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 Regeneration Next Initiative

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:

Awakening the dormant tumor: the role of the tumor microenvironment in breast cancer recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co-Sponsor
Start Date
End Date

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
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
Role
Investigator
Start Date
End Date

Publications:

Practice Patterns for the Treatment of Uveal Melanoma with Iodine-125 Plaque Brachytherapy: Ocular Oncology Study Consortium Report 5

© 2019 © 2019 S. Karger AG, Basel. Copyright: All rights reserved. Background: Treatment planning for I-125 plaque therapy for uveal melanoma has advanced significantly since the Collaborative Ocular Melanoma Study trial, with more widely available image-guided planning and improved dosimetry. Objective: We evaluated real-world practice patterns for I-125 plaque brachytherapy in the United States by studying practice patterns at centers that comprise the Ocular Oncology Study Consortium (OOSC). Methods: The OOSC database and responses to a treatment practice survey were evaluated. The database contains treatment information from 9 institutions. Patients included in the database were treated between 2010 and 2014. The survey was conducted in 2018 and current treatment planning methods and prescriptions were queried. Results: Examination of the OOSC database revealed that average doses to critical structures were highly consistent, with the exception of one institution. Survey responses indicated that most centers followed published guidelines regarding dose and prescription point. Dose rate ranged from 51 to 118 cGy/h. As of 2018, most institutions use pre-loaded plaques and fundus photographs and/or computed tomography or magnetic resonance imaging in planning. Conclusions: While there were differences in dosimetric practices, overall agreement in plaque brachytherapy practices was high among OOSC institutions. Clinical margins and planning systems were similar among institutions, while prescription dose, dose rates, and dosimetry varied.
Authors
Binder, C; Mruthyunjaya, P; Schefler, AC; Seider, MI; Crilly, R; Hung, A; Meltsner, S; Mowery, Y; Kirsch, DG; Teh, BS; Jennelle, RLS; Studenski, MT; Liu, W; Lee, C; Hayman, JA; Kastner, B; Hadsell, M; Skalet, AH
MLA Citation
Binder, C., et al. “Practice Patterns for the Treatment of Uveal Melanoma with Iodine-125 Plaque Brachytherapy: Ocular Oncology Study Consortium Report 5.” Ocular Oncology and Pathology, Jan. 2019. Scopus, doi:10.1159/000504312.
URI
https://scholars.duke.edu/individual/pub1424208
Source
scopus
Published In
Ocular Oncology and Pathology
Published Date
DOI
10.1159/000504312

Revisiting the Role of Radiation Therapy in Chondrosarcoma: A National Cancer Database Study.

Background: Although chondrosarcomas (CS) are mostly considered radioresistant, advancements in radiotherapy have brought attention to its use in these patients. Using the largest registry of primary bone tumors, the National Cancer Database (NCDB), we sought to better characterize the current use of radiotherapy in CS patients and identify any potential survival benefit with higher radiation doses and advanced radiation therapies. Methods: We retrospectively analyzed CS patients in the NCDB from 2004 to 2015 who underwent radiotherapy. The Kaplan-Meier method with statistical comparisons was used to identify which individual variables related to dosage and delivery modality were associated with improved 5-year survival rates. Multivariate proportional hazards analyses were performed to determine independent predictors of survival. Results: Of 5,427 patients with a histologic diagnosis of chondrosarcoma, 680 received a form of radiation therapy (13%). The multivariate proportional hazards analysis controlling for various patient, tumor, and treatment variables, including RT dose and modality, demonstrated that while overall radiation therapy (RT) was not associated with improved survival (HR 0.96, 95% CI 0.76-1.20), when examining just the patient cohort with positive surgical margins, RT trended towards improved survival (HR 0.81, 95% CI 0.58-1.13). When comparing advanced and conventional RT modalities, advanced RT was associated with significantly decreased mortality (HR 0.55, 95% CI 0.38-0.80). However, advanced modality and high-dose RT both trended only toward improved survival compared to patients who did not receive any RT (HR 0.74, 95% CI 0.52-1.06 and HR 0.93, 95% CI 0.71-1.21, respectively). Conclusions: Despite the suggested radioresistance of CS, modern radiotherapies may present a treatment option for certain patients. Our results support a role for high-dose, advanced radiation therapies in selected high-risk CS patients with tumors in surgically challenging locations or unplanned positive margins. While there is an associated survival rate benefit, further, prospective studies are needed for validation.
Authors
Catanzano, AA; Kerr, DL; Lazarides, AL; Dial, BL; Lane, WO; Blazer, DG; Larrier, NA; Kirsch, DG; Brigman, BE; Eward, WC
MLA Citation
Catanzano, Anthony A., et al. “Revisiting the Role of Radiation Therapy in Chondrosarcoma: A National Cancer Database Study..” Sarcoma, vol. 2019, 2019. Pubmed, doi:10.1155/2019/4878512.
URI
https://scholars.duke.edu/individual/pub1418046
PMID
31736653
Source
pubmed
Published In
Sarcoma
Volume
2019
Published Date
Start Page
4878512
DOI
10.1155/2019/4878512

Genome-wide CRISPR Screen to Identify Genes that Suppress Transformation in the Presence of Endogenous KrasG12D.

Cooperating gene mutations are typically required to transform normal cells enabling growth in soft agar or in immunodeficient mice. For example, mutations in Kras and transformation-related protein 53 (Trp53) are known to transform a variety of mesenchymal and epithelial cells in vitro and in vivo. Identifying other genes that can cooperate with oncogenic Kras and substitute for Trp53 mutation has the potential to lead to new insights into mechanisms of carcinogenesis. Here, we applied a genome-wide CRISPR/Cas9 knockout screen in KrasG12D immortalized mouse embryonic fibroblasts (MEFs) to search for genes that when mutated cooperate with oncogenic Kras to induce transformation. We also tested if mutation of the identified candidate genes could cooperate with KrasG12D to generate primary sarcomas in mice. In addition to identifying the well-known tumor suppressor cyclin dependent kinase inhibitor 2A (Cdkn2a), whose alternative reading frame product p19 activates Trp53, we also identified other putative tumor suppressors, such as F-box/WD repeat-containing protein 7 (Fbxw7) and solute carrier family 9 member 3 (Slc9a3). Remarkably, the TCGA database indicates that both FBXW7 and SLC9A3 are commonly co-mutated with KRAS in human cancers. However, we found that only mutation of Trp53 or Cdkn2a, but not Fbxw7 or Slc9a3 can cooperate with KrasG12D to generate primary sarcomas in mice. These results show that mutations in oncogenic Kras and either Fbxw7 or Slc9a3 are sufficient for transformation in vitro, but not for in vivo sarcomagenesis.
Authors
Huang, J; Chen, M; Xu, ES; Luo, L; Ma, Y; Huang, W; Floyd, W; Klann, TS; Kim, SY; Gersbach, CA; Cardona, DM; Kirsch, DG
MLA Citation
Huang, Jianguo, et al. “Genome-wide CRISPR Screen to Identify Genes that Suppress Transformation in the Presence of Endogenous KrasG12D..” Sci Rep, vol. 9, no. 1, Nov. 2019. Pubmed, doi:10.1038/s41598-019-53572-w.
URI
https://scholars.duke.edu/individual/pub1421434
PMID
31748650
Source
pubmed
Published In
Scientific Reports
Volume
9
Published Date
Start Page
17220
DOI
10.1038/s41598-019-53572-w

Establishing the Impact of Vascular Damage on Tumor Response to High-Dose Radiation Therapy.

Approximately half of all patients with cancer receive radiotherapy, which is conventionally delivered in relatively small doses (1.8-2 Gy) per daily fraction over one to two months. Stereotactic body radiation therapy (SBRT), in which a high daily radiation dose is delivered in 1 to 5 fractions, has improved local control rates for several cancers. However, despite the widespread adoption of SBRT in the clinic, controversy surrounds the mechanism by which SBRT enhances local control. Some studies suggest that high doses of radiation (≥10 Gy) trigger tumor endothelial cell death, resulting in indirect killing of tumor cells through nutrient depletion. On the other hand, mathematical models predict that the high radiation dose per fraction used in SBRT increases direct tumor cell killing, suggesting that disruption of the tumor vasculature is not a critical mediator of tumor cure. Here, we review the application of genetically engineered mouse models to radiosensitize tumor cells or endothelial cells to dissect the role of these cellular targets in mediating the response of primary tumors to high-dose radiotherapy in vivo These studies demonstrate a role for endothelial cell death in mediating tumor growth delay, but not local control following SBRT.
Authors
Castle, KD; Kirsch, DG
MLA Citation
Castle, Katherine D., and David G. Kirsch. “Establishing the Impact of Vascular Damage on Tumor Response to High-Dose Radiation Therapy..” Cancer Res, vol. 79, no. 22, Nov. 2019, pp. 5685–92. Pubmed, doi:10.1158/0008-5472.CAN-19-1323.
URI
https://scholars.duke.edu/individual/pub1406378
PMID
31427377
Source
pubmed
Published In
Cancer Res
Volume
79
Published Date
Start Page
5685
End Page
5692
DOI
10.1158/0008-5472.CAN-19-1323

Sensitization of Vascular Endothelial Cells to Ionizing Radiation Promotes the Development of Delayed Intestinal Injury in Mice.

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.
Authors
Lee, C-L; Daniel, AR; Holbrook, M; Brownstein, J; Silva Campos, LD; Hasapis, S; Ma, Y; Borst, LB; Badea, CT; Kirsch, DG
MLA Citation
Lee, Chang-Lung, et al. “Sensitization of Vascular Endothelial Cells to Ionizing Radiation Promotes the Development of Delayed Intestinal Injury in Mice..” Radiat Res, vol. 192, no. 3, Sept. 2019, pp. 258–66. Pubmed, doi:10.1667/RR15371.1.
URI
https://scholars.duke.edu/individual/pub1395673
PMID
31265788
Source
pubmed
Published In
Radiat Res
Volume
192
Published Date
Start Page
258
End Page
266
DOI
10.1667/RR15371.1