Browsing by Author "Holbrook, Matt"

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    Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.
    (Molecular cancer therapeutics, 2023-01) Patel, Rutulkumar; Mowery, Yvonne M; Qi, Yi; Bassil, Alex M; Holbrook, Matt; Xu, Eric S; Hong, Cierra S; Himes, Jonathon E; Williams, Nerissa T; Everitt, Jeffrey; Ma, Yan; Luo, Lixia; Selitsky, Sara R; Modliszewski, Jennifer L; Gao, Junheng; Jung, Sin-Ho; Kirsch, David G; Badea, Cristian T
    This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.
  • Thumbnail Image
    ItemOpen Access
    Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.
    (Molecular cancer therapeutics, 2023-01) Patel, Rutulkumar; Mowery, Yvonne M; Qi, Yi; Bassil, Alex M; Holbrook, Matt; Xu, Eric S; Hong, Cierra S; Himes, Jonathon E; Williams, Nerissa T; Everitt, Jeffrey; Ma, Yan; Luo, Lixia; Selitsky, Sara R; Modliszewski, Jennifer L; Gao, Junheng; Jung, Sin-Ho; Kirsch, David G; Badea, Cristian T
    This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.
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    ItemOpen Access
    Sensitization of Vascular Endothelial Cells to Ionizing Radiation Promotes the Development of Delayed Intestinal Injury in Mice.
    (Radiation research, 2019-09) Lee, Chang-Lung; Daniel, Andrea R; Holbrook, Matt; Brownstein, Jeremy; Silva Campos, Lorraine Da; Hasapis, Stephanie; Ma, Yan; Borst, Luke B; Badea, Cristian T; Kirsch, David G
    Exposure of the gastrointestinal (GI) tract to ionizing radiation can cause acute and delayed injury. However, critical cellular targets that regulate the development of radiation-induced GI injury remain incompletely understood. Here, we investigated the role of vascular endothelial cells in controlling acute and delayed GI injury after total-abdominal irradiation (TAI). To address this, we used genetically engineered mice in which endothelial cells are sensitized to radiation due to the deletion of the tumor suppressor p53. Remarkably, we found that VE-cadherin-Cre; p53FL/FL mice, in which both alleles of p53 are deleted in endothelial cells, were not sensitized to the acute GI radiation syndrome, but these mice were highly susceptible to delayed radiation enteropathy. Histological examination indicated that VE-cadherin-Cre; p53FL/FL mice that developed delayed radiation enteropathy had severe vascular injury in the small intestine, which was manifested by hemorrhage, loss of microvessels and tissue hypoxia. In addition, using dual-energy CT imaging, we showed that VE-cadherin-Cre; p53FL/FL mice had a significant increase in vascular permeability of the small intestine in vivo 28 days after TAI. Together, these findings demonstrate that while sensitization of endothelial cells to radiation does not exacerbate the acute GI radiation syndrome, it is sufficient to promote the development of late radiation enteropathy.