Daniel George

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor in Surgery

Surgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1992

Duke University

Medical Resident, Medicine

Johns Hopkins University

Fellow in Medical Oncology, Medicine

Johns Hopkins University

Grants:

Plasma Angiome and Serum Androgens as Predictors of Overall Survival in Metastatic Prostate Cancer

Administered By
Medicine, Medical Oncology
Awarded By
Department of Defense
Role
Collaborator
Start Date
End Date

Alternative splicing and epithelial-mesenchymal plasticity in prostate tumors

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Collaborating Investigator
Start Date
End Date

Disparities in the Use of Oral Anticancer Agents in Kidney Cancer

Administered By
Population Health Sciences
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

Calithera CX-839-008

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
End Date

A Phase II open-label, Multicenter study of Apalutamide, Abiraterone Acetate and Prednisone in African American and Caucasian men with metastatic castrate-resistant prostate cancer

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
End Date

Publications:

Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC. METHODS: Tumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1 criteria. RESULTS: Patients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03). CONCLUSIONS: Overall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies.
Authors
Labriola, MK; Zhu, J; Gupta, R; McCall, S; Jackson, J; Kong, EF; White, JR; Cerqueira, G; Gerding, K; Simmons, JK; George, D; Zhang, T
MLA Citation
Labriola, Matthew Kyle, et al. “Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma.J Immunother Cancer, vol. 8, no. 1, Mar. 2020. Pubmed, doi:10.1136/jitc-2019-000319.
URI
https://scholars.duke.edu/individual/pub1435838
PMID
32221016
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
8
Published Date
DOI
10.1136/jitc-2019-000319

The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC).

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.
Authors
Rini, BI; Battle, D; Figlin, RA; George, DJ; Hammers, H; Hutson, T; Jonasch, E; Joseph, RW; McDermott, DF; Motzer, RJ; Pal, SK; Pantuck, AJ; Quinn, DI; Seery, V; Voss, MH; Wood, CG; Wood, LS; Atkins, MB
MLA Citation
Rini, Brian I., et al. “The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC).J Immunother Cancer, vol. 7, no. 1, Dec. 2019, p. 354. Pubmed, doi:10.1186/s40425-019-0813-8.
URI
https://scholars.duke.edu/individual/pub1424580
PMID
31856918
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
7
Published Date
Start Page
354
DOI
10.1186/s40425-019-0813-8

PD-L1 status and clinical outcomes to cabozantinib, sunitinib and everolimus in patients with metastatic clear-cell RCC treated on CABOSUN and METEOR clinical trials.

Authors
Choueiri, TK; Flaifel, A; Xie, W; Braun, D; Ficial, M; Jennings, R; Nassar, A; Escudier, B; George, DJ; Motzer, RJ; Morris, MJ; Powles, T; Wang, E; Huang, Y; Freeman, G; Signoretti, S
MLA Citation
Choueiri, T. K., et al. “PD-L1 status and clinical outcomes to cabozantinib, sunitinib and everolimus in patients with metastatic clear-cell RCC treated on CABOSUN and METEOR clinical trials.Ann Oncol, vol. 29 Suppl 8, 2018, p. viii726. Pubmed, doi:10.1093/annonc/mdy424.040.
URI
https://scholars.duke.edu/individual/pub1373629
PMID
32138002
Source
pubmed
Published In
Ann Oncol
Volume
29 Suppl 8
Published Date
Start Page
viii726
DOI
10.1093/annonc/mdy424.040

Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.

Disulfiram in conjunction with copper has been shown to be a potent anticancer agent. However, disulfiram's therapeutic potential in prostate cancer is hindered by off-target effects due to its reactive and nucleophilic thiol-containing component, diethyldithiocarbamate (DTC). To minimize undesirable reactivity, we have strategically blocked the thiol moiety in DTC with a cleavable p-aminobenzyl (pAB) group linked to peptide substrates recognized by prostate specific antigen (PSA). Here we report the synthesis and evaluation in cancer cell models of two PSA-activatable prodrugs: HPD (Ac-HSSKLQL-pAB-DTC and RPD (RSSYYSL-pAB-DTC). In vitro exposure to PSA was found to trigger activation of HPD and RPD to release diethyldithiocarbamate, and both prodrugs were found to induce toxicity in prostate cancer cells, with HPD showing the most promising selectivity. With copper supplementation, the IC50 of HPD was 1.4 µM in PSA-expressing LNCaP cells, and 11 µM in PC3 cells that do not express PSA. These studies demonstrate the utility of using peptide recognition handles to direct the activity of dithiocarbamate prodrugs for selective cytotoxicity of cancer cells.
Authors
Bakthavatsalam, S; Wiangnak, P; George, DJ; Zhang, T; Franz, KJ
MLA Citation
Bakthavatsalam, Subha, et al. “Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.Bioorg Med Chem Lett, vol. 30, no. 11, June 2020, p. 127148. Pubmed, doi:10.1016/j.bmcl.2020.127148.
URI
https://scholars.duke.edu/individual/pub1436721
PMID
32253061
Source
pubmed
Published In
Bioorg Med Chem Lett
Volume
30
Published Date
Start Page
127148
DOI
10.1016/j.bmcl.2020.127148

genitourinary tumours, non prostate Phase III trial of sunitinib (SU) vs placebo (PBO) as adjuvant treatment for high-risk renal cell carcinoma (RCC) after nephrectomy (S-TRAC)

Authors
Ravaud, A; Motzer, RJ; Pandha, HS; Staehler, M; George, D; Pantuck, AJ; Patel, A; Chang, YH; Escudier, B; Donskov, F; Magheli, A; Carteni, G; Laguerre, B; Tomczak, P; Breza, J; Gerletti, P; Lin, X; Lechuga, M; Martini, JF; Patard, JJ
MLA Citation
URI
https://scholars.duke.edu/individual/pub1241485
Source
scopus
Published In
Annals of Oncology
Volume
27
Published Date
Start Page
vi565
DOI
10.1093/annonc/mdw435.22