David Kirsch

Overview:

My clinical interests are the multi-modality care of patients with bone and soft tissue sarcomas and developing new sarcoma therapies. My laboratory interests include utilizing mouse models of cancer to study cancer and radiation biology in order to develop new cancer therapies in the pre-clinical setting.

Positions:

Barbara Levine University Distinguished Professor

Radiation Oncology
School of Medicine

Professor of Radiation Oncology

Radiation Oncology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

M.D. 2000

Johns Hopkins University School of Medicine

Ph.D. 2000

Johns Hopkins University School of Medicine

Grants:

Defining the Cellular Target of Radiation Therapy

Administered By
Radiation Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Investigating the role of the transcriptional coactivator TAZ in alveolar rhabdomyosarcoma

Administered By
Pediatrics, Hematology-Oncology
Awarded By
St. Baldrick's Foundation
Role
Collaborator
Start Date
End Date

Clinical Trials Umbrella - Scanned Beam

Administered By
Radiation Oncology
Awarded By
Massachusetts General Hospital
Role
Co-Principal Investigator
Start Date
End Date

Engineered imaging nanoparticles for real-time detection of cancer in the tumor bed

Administered By
Orthopaedics
Awarded By
Lumicell Diagnostics
Role
Investigator
Start Date
End Date

A novel therap[eutic target for radiation-induced hematological malignancies: calcium calmodulin kinase kinase 2

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Department of Defense
Role
Investigator
Start Date
End Date

Publications:

Radiosensitizing the Vasculature of Primary Brainstem Gliomas Fails to Improve Tumor Response to Radiotherapy.

PURPOSE: Diffuse intrinsic pontine gliomas (DIPGs) arise in the pons and are the leading cause of death from brain tumors in children. DIPGs are routinely treated with radiation therapy, which temporarily improves neurological symptoms but generally fails to achieve local control. As numerous clinical trials have not improved survival from DIPG over standard radiotherapy alone, there is a pressing need to evaluate new therapeutic strategies for this devastating disease. Vascular damage caused by radiation therapy can increase permeability of tumor blood vessels and promote tumor cell death. METHODS AND MATERIALS: To investigate the impact of endothelial cell death on tumor response to radiotherapy in DIPG, we employed dual recombinase (Cre + FlpO) technology to generate primary brainstem gliomas which lack ataxia telangiectasia mutated (Atm) in the vasculature. RESULTS: Here, we show that Atm deficient tumor endothelial cells are sensitized to radiation therapy. Furthermore, radiosensitization of the vasculature in primary gliomas triggered an increase in total tumor cell death. Despite the observed increase in cell killing, in mice with autochthonous DIPGs treated with radiotherapy, deletion of Atm specifically in tumor endothelial cells failed to improve survival. CONCLUSIONS: These results suggest that targeting the tumor cells, rather than endothelial cells, during radiotherapy will be necessary to improve survival of children with DIPG.
Authors
Deland, K; Mercer, JS; Crabtree, DM; Garcia, MEG; Reinsvold, M; Campos, LDS; Williams, NT; Luo, L; Ma, Y; Reitman, ZJ; Becher, OJ; Kirsch, DG
MLA Citation
Deland, Katherine, et al. “Radiosensitizing the Vasculature of Primary Brainstem Gliomas Fails to Improve Tumor Response to Radiotherapy.Int J Radiat Oncol Biol Phys, Oct. 2021. Pubmed, doi:10.1016/j.ijrobp.2021.09.047.
URI
https://scholars.duke.edu/individual/pub1498798
PMID
34619331
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Published Date
DOI
10.1016/j.ijrobp.2021.09.047

Radiation-Induced Phosphorylation of a Prion-Like Domain Regulates Transformation by FUS-CHOP.

Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis is not well understood. Interestingly, some translocation-driven cancers exhibit dramatic clinical responses to therapy, such as radiotherapy, although the precise mechanism has not been elucidated. Here we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable sensitivity of myxoid liposarcomas to radiation therapy. FUS-CHOP interacted with chromatin remodeling complexes to regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, colocalized with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylated the prion-like domain of FUS-CHOP to impede these protein-protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupted oncogenic targeting of chromatin remodelers required for FUS-CHOP-driven sarcomagenesis. This mechanism of disruption links phosphorylation of the prion-like domain of an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma. SIGNIFICANCE: Prion-like domains, which are frequently translocated in cancers as oncogenic fusion proteins that drive global epigenetic changes, confer sensitivity to radiation via disruption of oncogenic interactions.
Authors
Chen, M; Foster, JP; Lock, IC; Leisenring, NH; Daniel, AR; Floyd, W; Xu, E; Davis, IJ; Kirsch, DG
MLA Citation
Chen, Mark, et al. “Radiation-Induced Phosphorylation of a Prion-Like Domain Regulates Transformation by FUS-CHOP.Cancer Res, vol. 81, no. 19, Oct. 2021, pp. 4939–48. Pubmed, doi:10.1158/0008-5472.CAN-20-1497.
URI
https://scholars.duke.edu/individual/pub1494133
PMID
34385184
Source
pubmed
Published In
Cancer Res
Volume
81
Published Date
Start Page
4939
End Page
4948
DOI
10.1158/0008-5472.CAN-20-1497

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.

BACKGROUND: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. METHODS: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. RESULTS: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. CONCLUSIONS: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.
Authors
Stacchiotti, S; Frezza, AM; Blay, J-Y; Baldini, EH; Bonvalot, S; Bovée, JVMG; Callegaro, D; Casali, PG; Chiang, RC-J; Demetri, GD; Demicco, EG; Desai, J; Eriksson, M; Gelderblom, H; George, S; Gounder, MM; Gronchi, A; Gupta, A; Haas, RL; Hayes-Jardon, A; Hohenberger, P; Jones, KB; Jones, RL; Kasper, B; Kawai, A; Kirsch, DG; Kleinerman, ES; Le Cesne, A; Lim, J; Chirlaque López, MD; Maestro, R; Marcos-Gragera, R; Martin Broto, J; Matsuda, T; Mir, O; Patel, SR; Raut, CP; Razak, ARA; Reed, DR; Rutkowski, P; Sanfilippo, RG; Sbaraglia, M; Schaefer, I-M; Strauss, DC; Sundby Hall, K; Tap, WD; Thomas, DM; van der Graaf, WTA; van Houdt, WJ; Visser, O; von Mehren, M; Wagner, AJ; Wilky, BA; Won, Y-J; Fletcher, CDM; Dei Tos, AP; Trama, A
MLA Citation
Stacchiotti, Silvia, et al. “Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.Cancer, vol. 127, no. 16, Aug. 2021, pp. 2934–42. Pubmed, doi:10.1002/cncr.33618.
URI
https://scholars.duke.edu/individual/pub1480890
PMID
33910263
Source
pubmed
Published In
Cancer
Volume
127
Published Date
Start Page
2934
End Page
2942
DOI
10.1002/cncr.33618

Whole-Exome Sequencing of Radiation-Induced Thymic Lymphoma in Mouse Models Identifies Notch1 Activation as a Driver of p53 Wild-Type Lymphoma.

Mouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-cell lymphoblastic leukemia/lymphoma. Here we aimed to identify key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53+/-, and KrasLA1 mice were not observed to harbor significantly higher numbers of nonsynonymous somatic mutations compared with thymic lymphomas from unirradiated p53-/- mice. However, distinct patterns of recurrent mutations arose in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Reporter mice for activation of Notch1 signaling revealed that total-body irradiation (TBI) enriched Notch1hi CD44+ thymocytes that could propagate in vivo after thymocyte transplantation. Mechanistically, genetic inhibition of Notch1 signaling in immature thymocytes prevented formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, these results demonstrate a critical role of activated Notch1 signaling in driving multistep carcinogenesis of thymic lymphoma following TBI in p53 WT mice. SIGNIFICANCE: These findings reveal the mutational landscape and key drivers in murine radiation-induced thymic lymphoma, a classic animal model that has been used to study radiation carcinogenesis for over 70 years.
Authors
Lee, C-L; Brock, KD; Hasapis, S; Zhang, D; Sibley, AB; Qin, X; Gresham, JS; Caraballo, I; Luo, L; Daniel, AR; Hilton, MJ; Owzar, K; Kirsch, DG
MLA Citation
Lee, Chang-Lung, et al. “Whole-Exome Sequencing of Radiation-Induced Thymic Lymphoma in Mouse Models Identifies Notch1 Activation as a Driver of p53 Wild-Type Lymphoma.Cancer Res, vol. 81, no. 14, July 2021, pp. 3777–90. Pubmed, doi:10.1158/0008-5472.CAN-20-2823.
URI
https://scholars.duke.edu/individual/pub1482957
PMID
34035082
Source
pubmed
Published In
Cancer Res
Volume
81
Published Date
Start Page
3777
End Page
3790
DOI
10.1158/0008-5472.CAN-20-2823

Metabolomics in cancer research and emerging applications in clinical oncology.

Cancer has myriad effects on metabolism that include both rewiring of intracellular metabolism to enable cancer cells to proliferate inappropriately and adapt to the tumor microenvironment, and changes in normal tissue metabolism. With the recognition that fluorodeoxyglucose-positron emission tomography imaging is an important tool for the management of many cancers, other metabolites in biological samples have been in the spotlight for cancer diagnosis, monitoring, and therapy. Metabolomics is the global analysis of small molecule metabolites that like other -omics technologies can provide critical information about the cancer state that are otherwise not apparent. Here, the authors review how cancer and cancer therapies interact with metabolism at the cellular and systemic levels. An overview of metabolomics is provided with a focus on currently available technologies and how they have been applied in the clinical and translational research setting. The authors also discuss how metabolomics could be further leveraged in the future to improve the management of patients with cancer.
Authors
Schmidt, DR; Patel, R; Kirsch, DG; Lewis, CA; Vander Heiden, MG; Locasale, JW
MLA Citation
Schmidt, Daniel R., et al. “Metabolomics in cancer research and emerging applications in clinical oncology.Ca: A Cancer Journal for Clinicians, vol. 71, no. 4, July 2021, pp. 333–58. Epmc, doi:10.3322/caac.21670.
URI
https://scholars.duke.edu/individual/pub1482071
PMID
33982817
Source
epmc
Published In
Ca: a Cancer Journal for Clinicians
Volume
71
Published Date
Start Page
333
End Page
358
DOI
10.3322/caac.21670