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:

Targeting the ATM Kinase to Enhance the Efficacy of Radiotherapy and Outcomes for Cancer Patients

Targeting the DNA damage response represents a promising approach to improve the efficacy of radiation therapy. One appealing target for this approach is the serine/threonine kinase ataxia telangiectasia mutated (ATM), which is activated by DNA double strand breaks to orchestrate the cellular response to ionizing radiation. Small-molecule inhibitors targeting ATM have entered clinical trials testing their safety in combination with radiation therapy or in combination with other DNA damaging agents. Here, we review biochemical, genetic, and cellular functional studies of ATM, phenotypes associated with germline and somatic cancer mutations in ATM in humans, and experiments in genetically engineered mouse models that support a rationale for investigating ATM inhibitors as radiosensitizers for cancer therapy. These data identify important synthetic lethal relationships, which suggest that ATM inhibitors may be particularly effective in tumors with defects in other nodes of the DNA damage response. The potential for ATM inhibition to improve immunotherapy responses in preclinical models represents another emerging area of research. We summarize ongoing clinical trials of ATM inhibitors with radiotherapy. We also discuss critical ongoing areas of investigation that include discovery of biomarkers that predict for radiosensitization by ATM inhibitors and identification of effective combinations of ATM inhibitors, radiation therapy, other DNA damage response-directed therapies, and/or immunotherapies.
Authors
García, MEG; Kirsch, DG; Reitman, ZJ
MLA Citation
García, M. E. G., et al. “Targeting the ATM Kinase to Enhance the Efficacy of Radiotherapy and Outcomes for Cancer Patients.” Seminars in Radiation Oncology, Jan. 2021. Scopus, doi:10.1016/j.semradonc.2021.09.008.
URI
https://scholars.duke.edu/individual/pub1499730
Source
scopus
Published In
Seminars in Radiation Oncology
Published Date
DOI
10.1016/j.semradonc.2021.09.008

Preoperative radiotherapy for retroperitoneal sarcoma.

Authors
DeLaney, T; Mullen, JT; Wang, D; Goldberg, SI; Kirsch, DG
MLA Citation
DeLaney, Thomas, et al. “Preoperative radiotherapy for retroperitoneal sarcoma.Lancet Oncol, vol. 22, no. 1, Jan. 2021, p. e1. Pubmed, doi:10.1016/S1470-2045(20)30632-X.
URI
https://scholars.duke.edu/individual/pub1470882
PMID
33387499
Source
pubmed
Published In
Lancet Oncol
Volume
22
Published Date
Start Page
e1
DOI
10.1016/S1470-2045(20)30632-X

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