A5019037264- Cancer Research and Treatments
- Pancreatic and Hepatic Oncology Research
- Cancer Immunotherapy and Biomarkers
- Biochemical and Molecular Research
- Cancer Cells and Metastasis
- Cancer, Hypoxia, and Metabolism
- Ferroptosis and cancer prognosis
- Immune cells in cancer
- IL-33, ST2, and ILC Pathways
- Phagocytosis and Immune Regulation
- Cancer-related Molecular Pathways
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- Amino Acid Enzymes and Metabolism
- Diet and metabolism studies
- Inflammasome and immune disorders
- Lymphoma Diagnosis and Treatment
- FOXO transcription factor regulation
University of Pennsylvania
2022-2024
University of Pittsburgh
2022
UPMC Hillman Cancer Center
2022
Cancer Research Institute
2022
Abstract Mutations in the KRAS oncogene are found more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), Gly-to-Asp mutations (KRASG12D) being most common. Here, we tested efficacy a small-molecule KRASG12D inhibitor, MRTX1133, implantable and autochthonous PDAC models an intact immune system. In vitro studies validated specificity potency MRTX1133. vivo, MRTX1133 prompted deep tumor regressions all tested, including complete or near-complete remissions after 14 days....
We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment heme metabolism genes. These iron-rich tumor-associated (iTAMs) supported angiogenesis immunosuppression were conserved between mice humans. iTAMs comprise two additional subsets based on gene expression profile location—perivascular (pviTAM) stromal (stiTAM). identified endothelin receptor type B (Ednrb) as specific marker found myeloid-specific deletion Ednrb to reduce...
Proliferating tumor cells take up glutamine for anabolic processes, engendering deficiency in the microenvironment. How this might impact immune is not well understood. Using multiple mouse models of soft tissue sarcomas, antagonists, as genetic and pharmacological inhibition utilization, we found that number frequency conventional dendritic (cDCs) dependent on microenvironmental levels. cDCs comprise two distinct subsets—cDC1s cDC2s, with former subset playing a critical role antigen...
Abstract Proliferating tumor cells take up glutamine for anabolic processes engendering deficiency in the microenvironment. How this might impact immune is not well understood. Using multiple mouse models of soft tissue sarcomas, antagonists, as genetic and pharmacological inhibition utilization, we found that number frequency conventional dendritic (cDC) dependent on microenvironmental levels. cDCs comprise two distinct subsets – cDC1 cDC2, with former subset playing a critical role antigen...
<h3>Background</h3> Tumor associated macrophages (TAMs) frequently comprise the most abundant leukocyte population within tumor microenvironment (TME). TAMs are phenotypically diverse and can be polarized towards either pro- or anti-tumor functions by signals TME. While microvascular dysfunction with red blood cell (RBC) extravasation intra-tumoral hemorrhage hallmarks of solid tumors,<sup>1</sup> role RBCs heme in polarizing TME is not known. <h3>Methods</h3> We performed single RNA-seq...
Abstract The KRAS oncogene is mutated in greater than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. MRTX1133 a non-covalent inhibitor targeting the most common mutant PDAC, KRASG12D, and has shown robust efficacy various tumor models, including PDAC (Hallin et al., Nature Medicine, 2022; Kemp Cancer Discovery, 2022). However, interplay between immune system not been characterized. Using immunocompetent mouse models we aimed to elucidate whether effects are dependent. Mice were...
<div>Abstract<p>Mutations in the <i>KRAS</i> oncogene are found more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), Gly-to-Asp mutations (<i>KRAS</i><sup>G12D</sup>) being most common. Here, we tested efficacy a small-molecule KRAS<sup>G12D</sup> inhibitor, MRTX1133, implantable and autochthonous PDAC models an intact immune system. <i>In vitro</i> studies validated specificity potency MRTX1133....
<p>MRTX1133 exerts in vivo effects early treatment</p>
<p>Supplementary Figures and Table with legend arranged in a single presentable package</p>
<div>Abstract<p>Mutations in the <i>KRAS</i> oncogene are found more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), Gly-to-Asp mutations (<i>KRAS</i><sup>G12D</sup>) being most common. Here, we tested efficacy a small-molecule KRAS<sup>G12D</sup> inhibitor, MRTX1133, implantable and autochthonous PDAC models an intact immune system. <i>In vitro</i> studies validated specificity potency MRTX1133....
<p>KRASG12D inhibition alters the tumor immune microenvironment</p>
<p>MRTX1133 elicits changes in the tumor stroma and vasculature</p>
<p>MRTX1133 is selective for KRASG12D in immunocompetent implantation tumor models</p>
<p>MRTX1133 reduces metastatic burden in a tail vein model</p>
<p>KRASG12D inhibition alters the tumor immune microenvironment</p>
<p>MRTX1133 is selective for KRASG12D in immunocompetent implantation tumor models</p>
<p>MRTX1133 elicits changes in the tumor stroma and vasculature</p>
<p>Effects of MRTX1133 in KPC/Y and subcutaneous models</p>
<p>MRTX1133 selectively inhibits KRASG12D and downstream MAPK signaling in vitro</p>
<p>Effects of MRTX1133 in KPC/Y and subcutaneous models</p>
<p>MRTX1133 exerts in vivo effects early treatment</p>
<p>MRTX1133 reduces metastatic burden in a tail vein model</p>