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:

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

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

Publications:

The p53 Transactivation Domain 1-Dependent Response to Acute DNA Damage in Endothelial Cells Protects against Radiation-Induced Cardiac Injury.

Thoracic radiation therapy can cause endothelial injury in the heart, leading to cardiac dysfunction and heart failure. Although it has been demonstrated that the tumor suppressor p53 functions in endothelial cells to prevent the development of radiation-induced myocardial injury, the key mechanism(s) by which p53 regulates the radiosensitivity of cardiac endothelial cells is not completely understood. Here, we utilized genetically engineered mice that express mutations in p53 transactivation domain 1 (TAD1) (p5325,26) or mutations in p53 TAD1 and TAD2 (p5325,26,53,54) specifically in endothelial cells to study the p53 transcriptional program that protects cardiac endothelial cells from ionizing radiation in vivo. p5325,26,53,54 loses the ability to drive transactivation of p53 target genes after irradiation while p5325,26 can induce transcription of a group of non-canonical p53 target genes, but not the majority of classic radiation-induced p53 targets critical for p53-mediated cell cycle arrest and apoptosis. After 12 Gy whole-heart irradiation, we found that both p5325,26 and p5325,26,53,54 sensitized mice to radiation-induced cardiac injury, in contrast to wild-type p53. Histopathological examination suggested that mutation of TAD1 contributes to myocardial necrosis after whole-heart irradiation, while mutation of both TAD1 and TAD2 abolishes the ability of p53 to prevent radiation-induced heart disease. Taken together, our results show that the transcriptional program downstream of p53 TAD1, which activates the acute DNA damage response after irradiation, is necessary to protect cardiac endothelial cells from radiation injury in vivo.
Authors
Kuo, H-C; Luo, L; Ma, Y; Williams, NT; da Silva Campos, L; Attardi, LD; Lee, C-L; Kirsch, DG
MLA Citation
Kuo, Hsuan-Cheng, et al. “The p53 Transactivation Domain 1-Dependent Response to Acute DNA Damage in Endothelial Cells Protects against Radiation-Induced Cardiac Injury.Radiat Res, vol. 198, no. 2, Aug. 2022, pp. 145–53. Pubmed, doi:10.1667/RADE-22-00001.1.
URI
https://scholars.duke.edu/individual/pub1520690
PMID
35512345
Source
pubmed
Published In
Radiat Res
Volume
198
Published Date
Start Page
145
End Page
153
DOI
10.1667/RADE-22-00001.1

Soft tissue sarcomas

Sarcomas are malignant tumours that arise from skeletal and extra-skeletal connective tissues, including the peripheral nervous system. The term ‘sarcomas of soft tissues’ embraces all of the malignant tumours which arise from the mesenchymal tissues excluding bone, i.e. malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma, rhabdomyosarcoma, epithelioid sarcoma, angiosarcoma, fibrosarcoma, etc. In addition, malignant tumours of peripheral nerve sheaths are included despite being ectodermal in origin, as their clinical behaviour is not measurably different from the other sarcomas. Gastrointestinal stromal tumours are derived from cells (interstitial cells of Cajal) with neural and smooth muscle features and are also considered soft tissue sarcomas. The relative frequency of different histological subtypes of sarcomas is shown in Table 40.1. This chapter discusses current practice in the management of patients with soft tissue sarcoma (other than rhabdomyosarcoma of the paediatric age group) as well as selected benign, infiltrative soft tissue tumours such as desmoids whose management is similar.
Authors
Delaney, TF; Rosenberg, AE; Harmon, DC; Hornicek, FJ; Yoon, S; Kirsch, DG; Mankin, HJ; Rosenthal, D
MLA Citation
Delaney, T. F., et al. “Soft tissue sarcomas.” Treatment of Cancer, Fifth Edition, 2008, pp. 924–80. Scopus, doi:10.1201/b13550-47.
URI
https://scholars.duke.edu/individual/pub1535295
Source
scopus
Published Date
Start Page
924
End Page
980
DOI
10.1201/b13550-47

Retrospective observational studies in ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society (CTOS) community of experts on the minimum requirements for the evaluation of activity of systemic treatments.

BACKGROUND: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. METHODS: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021). RESULTS: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. CONCLUSIONS: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.
Authors
Stacchiotti, S; Maria Frezza, A; Demetri, GD; Blay, J-Y; Bajpai, J; Baldi, GG; Baldini, EH; Benjamin, RS; Bonvalot, S; Bovée, JVMG; Callegaro, D; Casali, PG; D'Angelo, SP; Davis, EJ; Dei Tos, AP; Demicco, EG; Desai, J; Dileo, P; Eriksson, M; Gelderblom, H; George, S; Gladdy, RA; Gounder, MM; Gupta, AA; Haas, R; Hayes, A; Hohenberger, P; Jones, KB; Jones, RL; Kasper, B; Kawai, A; Kirsch, DG; Kleinerman, ES; Le Cesne, A; Maestro, R; Martin Broto, J; Maki, RG; Miah, AB; Palmerini, E; Patel, SR; Raut, CP; Razak, ARA; Reed, DR; Rutkowski, P; Sanfilippo, RG; Sbaraglia, M; Schaefer, I-M; Strauss, DC; Strauss, SJ; Tap, WD; Thomas, DM; Trama, A; Trent, JC; van der Graaf, WTA; van Houdt, WJ; von Mehren, M; Wilky, BA; Fletcher, CDM; Gronchi, A; Miceli, R; Wagner, AJ
URI
https://scholars.duke.edu/individual/pub1534892
PMID
36031697
Source
pubmed
Published In
Cancer Treat Rev
Volume
110
Published Date
Start Page
102455
DOI
10.1016/j.ctrv.2022.102455

A Randomized Trial of Pembrolizumab & Radiotherapy Versus Radiotherapy in High-Risk Soft Tissue Sarcoma of the Extremity (SU2C-SARC032).

Authors
Saif, A; Verbus, EA; Sarvestani, AL; Teke, ME; Lambdin, J; Hernandez, JM; Kirsch, DG
MLA Citation
Saif, Areeba, et al. “A Randomized Trial of Pembrolizumab & Radiotherapy Versus Radiotherapy in High-Risk Soft Tissue Sarcoma of the Extremity (SU2C-SARC032).Annals of Surgical Oncology, Nov. 2022. Epmc, doi:10.1245/s10434-022-12762-z.
URI
https://scholars.duke.edu/individual/pub1556542
PMID
36396869
Source
epmc
Published In
Annals of Surgical Oncology
Published Date
DOI
10.1245/s10434-022-12762-z

Identification and targeting of a HES1-YAP1-CDKN1C functional interaction in fusion-negative rhabdomyosarcoma.

Rhabdomyosarcoma (RMS), a cancer characterized by features of skeletal muscle, is the most common soft-tissue sarcoma of childhood. With 5-year survival rates among high-risk groups at < 30%, new therapeutics are desperately needed. Previously, using a myoblast-based model of fusion-negative RMS (FN-RMS), we found that expression of the Hippo pathway effector transcriptional coactivator YAP1 (YAP1) permitted senescence bypass and subsequent transformation to malignant cells, mimicking FN-RMS. We also found that YAP1 engages in a positive feedback loop with Notch signaling to promote FN-RMS tumorigenesis. However, we could not identify an immediate downstream impact of this Hippo-Notch relationship. Here, we identify a HES1-YAP1-CDKN1C functional interaction, and show that knockdown of the Notch effector HES1 (Hes family BHLH transcription factor 1) impairs growth of multiple FN-RMS cell lines, with knockdown resulting in decreased YAP1 and increased CDKN1C expression. In silico mining of published proteomic and transcriptomic profiles of human RMS patient-derived xenografts revealed the same pattern of HES1-YAP1-CDKN1C expression. Treatment of FN-RMS cells in vitro with the recently described HES1 small-molecule inhibitor, JI130, limited FN-RMS cell growth. Inhibition of HES1 in vivo via conditional expression of a HES1-directed shRNA or JI130 dosing impaired FN-RMS tumor xenograft growth. Lastly, targeted transcriptomic profiling of FN-RMS xenografts in the context of HES1 suppression identified associations between HES1 and RAS-MAPK signaling. In summary, these in vitro and in vivo preclinical studies support the further investigation of HES1 as a therapeutic target in FN-RMS.
Authors
Kovach, AR; Oristian, KM; Kirsch, DG; Bentley, RC; Cheng, C; Chen, X; Chen, P-H; Chi, J-TA; Linardic, CM
MLA Citation
Kovach, Alexander R., et al. “Identification and targeting of a HES1-YAP1-CDKN1C functional interaction in fusion-negative rhabdomyosarcoma.Mol Oncol, vol. 16, no. 20, Oct. 2022, pp. 3587–605. Pubmed, doi:10.1002/1878-0261.13304.
URI
https://scholars.duke.edu/individual/pub1534097
PMID
36037042
Source
pubmed
Published In
Mol Oncol
Volume
16
Published Date
Start Page
3587
End Page
3605
DOI
10.1002/1878-0261.13304