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:

An Activatable Nanoparticle Probe for Molecular Imaging of Protease Activity by Dual Energy CT

Administered By
School of Medicine
Awarded By
National Institutes of Health
Role
Investigator
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
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

Awarded By
Lumicell Diagnostics
Role
Investigator
Start Date
End Date

Publications:

Sensitization of Endothelial Cells to Ionizing Radiation Exacerbates Delayed Radiation Myelopathy in Mice.

Delayed radiation myelopathy is a rare, but significant late side effect from radiation therapy that can lead to paralysis. The cellular and molecular mechanisms leading to delayed radiation myelopathy are not completely understood but may be a consequence of damage to oligodendrocyte progenitor cells and vascular endothelial cells. Here, we aimed to determine the contribution of endothelial cell damage to the development of radiation-induced spinal cord injury using a genetically defined mouse model in which endothelial cells are sensitized to radiation due to loss of the tumor suppressor p53. Tie2Cre; p53FL/+ and Tie2Cre; p53FL/- mice, which lack one and both alleles of p53 in endothelial cells, respectively, were treated with focal irradiation that specifically targeted the lumbosacral region of the spinal cord. The development of hindlimb paralysis was followed for up to 18 weeks after either a 26.7 Gy or 28.4 Gy dose of radiation. During 18 weeks of follow-up, 83% and 100% of Tie2Cre; p53FL/- mice developed hindlimb paralysis after 26.7 and 28.4 Gy, respectively. In contrast, during this period only 8% of Tie2Cre; p53FL/+ mice exhibited paralysis after 28.4 Gy. In addition, 8 weeks after 28.4 Gy the irradiated spinal cord from Tie2Cre; p53FL/- mice showed a significantly higher fractional area positive for the neurological injury marker glial fibrillary acidic protein (GFAP) compared with the irradiated spinal cord from Tie2Cre; p53FL/+ mice. Together, our findings show that deletion of p53 in endothelial cells sensitizes mice to the development of delayed radiation myelopathy indicating that endothelial cells are a critical cellular target of radiation that regulates myelopathy.
Authors
Lee, C-L; Wright, AO; Lee, JW; Brownstein, J; Hasapis, S; Satow, S; Da Silva Campos, L; Williams, N; Ma, Y; Luo, L; Johnson, T; Daniel, AR; Harrison, WT; Oldham, M; Kirsch, DG
MLA Citation
Lee, Chang-Lung, et al. “Sensitization of Endothelial Cells to Ionizing Radiation Exacerbates Delayed Radiation Myelopathy in Mice.Radiat Res, vol. 197, no. 3, Nov. 2021, p. 0. Pubmed, doi:10.1667/RADE-21-00166.1.
URI
https://scholars.duke.edu/individual/pub1500486
PMID
34724704
Source
pubmed
Published In
Radiat Res
Volume
197
Published Date
Start Page
0
DOI
10.1667/RADE-21-00166.1

A Novel Combination of Immunotherapy and Radiation Therapy in a Primary Mouse Model of Soft Tissue Sarcoma With High Mutational Load.

<h4>Purpose/objective(s)</h4>Preclinical studies using transplant tumor models have shown promising results for immunotherapy combined with radiotherapy (RT). However, research using primary tumor models is limited, and results from tumors using transplanted cell lines that do not develop in a native microenvironment under immunosurveillance often do not translate to the clinic. We previously found that tumors generated by transplanting cell lines from primary mouse sarcomas into syngeneic mice were cured by anti-PD-1 and RT. However, identical treatment failed to achieve local control in autochthonous sarcomas from the same model. Recent data has shown agonistic anti-OX40 immunotherapy combined with CpG oligonucleotide, a TLR9 agonist, eradicates tumors in a spontaneous mouse model of mammary cancer. Other studies have shown synergistic effects of anti-OX40 with anti-PD-1 or RT in transplant models. We hypothesize that the combination of anti-OX40, CpG, anti-PD-1, and RT will improve local control compared to RT or immunotherapy alone in a primary mouse model of soft tissue sarcoma with high mutational load.<h4>Materials/methods</h4>We generated autochthonous soft tissue sarcomas in 129/SvJ mice by intramuscular injection of adenovirus expressing Cas9 and a gRNA targeting Trp53 followed by exposure to the carcinogen 3-methylcholanthrene. Once tumors reached 70 mm<sup>3</sup>, mice were treated with RT (20 Gy, day 0), anti-OX40 (20 µg intraperitoneal (IP), randomized to one of two schedules: days 1 & 8 or days 3 & 10), CpG (50 µg intratumor, days 1 & 8 or 3 & 10), and anti-PD-1 (200 µg IP, days 1, 4, 7 or 3, 7, 10). Tumors were measured 3x/week. Time to tumor quintupling was compared to historical control mice treated with RT and isotype controls for anti-PD-1 and/or anti-CTLA-4 using the Mann-Whitney test.<h4>Results</h4>Sarcomas from this model are histologically similar to undifferentiated pleomorphic sarcoma. For mice treated with anti-OX40, CpG, and anti-PD-1 beginning day 1 (n = 17) compared to day 3 after RT (n = 13), median time to tumor quintupling was 36.2 vs. 44.3 days, respectively (P = 0.09). Time to tumor quintupling for mice treated with RT, anti-OX40, CpG, and anti-PD-1 (pooled groups with immunotherapy-initiated day 1 or 3) was significantly delayed compared to historical control mice treated with RT and isotype controls (n = 52) (median 38.7 vs. 30.5 days, respectively, P = 0.0009). Studies comparing combined RT, anti-OX40, CpG, and anti-PD-1 to contemporaneous controls are ongoing.<h4>Conclusion</h4>In a high mutational load primary mouse model of soft tissue sarcoma that is resistant to RT and anti-PD-1, RT combined with anti-OX40, CpG, and anti-PD-1 immunotherapy significantly delays tumor growth compared to historical controls. Results using this novel treatment combination with contemporaneous control groups are pending to determine if this regimen warrants further evaluation in a phase I clinical trial.
Authors
Kent, CL; Mowery, YM; Wisdom, AJ; Himes, J; Bassil, AM; Odhiambo, D; Kirsch, DG
MLA Citation
Kent, C. L., et al. “A Novel Combination of Immunotherapy and Radiation Therapy in a Primary Mouse Model of Soft Tissue Sarcoma With High Mutational Load.International Journal of Radiation Oncology, Biology, Physics, vol. 111, no. 3S, 2021, pp. S122–23. Epmc, doi:10.1016/j.ijrobp.2021.07.280.
URI
https://scholars.duke.edu/individual/pub1502891
PMID
34700441
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
111
Published Date
Start Page
S122
End Page
S123
DOI
10.1016/j.ijrobp.2021.07.280

The microRNA-183/96/182 cluster inhibits lung cancer progression and metastasis by inducing an interleukin-2-mediated antitumor CD8+ cytotoxic T-cell response.

One of the mechanisms by which cancer cells acquire hyperinvasive and migratory properties with progressive loss of epithelial markers is the epithelial-to-mesenchymal transition (EMT). We have previously reported that in different cancer types, including nonsmall cell lung cancer (NSCLC), the microRNA-183/96/182 cluster (m96cl) is highly repressed in cells that have undergone EMT. In the present study, we used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of Kras mutant autochthonous lung adenocarcinomas. In contrast, ectopic expression of the m96cl in NSCLC cells results in a robust suppression of migration and invasion in vitro, and tumor growth and metastasis in vivo. Detailed immune profiling of the tumors revealed a significant enrichment of activated CD8+ cytotoxic T lymphocytes (CD8+ CTLs) in m96cl-expressing tumors, and m96cl-mediated suppression of tumor growth and metastasis was CD8+ CTL-dependent. Using coculture assays with naïve immune cells, we show that m96cl expression drives paracrine stimulation of CD8+ CTL proliferation and function. Using tumor microenvironment-associated gene expression profiling, we identified that m96cl elevates the interleukin-2 (IL2) signaling pathway and results in increased IL2-mediated paracrine stimulation of CD8+ CTLs. Furthermore, we identified that the m96cl modulates the expression of IL2 in cancer cells by regulating the expression of transcriptional repressors Foxf2 and Zeb1, and thereby alters the levels of secreted IL2 in the tumor microenvironment. Last, we show that in vivo depletion of IL2 abrogates m96cl-mediated activation of CD8+ CTLs and results in loss of metastatic suppression. Therefore, we have identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.
Authors
Kundu, ST; Rodriguez, BL; Gibson, LA; Warner, AN; Perez, MG; Bajaj, R; Fradette, JJ; Class, CA; Solis, LM; Rojas Alvarez, FR; Wistuba, II; Diao, L; Chen, F; Sachdeva, M; Wang, J; Kirsch, DG; Creighton, CJ; Gibbons, DL
MLA Citation
Kundu, Samrat T., et al. “The microRNA-183/96/182 cluster inhibits lung cancer progression and metastasis by inducing an interleukin-2-mediated antitumor CD8+ cytotoxic T-cell response.Genes Dev, vol. 36, no. 9–10, May 2022, pp. 582–600. Pubmed, doi:10.1101/gad.349321.121.
URI
https://scholars.duke.edu/individual/pub1524193
PMID
35654454
Source
pubmed
Published In
Genes Dev
Volume
36
Published Date
Start Page
582
End Page
600
DOI
10.1101/gad.349321.121

Preliminary Results of Uveal Melanoma Treated With Iodine-125 Plaques: Analysis of Disease Control and Visual Outcomes With 63 Gy to the Target Volume.

Purpose: Our purpose was to review the preliminary outcomes of patients with uveal melanoma treated with iodine-125 plaques using a novel treatment planning approach. Methods and Materials: This was a single institution, retrospective review of patients treated with iodine-125 brachytherapy for uveal melanoma from November 2016 to February 2019. We used 3-dimensional treatment planning with the Eye Physics Plaque Simulator to ensure that a minimum of 63 Gy covered a 2-mm circumferential tumor margin and the apex height of the tumor over 94 hours. Primary endpoints were local failure, systemic metastasis, final visual acuity (VA), and radiation retinopathy. Associations between primary endpoints and tumor characteristics/radiation dose were performed using univariate analysis. Results: Sixty-nine patients were included in the analysis. Mean largest basal diameter was 11.67 mm (range, 6-18; median, 12), and the average tumor thickness to the inner sclera was 3.18 mm (range, 0.5-9.3; median, 2.8). Molecular testing that was successfully performed in 59 patients revealed that 27% (16 of 59) had class 2 gene expression profile designation. Average follow-up posttreatment was 28.3 months (range, 4-46; median, 29), with 6% (4 of 69) developing local failure and 6% (4 of 69) developing metastasis over this duration. Average final VA (0.57 logMAR [Snellen 20/74]; range, 0-2.9; median, 0.3) was decreased from baseline (0.34 logMAR [Snellen 20/44]; range, 0-2.3; median, 0.1), and 48% (33 of 69) developed radiation retinopathy. Fifty percent of patients had a final VA 20/40 or better and 22% had a final VA 20/200 or worse. Conclusions: In patients with uveal melanoma, preliminary results with brachytherapy using Eye Physics plaques with a treatment plan that delivers 63 Gy to a 2-mm circumferential tumor margin and the tumor apex suggest effective disease control and favorable VA outcomes.
Authors
Kheir, WJ; Stinnett, SS; Meltsner, S; Semenova, E; Mowery, YM; Craciunescu, O; Kirsch, DG; Materin, MA
MLA Citation
Kheir, Wajiha J., et al. “Preliminary Results of Uveal Melanoma Treated With Iodine-125 Plaques: Analysis of Disease Control and Visual Outcomes With 63 Gy to the Target Volume.Adv Radiat Oncol, vol. 7, no. 2, Mar. 2022, p. 100869. Pubmed, doi:10.1016/j.adro.2021.100869.
URI
https://scholars.duke.edu/individual/pub1509582
PMID
35387419
Source
pubmed
Published In
Advances in Radiation Oncology
Volume
7
Published Date
Start Page
100869
DOI
10.1016/j.adro.2021.100869

Treating the Unknown: First Refine the Diagnosis.

Authors
MLA Citation
Kirsch, David G. “Treating the Unknown: First Refine the Diagnosis.Int J Radiat Oncol Biol Phys, vol. 112, no. 1, Jan. 2022, pp. 37–38. Pubmed, doi:10.1016/j.ijrobp.2021.05.128.
URI
https://scholars.duke.edu/individual/pub1504071
PMID
34919879
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
112
Published Date
Start Page
37
End Page
38
DOI
10.1016/j.ijrobp.2021.05.128