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:

Phase 2 clinical trial of TORC1 inhibition with everolimus in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Activation of the PI3K-Akt-mTOR signaling pathway is common in advanced castration resistant prostate cancer (CRPC), typically through PTEN loss. Preclinical studies suggest that Akt-driven CaP cells are genetically susceptible to mammalian target of rapamycin (mTOR, or TORC1) inhibition. Everolimus is a Food and Drug Administration-approved inhibitor of TORC1. MATERIALS AND METHODS: We performed a phase II study of everolimus in patients with mCRPC, who were refractory to standard of care hormonal and chemotherapeutic agents. Patients received everolimus 10 mg daily until unacceptable adverse events or disease progression. The primary efficacy outcome was confirmed 50% or greater prostate-specific antigen (PSA) response, using a 2 stage design with futility rules. Paired biopsies were utilized to assess for treatment effect on downstream TORC1 targets as well as tumor cell proliferation and apoptosis. RESULTS: Out of 35 men enrolled with heavily pretreated mCRPC, 32 were evaluable for clinical efficacy. No PSA responses were observed, the median progression-free survival time was 3.6 months (95% confidence interval = 2.9-4.8) and the median overall survival time was 10.4 months (95% confidence interval = 5.8-15.8). Several patients had declines in serum PSA upon cessation of everolimus. Thus, the study was closed due to clinical futility. The most common toxicities were mucositis, fatigue, anorexia, hypertriglyceridemia, and thrombocytopenia and were largely low grade. Pathologic evaluation of paired metastatic biopsies demonstrated consistent inhibition of pS6, a downstream mTOR pharmacodynamics biomarker, but the tumor proliferation marker Ki-67 increased with therapy. CONCLUSIONS: Everolimus demonstrated predictable toxicity in advanced and heavily pretreated patients with mCRPC. No clinical or clear pathologic effects despite downstream TORC1 target inhibition, suggesting that single agent everolimus has no clinical utility in men with mCRPC.
Authors
George, DJ; Halabi, S; Healy, P; Jonasch, D; Anand, M; Rasmussen, J; Wood, SY; Spritzer, C; Madden, JF; Armstrong, AJ
MLA Citation
George, Daniel J., et al. “Phase 2 clinical trial of TORC1 inhibition with everolimus in men with metastatic castration-resistant prostate cancer..” Urol Oncol, Sept. 2019. Pubmed, doi:10.1016/j.urolonc.2019.08.015.
URI
https://scholars.duke.edu/individual/pub1411800
PMID
31522863
Source
pubmed
Published In
Urol Oncol
Published Date
DOI
10.1016/j.urolonc.2019.08.015

Caring for every patient, learning from every patient

Authors
MLA Citation
George, D. J. “Caring for every patient, learning from every patient.” Clinical Advances in Hematology and Oncology, vol. 17, no. 7, July 2019.
URI
https://scholars.duke.edu/individual/pub1416993
Source
scopus
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
17
Published Date
Start Page
364

Treatment options for patients with prostate cancer who develop metastatic disease after hormonal therapy.

Authors
MLA Citation
George, Daniel J. “Treatment options for patients with prostate cancer who develop metastatic disease after hormonal therapy..” Clin Adv Hematol Oncol, vol. 17, no. 7, July 2019, pp. 382–85.
URI
https://scholars.duke.edu/individual/pub1406905
PMID
31449503
Source
pubmed
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
17
Published Date
Start Page
382
End Page
385

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer.

Circulating tumor cell (CTC) and cell-free (cf) DNA-based genomic alterations are increasingly being used for clinical decision-making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low-pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium-223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR-V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC-specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA-discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR-V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.
Authors
Gupta, S; Hovelson, DH; Kemeny, G; Halabi, S; Foo, W-C; Anand, M; Somarelli, JA; Tomlins, SA; Antonarakis, ES; Luo, J; Dittamore, RV; George, DJ; Rothwell, C; Nanus, DM; Armstrong, AJ; Gregory, SG
URI
https://scholars.duke.edu/individual/pub1421556
PMID
31705765
Source
pubmed
Published In
Genes Chromosomes Cancer
Published Date
DOI
10.1002/gcc.22824

PD-L1 Expression and Clinical Outcomes to Cabozantinib, Everolimus, and Sunitinib in Patients with Metastatic Renal Cell Carcinoma: Analysis of the Randomized Clinical Trials METEOR and CABOSUN.

PURPOSE: Programmed death-ligand 1 (PD-L1) status by IHC is prognostic in metastatic renal cell carcinoma (mRCC), and its role as a potential predictive biomarker is under investigation. Using tumor tissue from the METEOR (NCT01865747) and CABOSUN (NCT01835158) clinical trials, we explored whether PD-L1 expression and the extent of the immune cell infiltrate can serve as prognostic and/or predictive biomarkers for cabozantinib and other targeted agents. EXPERIMENTAL DESIGN: IHC double staining for PD-L1 and CD45/CD163 (immune cell markers) was performed on tumor tissue from METEOR (n = 306) and CABOSUN (n = 110) clinical trials. Immune cell density and MET expression levels were also analyzed. Our primary aim was to correlate progression-free survival (PFS) by independent central review with PD-L1 status in patients treated with cabozantinib, everolimus (METEOR), or sunitinib (CABOSUN). Overall survival (OS) was also interrogated. RESULTS: Tumor cell (TC) PD-L1 expression (≥1% cutoff) was detected in 29% and 23% of tumors from patients in the METEOR and CABOSUN trials, respectively. On univariate analysis, patients with PD-L1-positive TC had poorer PFS and OS than patients with PD-L1-negative TC on both trials, independent of therapy. On multivariable analysis and when combining the two trials, the association between TC PD-L1 expression and OS was statistically significant for all patients (P = 0.034) and for patients treated with cabozantinib only (P = 0.038). Cabozantinib was associated with improved PFS (HR < 0.70) and OS (HR < 0.85) compared with everolimus and sunitinib irrespective of PD-L1 expression. CONCLUSIONS: Higher PD-L1 expression results in worse clinical outcomes in mRCC treated with targeted therapy. Furthermore, PD-L1 expression is not predictive of response to cabozantinib therapy.
Authors
Flaifel, A; Xie, W; Braun, DA; Ficial, M; Bakouny, Z; Nassar, AH; Jennings, RB; Escudier, B; George, DJ; Motzer, RJ; Morris, MJ; Powles, T; Wang, E; Huang, Y; Freeman, GJ; Choueiri, TK; Signoretti, S
MLA Citation
Flaifel, Abdallah, et al. “PD-L1 Expression and Clinical Outcomes to Cabozantinib, Everolimus, and Sunitinib in Patients with Metastatic Renal Cell Carcinoma: Analysis of the Randomized Clinical Trials METEOR and CABOSUN..” Clin Cancer Res, vol. 25, no. 20, Oct. 2019, pp. 6080–88. Pubmed, doi:10.1158/1078-0432.CCR-19-1135.
URI
https://scholars.duke.edu/individual/pub1402500
PMID
31371341
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
25
Published Date
Start Page
6080
End Page
6088
DOI
10.1158/1078-0432.CCR-19-1135