Selected Grantee Publications
Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
Evolution of the Clinical-Stage Hyperactive TcBuster Transposase as a Platform for Robust Non-Viral Production of Adoptive Cellular Therapies
Skeate et al., Molecular Therapy. 2024.
https://pubmed.ncbi.nlm.nih.gov/38627969/
In this study, the authors report the development of a novel hyperactive TcBuster (TcB-M) transposase engineered through structure-guided and in vitro evolution approaches that achieve high-efficiency integration of large, multicistronic CAR-expression cassettes in primary human cells. This proof-of-principle TcB-M engineering of CAR-NK and CAR-T cells shows low integrated vector copy number, a safe insertion site profile, robust in vitro function, and improved survival in a Burkitt lymphoma xenograft model in vivo. Their work suggests that TcB-M is a versatile, safe, efficient, and open-source option for the rapid manufacture and preclinical testing of primary human immune cell therapies through delivery of multicistronic large cargo via transposition. Supported by ORIP (F30OD030021), NCI, NHLBI, and NIAID.
AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys
Liang et al., Human Gene Therapy. 2024.
https://pubmed.ncbi.nlm.nih.gov/38767512/
Genome editing in somatic cells and tissues has the potential to provide long-term expression of therapeutic proteins to treat a variety of genetic lung disorders. However, delivering genome-editing machinery to disease-relevant cell types in the lungs of primates has remained a challenge. Investigators of this article are participating in the NIH Somatic Cell Genome Editing Consortium. Herein, they demonstrate that intratracheal administration of a dual adeno-associated virus type 5 vector encoding CRISPR/Cas9 can mediate genome editing in rhesus (male and female) airways. Up to 8% editing was observed in lung lobes, including a housekeeping gene, GAPDH, and a disease-related gene, angiotensin-converting enzyme 2. Using single-nucleus RNA-sequencing, investigators systematically characterized cell types transduced by the vector. Supported by ORIP (P51OD01110, U42OD027094, S10OD028713), NCATS, NCI, and NHLBI.
CD8+ T Cell Targeting of Tumor Antigens Presented by HLA-E
Iyer, Science Advances. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11086602/
Researchers have hypothesized that human leukocyte antigen-E (HLA-E)–positive cancer cells could be targeted by HLA-E–restricted CD8+ T cells. In this study, the authors assessed whether major histocompatibility complex E (MHC-E) expression by cancer cells can be targeted for MHC-E–restricted T cell control. Using male rhesus macaques, they found that a cytomegalovirus can be used as a vector to generate specific immune cells that can target cancer cells. The authors conclude that targeting HLA-E with restricted, specific CD8+ T cells could offer a new approach for immunotherapy of prostate cancer. Overall, this study supports the concept of a cancer vaccine. Supported by ORIP (P51OD011092) and NIAID.
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.
CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis
Nayyer et al., Clinical Cancer Research. 2024.
Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. In this study, investigators evaluated the efficacy of combining CDKi (abemaciclib) and anti–PD-1 therapy (“combination therapy”) in mouse models for brain metastases, elucidated how combination therapy remodeled the tumor–immune microenvironment (TIME) and T-cell receptor (TCR) repertoires, and investigated the effects of CDKi on T-cell development and maintenance in NOD-scid Il2rgnull (NSG) mice engrafted with human immune systems (“humanized mice”). Results offer a strong rationale for the clinical evaluation of combination CDKi and PD-1 blockade in patients with brain metastases. Supported by ORIP (R24OD026440), NCI, and NIAID.
Targeting Pancreatic Cancer Metabolic Dependencies Through Glutamine Antagonism
Encarnación-Rosado et al., Nature Cancer. 2024.
https://pubmed.ncbi.nlm.nih.gov/37814010/
Pancreatic ductal adenocarcinoma (PDAC) cells thrive in the austere, complex tumor microenvironment by reprogramming their metabolism and relying on scavenging pathways, but more work is needed to translate this knowledge into clinically relevant therapeutic interventions. Investigators demonstrated that treating PDAC cells with a Gln antagonist, 6‑diazo-5-oxo-l-norleucine (DON), caused a metabolic crisis by globally impairing Gln metabolism, resulting in a significant decrease in proliferation. They observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. Combining this therapeutic with an extracellular-signal-regulated kinase (or ERK) signaling pathway inhibitor could further improve it. Supported by ORIP (S10OD021747), NCI, and NIAID.
Host-Derived Growth Factors Drive ERK Phosphorylation and MCL1 Expression to Promote Osteosarcoma Cell Survival During Metastatic Lung Colonization
McAloney et al., Cellular Oncology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37676378/
Mortality from osteosarcoma is closely linked to lung metastasis, even though the lung appears to be a hostile environment for tumor cells. Using female mice, researchers assessed changes in both host and tumor cells during colonization. Their findings suggest that the mitogen-activated protein kinase (MAPK) pathway is significantly elevated in early and established metastases, which correlates with expression of anti-apoptotic genes (e.g., MCL1). The authors conclude that niche-derived growth factors drive increased MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. This gene is a promising target for future therapeutic development. Supported by ORIP (K01OD031811), NCI, and NCATS.
Simultaneous Evaluation of Treatment Efficacy and Toxicity for Bispecific T-Cell Engager Therapeutics in a Humanized Mouse Model
Yang et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300040R
Immuno-oncology–based therapies are an evolving powerful treatment strategy that targets the immune system and harnesses it to kill tumor cells directly. Investigators describe the novel application of a humanized mouse model that can simultaneously evaluate the efficacy of bispecific T cell engagers to control tumor burden and the development of cytokine release syndrome. The model also captures variability in responses for individual patients. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.