carnosine, a copper ionophore, thus protecting metastatic cells from carnosine-induced copper toxicity. Our studies reveal a novel metabolic adaptation during brain metastasis, which can be leveraged for therapeutic purposes.

cancer biology↗

bioRxiv2023

Human Rhinoviruses: a novel class of oncolytic virus

While continuing to develop new and improved OVs, researchers have been vigilant in optimizing their ability to safely infect, replicate, and induce an immune response within tumors. There are currently two crucial limitations in OV development, however: modification of viruses often negatively impact their ability to infect, and induction of strong immune responses also promotes rapid viral clearance. In this study, we investigate wild-type HRVs as a novel class of OV. Multiple HRV serotypes were propagated in human melanoma cell lines to produce highly oncolytic populations of virus. A large panel of cancer types were infected, with cytotoxicity evaluated using flow cytometry and real time live imaging. Pro-inflammatory signaling was assessed by cytokine multiplexing. Tumor responses to HRV were assessed in human xenograft and in syngeneic, immune-competent mouse tumor models. We find that HRVs are capable of infecting and killing a wide variety of human cancer cell lines in vitro and in vivo, inducing pro-inflammatory responses and, ultimately, tumor regression. We propose that the natural safety profile of these viruses, coupled with their anti-tumor efficacy and multivalent potential seen in our preclinical model systems, make HRVs ideal candidates for development as oncolytic viruses for clinical testing. Simple SummaryThe idea of utilizing viruses to combat cancer has been around for over a century, yet in practice has seen relatively modest therapeutic success following decades of strategic design to improve safety, efficacy, and tumor selectivity. Engagement of an immune response is critical to have lasting tumor regression upon treatment, but many patients are unable to mount a sufficient response to standard-of-care immunotherapy alone. Oncolytic viruses (OVs) have been shown to synergize with such therapies to accomplish this goal to varying degrees. The purpose of this study is to investigate human rhinoviruses (HRVs) to establish their efficacy as a novel class of anti-cancer agents. We aim to use HRVs to promote longer lasting and more effective immune responses to tumors by fostering viral persistence and immune evasion, in addition to developing multivalent treatment strategies that enhance tumor regression by preventing tumor escape from viral infection.

immunology↗