Ken Young

Overview:

I am a clinically-oriented diagnostic physician with clinical expertise in the pathologic diagnosis of hematologic cancers including tumors of the bone marrow, lymphoid tissue, spleen and pre-malignant hematologic conditions. Another area of interest is blood cancer classification with molecular and genetic profiling. In my research program, we focus on molecular mechanisms of tumor progression, cell-of-origin, biomarkers, and novel therapeutic strategies in lymphoma, myeloma and leukemia. In addition to patient care and translational research, medical education and scientific communication are also part of interest. Many residents, fellows, graduates and postdocs have worked and been trained in our program. We perform comprehensive clinical and research functions that include bone marrow, lymphoma pathology, clinical flow cytometry, cytogenetics, molecular diagnostics and outside services.

I am currently the director of hematopathology division that provides diagnostic consultation services and relevant specialized testing for patients with various types of acute and chronic leukemia, lymphoma and benign hematologic disorders. I am specialized in the diagnosis of hematological disorders, including acute and chronic leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, B and T-cell lymphomas, Hodgkin lymphoma, cutaneous and orbital lymphomas and benign bone marrow and lymph node disorders. 

Positions:

Professor of Pathology

Pathology
School of Medicine

Professor and Director, Hematopathology Division in the Department of Pathology

Pathology
School of Medicine

Professor and Chief, Blood Cancer Pathology Program in the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1984

Zhejiang University (China)

Grants:

Genetic and Epigenetic Biomarkers for B-cell Lymphoma

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Genetic and Epigenetic Biomarkers for B-cell Lymphoma

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies.

CD19-targeted chimeric antigen receptor T (CAR T) cell therapy is a promising option to treat relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). However, the majority of CAR T-treated patients will eventually progress and require salvage treatment, for which there is no current standard. In this study, we analyzed data from 6 patients with R/R DLBCL who experienced progression following CD19-CAR T therapy, and then received CD19-specific CAR T cells that express a PD-1/CD28 chimeric switch-receptor (CD19-PD-1/CD28-CAR T) as salvage therapy at our institution. After the second infusion of CAR T cells, 3 of 6 patients achieved complete remissions and the duration of the response of responsive patients ranged from 8 to 25 months. One patient showed a stable disease. In contrast, 2/6 patients died on 60 days because of progression disease. Importantly, no severe neurologic toxicity or cytokine release syndrome was observed. These data suggest that CD19-PD-1/CD28-CAR-T cells, a novel anti-CD19 CAR-T cell therapy, elicit a potent and durable anticancer response, and can be used in the post-CD19-CAR T failure setting.
Authors
Liang, Y; Liu, H; Lu, Z; Lei, W; Zhang, C; Li, P; Liang, A; Young, KH; Qian, W
MLA Citation
Liang, Yun, et al. “CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies.J Hematol Oncol, vol. 14, no. 1, Feb. 2021, p. 26. Pubmed, doi:10.1186/s13045-021-01044-y.
URI
https://scholars.duke.edu/individual/pub1474923
PMID
33593414
Source
pubmed
Published In
Journal of Hematology & Oncology
Volume
14
Published Date
Start Page
26
DOI
10.1186/s13045-021-01044-y

Targeting PD-L1 in non-small cell lung cancer using CAR T cells.

Antibodies against programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the landscape of therapies for non-small cell lung carcinoma (NSCLC); however, the majority of patients do not respond to these agents. In addition, hyperprogressive disease (HPD) develops in a larger portion of NSCLC patients treated with PD-1/PD-L1 inhibitors than in patients treated with standard chemotherapy. The use of chimeric antigen receptor (CAR) T cells has been successful to treat blood cancers but not for solid tumors like NSCLC. In this work, we constructed CAR T cells that target PD-L1 and evaluated their efficacy in NSCLC with either high or low PD-L1 expression. PD-L1-CAR T cells exhibited antigen-specific activation, cytokine production, and cytotoxic activity against PD-L1high NSCLC cells and xenograft tumors. Furthermore, the addition of a subtherapeutic dose of local radiotherapy improved the efficacy of PD-L1-CAR T cells against PD-L1low NSCLC cells and tumors. Our findings indicate that PD-L1-CAR T cells represent a novel therapeutic strategy for patients with PD-L1-positive NSCLC, particularly for those who are susceptible to HPD.
Authors
Liu, M; Wang, X; Li, W; Yu, X; Flores-Villanueva, P; Xu-Monette, ZY; Li, L; Zhang, M; Young, KH; Ma, X; Li, Y
MLA Citation
Liu, Ming, et al. “Targeting PD-L1 in non-small cell lung cancer using CAR T cells.Oncogenesis, vol. 9, no. 8, Aug. 2020, p. 72. Pubmed, doi:10.1038/s41389-020-00257-z.
URI
https://scholars.duke.edu/individual/pub1456347
PMID
32792499
Source
pubmed
Published In
Oncogenesis
Volume
9
Published Date
Start Page
72
DOI
10.1038/s41389-020-00257-z

Addition of Drug-Response Specific Micro-RNAs to the International Prognostic Index Improves Prognostic Stratification of GCB-DLBCL Patients Treated with R-CHOP

<jats:p>Background: Patients with Diffuse large B-cell lymphoma (DLBCL) in approximately 40% of cases suffer from primary refractory disease and treatment induced immuno-chemotherapy resistance demonstrating that standard provided treatment regimens are not sufficient to cure all patients. Early detection of resistance is of great importance and defining microRNA (miRNA) involvement in resistance could be useful to guide treatment selection and help monitor treatment administration while sparing patients for inefficient, but still toxic therapy.</jats:p> <jats:p>Concept and Aims: With information on drug-response specific miRNAs, we hypothesized that multi-miRNA panels can improve robustness of individual clinical markers and serve as a prognostic classifier predicting disease progression in DLBCL patients.</jats:p> <jats:p>Methods: Fifteen DLBCL cell lines were tested for sensitivity towards rituximab (R), cyclophosphamide (C), doxorubicin (H), and vincristine (O). Cell line specific seeding concentrations was used to ensure exponential growth and each cell line was subjected to 16 concentrations in serial 2-fold dilutions and number of metabolic active cells was evaluated after 48 hours of drug exposure using MTS assay. For each drug, we ranked the cell lines according to their sensitivity and categorized them as sensitive, intermediate responsive, or resistant. Differential miRNA expression analysis between sensitive and resistant cell lines identified 43 miRNAs to be associated with response to compounds of the R-CHOP regimen, by selecting probes with a log fold change larger than 2. Baseline miRNA expression data were obtained for each cell line in untreated condition, and differential miRNA expression analysis identified 43 miRNAs associated to response to R-CHOP. Using the Affymetrix HG-U133+2 platform, expression levels of the miRNA precursors were assessed in 701 diagnostic DLBCL biopsies, and miRNA-panel classifiers were build using multiple Cox regression or random survival forest.</jats:p> <jats:p>Results: Generated prognostic miRNA-panel classifiers were tested for predictive accuracies and were subsequently evaluated by Brier scores and time varying area under the ROC curves (tAUC). Progression-free survival (PFS) was chosen as the outcome, since it is a treatment evaluation parameter as closely as possible to the time of drug exposure and the tested miRNAs were all associated directly to drug specific response. Furthermore, overall survival (OS) was used for verification of findings. Comparison of analyses conducted for the respective cohorts (All DLBCL, ABC, and GCB patients) showed the lowest prediction errors for all models within the GCB subclass with a multivariate Cox miRNA-panel model including miR-146a, miR-155, miR-21, miR-34a, and miR-23a~miR-27a~miR-24-2 cluster performed the best and successfully stratified GCB-DLBCL patients into high- and low-risk of disease progression. In addition, combination of the miRNA-panel and international prognostic index (IPI) substantially increased prognostic performance in GCB classified patients, indicating a prognostic signal from the response-specific miRNAs independent of IPI.</jats:p> <jats:p>In conclusion: We found as proof of concept that adding gene expression data detecting drug-response specific miRNAs to the clinically established IPI improved the prognostic stratification of GCB-DLBCL patients treated with R-CHOP.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec>
Authors
Dybkær, K; Due, H; Brøndum, RF; Young, KH; Bøgsted, M
MLA Citation
Dybkær, Karen, et al. “Addition of Drug-Response Specific Micro-RNAs to the International Prognostic Index Improves Prognostic Stratification of GCB-DLBCL Patients Treated with R-CHOP.” Blood, vol. 134, no. Supplement_1, American Society of Hematology, 2019, pp. 1623–1623. Crossref, doi:10.1182/blood-2019-122351.
URI
https://scholars.duke.edu/individual/pub1470249
Source
crossref
Published In
Blood
Volume
134
Published Date
Start Page
1623
End Page
1623
DOI
10.1182/blood-2019-122351

Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2-targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. IMPLICATIONS: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.
Authors
Deng, M; Xu-Monette, ZY; Pham, LV; Wang, X; Tzankov, A; Fang, X; Zhu, F; Visco, C; Bhagat, G; Dybkaer, K; Chiu, A; Tam, W; Zu, Y; Hsi, ED; You, H; Huh, J; Ponzoni, M; Ferreri, AJM; Møller, MB; Parsons, BM; Hagemeister, F; van Krieken, JH; Piris, MA; Winter, JN; Li, Y; Xu, B; Liu, P; Young, KH
MLA Citation
Deng, Manman, et al. “Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents.Mol Cancer Res, vol. 19, no. 2, Feb. 2021, pp. 249–60. Pubmed, doi:10.1158/1541-7786.MCR-20-0466.
URI
https://scholars.duke.edu/individual/pub1464350
PMID
33154093
Source
pubmed
Published In
Mol Cancer Res
Volume
19
Published Date
Start Page
249
End Page
260
DOI
10.1158/1541-7786.MCR-20-0466

Novel bioinformatic classification system for genetic signatures identification in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a spectrum of disease comprising more than 30% of non-Hodgkin lymphomas. Although studies have identified several molecular subgroups, the heterogeneous genetic background of DLBCL remains ambiguous. In this study we aimed to develop a novel approach and to provide a distinctive classification system to unravel its molecular features. METHOD: A cohort of 342 patient samples diagnosed with DLBCL in our hospital were retrospectively enrolled in this study. A total of 46 genes were included in next-generation sequencing panel. Non-mutually exclusive genetic signatures for the factorization of complex genomic patterns were generated by random forest algorithm. RESULTS: A total of four non-mutually exclusive signatures were generated, including those with MYC-translocation (MYC-trans) (n = 62), with BCL2-translocation (BCL2-trans) (n = 69), with BCL6-translocation (BCL6-trans) (n = 108), and those with MYD88 and/or CD79B mutations (MC) signatures (n = 115). Comparison analysis between our model and traditional mutually exclusive Schmitz's model demonstrated consistent classification pattern. And prognostic heterogeneity existed within EZB subgroup of de novo DLBCL patients. As for prognostic impact, MYC-trans signature was an independent unfavorable prognostic factor. Furthermore, tumors carrying three different signature markers exhibited significantly inferior prognoses compared with their counterparts with no genetic signature. CONCLUSION: Compared with traditional mutually exclusive molecular sub-classification, non-mutually exclusive genetic fingerprint model generated from our study provided novel insight into not only the complex genetic features, but also the prognostic heterogeneity of DLBCL patients.
Authors
Zhang, W; Yang, L; Guan, YQ; Shen, KF; Zhang, ML; Cai, HD; Wang, JC; Wang, Y; Huang, L; Cao, Y; Wang, N; Tan, XH; Young, KH; Xiao, M; Zhou, JF
MLA Citation
Zhang, Wei, et al. “Novel bioinformatic classification system for genetic signatures identification in diffuse large B-cell lymphoma.Bmc Cancer, vol. 20, no. 1, July 2020, p. 714. Pubmed, doi:10.1186/s12885-020-07198-1.
URI
https://scholars.duke.edu/individual/pub1453931
PMID
32736575
Source
pubmed
Published In
Bmc Cancer
Volume
20
Published Date
Start Page
714
DOI
10.1186/s12885-020-07198-1

Research Areas:

Biomarkers, Pharmacological
Genetic Association Studies
Leukemia
Lymphoblastic leukemia
Lymphoma
Multiple Myeloma