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  1. Article ; Online: Dissecting the Functional Significance of DNA Polymerase Mutations in Cancer.

    Wisdom, Amy J / Kirsch, David G

    Cancer research

    2020  Volume 80, Issue 24, Page(s) 5459–5461

    Abstract: DNA polymerase mutations can cause hypermutant cancers, but the mechanisms of tumorigenesis and the impact of various DNA polymerase mutations on treatment response is poorly understood. In this issue ... ...

    Abstract DNA polymerase mutations can cause hypermutant cancers, but the mechanisms of tumorigenesis and the impact of various DNA polymerase mutations on treatment response is poorly understood. In this issue of
    MeSH term(s) Animals ; DNA Polymerase II/genetics ; Immune Checkpoint Inhibitors ; Immunotherapy ; Mice ; Mutation ; Neoplasms/genetics ; Neoplasms/therapy ; Tumor Microenvironment
    Chemical Substances Immune Checkpoint Inhibitors ; DNA Polymerase II (EC 2.7.7.7)
    Language English
    Publishing date 2020-11-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-20-3241
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  2. Article ; Online: Functional assay to guide precision radiotherapy by assessing individual patient radiosensitivity.

    Wisdom, Amy J / Kirsch, David G

    EBioMedicine

    2019  Volume 41, Page(s) 26–27

    MeSH term(s) Biological Assay/methods ; Humans ; Neoplasms/diagnosis ; Neoplasms/radiotherapy ; Precision Medicine/methods ; Radiation Tolerance ; Radiotherapy ; Treatment Outcome
    Language English
    Publishing date 2019-03-07
    Publishing country Netherlands
    Document type Letter
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2019.03.002
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  3. Article: Loss of function of

    Pierpoint, Matthew / Floyd, Warren / Wisdom, Amy J / Luo, Lixia / Ma, Yan / Waitkus, Matthew S / Kirsch, David G

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of ... ...

    Abstract The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of telomeres (ALT). In this work, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice which displays multiple molecular features of ALT activation after CRISPR/Cas9 introduction of oncogenic
    Language English
    Publishing date 2023-11-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.06.565874
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  4. Article ; Online: Health-related quality of life analyses in nonfunctioning pituitary macroadenoma patients identifies at-risk populations.

    Wisdom, Amy J / Dyer, M Aiven / Horick, Nora K / Yeap, Beow Y / Miller, Karen K / Swearingen, Brooke / Loeffler, Jay S / Shih, Helen A

    Pituitary

    2023  Volume 26, Issue 4, Page(s) 510–520

    Abstract: Purpose: The quality of life (QoL) impact of multidisciplinary treatment for patients with nonfunctioning pituitary macroadenomas (NFPMA) is unclear. We sought to investigate associations between patient factors, clinical data, and patient-reported QoL ... ...

    Abstract Purpose: The quality of life (QoL) impact of multidisciplinary treatment for patients with nonfunctioning pituitary macroadenomas (NFPMA) is unclear. We sought to investigate associations between patient factors, clinical data, and patient-reported QoL in patients with NFPMA.
    Methods: Patients with treated NFPMA and > 1 year of follow up after transsphenoidal surgery (TSS) and with no evidence of progressive disease were evaluated utilizing the following patient-reported outcome measures: RAND-36-Item Health Survey, Multidimensional Fatigue Inventory, Cognitive Failures Questionnaire.
    Results: 229 eligible patients completed QoL questionnaires a median of 7.7 years after initial transsphenoidal surgery (TSS). 25% of participants received radiation therapy (RT) a median of 2.0 years (0.1-22.5) after initial TSS. Patients who received RT were younger (median age 46 v 58, p < 0.0001), had larger tumors (28 mm v 22 mm, p < 0.0001), were more likely to have visual symptoms (65% v 34%, p = 0.0002), and were more likely to have hypopituitarism (93% v 62%, p < 0.0001). Patients with hypopituitarism reported worse energy and fatigue and cognitive function (p < 0.03). Patients who received RT reported significantly worse general health, physical health, physical fatigue and cognitive functioning (p < 0.05). The largest QoL differences were in patients who experienced a financial stressor, independent of treatment type.
    Conclusion: Hypopituitarism, radiation therapy after TSS, and financial stressors are associated with more impaired QoL in patients with NFPMA. Awareness of these factors can better guide use and timing of radiation therapy in addition to identifying patients who can benefit from multidisciplinary surveillance.
    MeSH term(s) Humans ; Middle Aged ; Quality of Life ; Pituitary Neoplasms/radiotherapy ; Pituitary Neoplasms/surgery ; Surveys and Questionnaires ; Hypopituitarism/diagnosis ; Fatigue ; Treatment Outcome
    Language English
    Publishing date 2023-07-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1385151-2
    ISSN 1573-7403 ; 1386-341X
    ISSN (online) 1573-7403
    ISSN 1386-341X
    DOI 10.1007/s11102-023-01334-3
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  5. Article: Genetically engineered mouse models for studying radiation biology.

    Castle, Katherine D / Chen, Mark / Wisdom, Amy J / Kirsch, David G

    Translational cancer research

    2019  Volume 6, Issue Suppl 5, Page(s) S900–S913

    Abstract: Genetically engineered mouse models (GEMMs) are valuable research tools that have transformed our understanding of cancer. The first GEMMs generated in the 1980s and 1990s were knock-in and knock-out models of single oncogenes or tumor suppressors. The ... ...

    Abstract Genetically engineered mouse models (GEMMs) are valuable research tools that have transformed our understanding of cancer. The first GEMMs generated in the 1980s and 1990s were knock-in and knock-out models of single oncogenes or tumor suppressors. The advances that made these models possible catalyzed both technological and conceptual shifts in the way cancer research was conducted. As a result, dozens of mouse models of cancer exist today, covering nearly every tissue type. The advantages inherent to GEMMs compared to
    Language English
    Publishing date 2019-01-23
    Publishing country China
    Document type Journal Article
    ZDB-ID 2901601-0
    ISSN 2219-6803 ; 2218-676X
    ISSN (online) 2219-6803
    ISSN 2218-676X
    DOI 10.21037/tcr.2017.06.19
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  6. Article ; Online: The Next Chapter in Immunotherapy and Radiation Combination Therapy: Cancer-Specific Perspectives.

    Wisdom, Amy J / Barker, Christopher A / Chang, Joe Y / Demaria, Sandra / Formenti, Silvia / Grassberger, Clemens / Gregucci, Fabiana / Hoppe, Bradford S / Kirsch, David G / Marciscano, Ariel E / Mayadev, Jyoti / Mouw, Kent W / Palta, Manisha / Wu, Cheng-Chia / Jabbour, Salma K / Schoenfeld, Jonathan D

    International journal of radiation oncology, biology, physics

    2024  Volume 118, Issue 5, Page(s) 1404–1421

    Abstract: Immunotherapeutic agents have revolutionized cancer treatment over the past decade. However, most patients fail to respond to immunotherapy alone. A growing body of preclinical studies highlights the potential for synergy between radiation therapy and ... ...

    Abstract Immunotherapeutic agents have revolutionized cancer treatment over the past decade. However, most patients fail to respond to immunotherapy alone. A growing body of preclinical studies highlights the potential for synergy between radiation therapy and immunotherapy, but the outcomes of clinical studies have been mixed. This review summarizes the current state of immunotherapy and radiation combination therapy across cancers, highlighting existing challenges and promising areas for future investigation.
    MeSH term(s) Humans ; Neoplasms/radiotherapy ; Neoplasms/drug therapy ; Immunotherapy ; Combined Modality Therapy
    Language English
    Publishing date 2024-01-05
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 197614-x
    ISSN 1879-355X ; 0360-3016
    ISSN (online) 1879-355X
    ISSN 0360-3016
    DOI 10.1016/j.ijrobp.2023.12.046
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  7. Article: Both CD8 and CD4 T cells contribute to immunosurveillance preventing the development of neoantigen-expressing autochthonous sarcomas.

    Himes, Jonathon E / Wisdom, Amy J / Wang, Laura / Shepard, Sam J / Daniel, Andrea R / Williams, Nerissa / Luo, Lixia / Ma, Yan / Mowery, Yvonne M / Kirsch, David G

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The adaptive immune system plays an essential anti-tumor role through immunosurveillance and response to immunotherapies. Characterizing phenotypic features and mechanisms of dysfunction of tumor-specific T cell populations may uncover novel ... ...

    Abstract The adaptive immune system plays an essential anti-tumor role through immunosurveillance and response to immunotherapies. Characterizing phenotypic features and mechanisms of dysfunction of tumor-specific T cell populations may uncover novel immunotherapeutic targets and biomarkers of response. To study tumor-specific T cell responses
    Language English
    Publishing date 2023-04-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.04.535550
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  8. Article ; Online: Rationale and emerging strategies for immune checkpoint blockade in soft tissue sarcoma.

    Wisdom, Amy J / Mowery, Yvonne M / Riedel, Richard F / Kirsch, David G

    Cancer

    2018  Volume 124, Issue 19, Page(s) 3819–3829

    Abstract: Soft tissue sarcomas (STS) are heterogeneous, mesenchymal malignancies with variable biologic behavior. The primary management for localized STS is surgical resection, which may be combined with neoadjuvant or adjuvant radiation therapy to increase the ... ...

    Abstract Soft tissue sarcomas (STS) are heterogeneous, mesenchymal malignancies with variable biologic behavior. The primary management for localized STS is surgical resection, which may be combined with neoadjuvant or adjuvant radiation therapy to increase the probability of achieving local control. Many patients with large, high-grade STS develop metastatic disease. Several clinical trials of immune checkpoint blockade for STS have produced promising responses in patients with metastatic disease. In this review, recent and ongoing clinical trials of immune checkpoint inhibition for STS are discussed. The authors explain the rationale for immune checkpoint inhibition and radiation therapy and highlight new studies testing this combination in the neoadjuvant setting for patients with high-risk STS. In addition, they describe novel combinations of immunotherapy with targeted therapies and chemotherapies being tested in the metastatic setting and discuss how these combinations have the potential to be integrated into adjuvant therapy in the future.
    MeSH term(s) Antineoplastic Agents, Immunological/therapeutic use ; Cell Cycle Checkpoints/drug effects ; Cell Cycle Checkpoints/immunology ; Combined Modality Therapy ; Humans ; Immunotherapy/methods ; Immunotherapy/trends ; Medical Oncology/methods ; Medical Oncology/trends ; Molecular Targeted Therapy/methods ; Molecular Targeted Therapy/trends ; Protein Kinase Inhibitors/therapeutic use ; Rationalization ; Sarcoma/drug therapy ; Sarcoma/pathology ; Soft Tissue Neoplasms/drug therapy ; Soft Tissue Neoplasms/pathology ; Therapies, Investigational/methods ; Therapies, Investigational/trends
    Chemical Substances Antineoplastic Agents, Immunological ; Protein Kinase Inhibitors
    Language English
    Publishing date 2018-05-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1429-1
    ISSN 1097-0142 ; 0008-543X ; 1934-662X
    ISSN (online) 1097-0142
    ISSN 0008-543X ; 1934-662X
    DOI 10.1002/cncr.31517
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  9. Article: Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma.

    Su, Chang / Kent, Collin L / Pierpoint, Matthew / Floyd, Warren / Luo, Lixia / Wiliams, Nerissa T / Ma, Yan / Peng, Brian / Lazarides, Alexander L / Subramanian, Ajay / Himes, Jonathan E / Perez, Vincent M / Hernansaiz-Ballesteros, Rosa D / Roche, Kimberly E / Modliszewski, Jennifer L / Selitsky, Sara R / Mari Shinohara / Wisdom, Amy J / Moding, Everett J /
    Mowery, Yvonne M / Kirsch, David G

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy ( ...

    Abstract Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, we performed bulk RNA-seq, single-cell RNA-seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and interferon-γ. CpG + RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG + RT, TCR clonality analysis suggests an increase in clonal T-cell dominance. Collectively, these findings demonstrate that RT + CpG significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft tissue sarcoma.
    Language English
    Publishing date 2024-01-04
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.03.573968
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  10. Article ; Online: Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus.

    Floyd, Warren / Pierpoint, Matthew / Su, Chang / Patel, Rutulkumar / Luo, Lixia / Deland, Katherine / Wisdom, Amy J / Zhu, Daniel / Ma, Yan / DeWitt, Suzanne Bartholf / Williams, Nerissa T / Lazarides, Alexander L / Somarelli, Jason A / Corcoran, David L / Eward, William C / Cardona, Diana M / Kirsch, David G

    The Journal of clinical investigation

    2023  Volume 133, Issue 13

    Abstract: ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a ...

    Abstract ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx-deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus. In the absence of Atrx, irradiated sarcomas had increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. Our work also showed that Atrx deletion resulted in downregulation of the CGAS/STING signaling pathway at multiple points in the pathway and was not driven by mutations or transcriptional downregulation of the CGAS/STING pathway components. We found that both human and mouse models of Atrx-deleted sarcoma had a reduced adaptive immune response, markedly impaired CGAS/STING signaling, and increased sensitivity to TVEC, an oncolytic herpesvirus that is currently FDA approved for the treatment of aggressive melanomas. Translation of these results to patients with ATRX-mutant cancers could enable genomically guided cancer therapy approaches to improve patient outcomes.
    MeSH term(s) Animals ; Mice ; Humans ; Signal Transduction ; Sarcoma/genetics ; Sarcoma/radiotherapy ; X-linked Nuclear Protein/genetics ; Herpesviridae ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Immunity, Innate
    Chemical Substances X-linked Nuclear Protein (EC 3.6.4.12) ; Nucleotidyltransferases (EC 2.7.7.-) ; Atrx protein, mouse (EC 3.6.4.12)
    Language English
    Publishing date 2023-07-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI149310
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