Kouros Owzar

Overview:

cancer pharmacogenomics
drug induced neuropathy, neutropenia and hypertension
statistical genetics
statistical methods for high-dimensional data
copulas
survival analysis
statistical computing

Positions:

Professor of Biostatistics and Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Director, DCI Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2002

University of North Carolina - Chapel Hill

Grants:

Preoperative Breast Radiotherapy: A Tool to Provide Individualized and Biologically-Based Radiation Therapy

Administered By
Radiation Oncology
Awarded By
Gateway for Cancer Research
Role
Collaborator
Start Date
End Date

mTOR Therapy in Prostate Cancer: Signatures of Response and Biology of Resistance

Administered By
Institutes and Centers
Awarded By
National Institutes of Health
Role
Statistician
Start Date
End Date

Health Disparity in African Americans: A Meta-analysis of Six Phase III Trials in Metastatic Castration-Resistant Prostate Cancer Men treated with Docetaxel

Administered By
Biostatistics & Bioinformatics
Awarded By
Department of Defense
Role
Collaborator
Start Date
End Date

Profiling the Adenosine Axis in Metastatic Colorectal Cancer

Administered By
Medicine, Medical Oncology
Awarded By
MedImmune, Inc.
Role
Statistician
Start Date
End Date

Computational Resources and Dissemination Core

Administered By
Integrative Genomics
Awarded By
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
End Date

Publications:

Long-Term Follow-up of CALGB (Alliance) 100001: Autologous Followed by Nonmyeloablative Allogeneic Transplant for Multiple Myeloma.

CALGB (Alliance) 100001 was a phase II study evaluating autologous stem cell transplant (ASCT) followed by nonmyeloablative allogeneic stem cell transplant (alloSCT) in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than 1 prior progression event. Conditioning for ASCT was with high-dose melphalan (200 mg/m2). The alloSCT reduced-intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m2/d i.v. on days -7 through -3) and cyclophosphamide (1 g/m2/d i.v. on days -4 through -3). The primary objective was to determine the 6-month post-alloSCT treatment-related mortality (TRM) rate. Additional objectives included determining the proportion of patients who could complete this tandem ASCT-alloSCT approach in a cooperative group setting, overall response rates, rates of donor chimerism, rates of graft-versus-host disease (GVHD), disease-free survival, and overall survival (OS). Sixty patients were enrolled, of whom 57 (95%) completed ASCT and 49 (82%) completed tandem ASCT-alloSCT. The TRM rate was 2% (1/49; 90% confidence interval, 0.10% to 9.3%). Moderate to severe (grades 2 to 3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of nonprotocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years. Similar to other studies, this study confirmed that tandem ASCT/alloSCT is associated with durable disease control in a subset of patients. This study demonstrated the feasibility of performing tandem ASCT/alloSCT in a cooperative group setting and determined that a fludarabine/cyclophosphamide RIC regimen is associated with a very low TRM rate.
Authors
Holstein, SA; Suman, VJ; Owzar, K; Santo, K; Benson, DM; Shea, TC; Martin, T; Silverman, M; Isola, L; Vij, R; Cheson, BD; Linker, C; Anderson, KC; Richardson, PG; McCarthy, PL
MLA Citation
Holstein, Sarah A., et al. “Long-Term Follow-up of CALGB (Alliance) 100001: Autologous Followed by Nonmyeloablative Allogeneic Transplant for Multiple Myeloma.Biol Blood Marrow Transplant, vol. 26, no. 8, Aug. 2020, pp. 1414–24. Pubmed, doi:10.1016/j.bbmt.2020.03.028.
URI
https://scholars.duke.edu/individual/pub1438112
PMID
32325171
Source
pubmed
Published In
Biol Blood Marrow Transplant
Volume
26
Published Date
Start Page
1414
End Page
1424
DOI
10.1016/j.bbmt.2020.03.028

Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genomewide association studies (GWAS) from two clinical cohorts treated with MTAs (Cancer and Leukemia Group B (CALGB) 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1 ; e.g., rs74497159, βCALGB 40101 per allele log hazard ratio (95% confidence interval (CI)) = 0.591 (0.254-0.928), βCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334-1.053); PMETA  = 3.62 × 10-7 ) were the most highly ranked associations based on P values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in induced pluripotent stem cell-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.
Authors
Chua, KC; Xiong, C; Ho, C; Mushiroda, T; Jiang, C; Mulkey, F; Lai, D; Schneider, BP; Rashkin, SR; Witte, JS; Friedman, PN; Ratain, MJ; McLeod, HL; Rugo, HS; Shulman, LN; Kubo, M; Owzar, K; Kroetz, DL
MLA Citation
Chua, Katherina C., et al. “Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.Clin Pharmacol Ther, June 2020. Pubmed, doi:10.1002/cpt.1958.
URI
https://scholars.duke.edu/individual/pub1448486
PMID
32562552
Source
pubmed
Published In
Clinical Pharmacology and Therapeutics
Published Date
DOI
10.1002/cpt.1958

The Long Noncoding RNA NEAT1 Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways.

Soft-tissue sarcomas (STS) are rare malignancies showing lineage differentiation toward diverse mesenchymal tissues. Half of all high-grade STSs develop lung metastasis with a median survival of 15 months. Here, we used a genetically engineered mouse model that mimics undifferentiated pleomorphic sarcoma (UPS) to study the molecular mechanisms driving metastasis. High-grade sarcomas were generated with Cre recombinase technology using mice with conditional mutations in Kras and Trp53 (KP) genes. After amputation of the limb bearing the primary tumor, mice were followed for the development of lung metastasis. Using RNA-sequencing of matched primary KP tumors and lung metastases, we found that the long noncoding RNA (lncRNA) Nuclear Enriched Abundant Transcript 1 (Neat1) is significantly upregulated in lung metastases. Furthermore, NEAT1 RNA ISH of human UPS showed that NEAT1 is upregulated within a subset of lung metastases compared with paired primary UPS. Remarkably, CRISPR/Cas9-mediated knockout of Neat1 suppressed the ability of KP tumor cells to colonize the lungs. To gain insight into the underlying mechanisms by which the lncRNA Neat1 promotes sarcoma metastasis, we pulled down Neat1 RNA and used mass spectrometry to identify interacting proteins. Interestingly, most Neat1 interacting proteins are involved in RNA splicing regulation. In particular, KH-Type Splicing Regulatory Protein (KHSRP) interacts with Neat1 and is associated with poor prognosis of human STS. Moreover, depletion of KHSRP suppressed the ability of KP tumor cells to colonize the lungs. Collectively, these results suggest that Neat1 and its interacting proteins, which regulate RNA splicing, are involved in mediating sarcoma metastasis. IMPLICATIONS: Understanding that lncRNA NEAT1 promotes sarcoma metastasis, at least in part, through interacting with the RNA splicing regulator KHSRP may translate into new therapeutic approaches for sarcoma.
Authors
Huang, J; Sachdeva, M; Xu, E; Robinson, TJ; Luo, L; Ma, Y; Williams, NT; Lopez, O; Cervia, LD; Yuan, F; Qin, X; Zhang, D; Owzar, K; Gokgoz, N; Seto, A; Okada, T; Singer, S; Andrulis, IL; Wunder, JS; Lazar, AJ; Rubin, BP; Pipho, K; Mello, SS; Giudice, J; Kirsch, DG
MLA Citation
Huang, Jianguo, et al. “The Long Noncoding RNA NEAT1 Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways.Mol Cancer Res, June 2020. Pubmed, doi:10.1158/1541-7786.MCR-19-1170.
URI
https://scholars.duke.edu/individual/pub1448363
PMID
32561656
Source
pubmed
Published In
Mol Cancer Res
Published Date
DOI
10.1158/1541-7786.MCR-19-1170

Predictive accuracy of markers or risk scores for interval censored survival data.

Methods for the evaluation of the predictive accuracy of biomarkers with respect to survival outcomes subject to right censoring have been discussed extensively in the literature. In cancer and other diseases, survival outcomes are commonly subject to interval censoring by design or due to the follow up schema. In this article, we present an estimator for the area under the time-dependent receiver operating characteristic (ROC) curve for interval censored data based on a nonparametric sieve maximum likelihood approach. We establish the asymptotic properties of the proposed estimator and illustrate its finite-sample properties using a simulation study. The application of our method is illustrated using data from a cancer clinical study. An open-source R package to implement the proposed method is available on Comprehensive R Archive Network.
MLA Citation
Wu, Yuan, et al. “Predictive accuracy of markers or risk scores for interval censored survival data.Stat Med, vol. 39, no. 18, Aug. 2020, pp. 2437–46. Pubmed, doi:10.1002/sim.8547.
URI
https://scholars.duke.edu/individual/pub1437823
PMID
32293745
Source
pubmed
Published In
Stat Med
Volume
39
Published Date
Start Page
2437
End Page
2446
DOI
10.1002/sim.8547

Plasmonic nanobiosensors for detection of microRNA cancer biomarkers in clinical samples.

MicroRNAs (miRNAs) play an important role in the regulation of biological processes and have demonstrated great potential as biomarkers for the early detection of various diseases, including esophageal adenocarcinoma (EAC) and Barrett's esophagus (BE), the premalignant metaplasia associated with EAC. Herein, we demonstrate the direct detection of the esophageal cancer biomarker, miR-21, in RNA extracted from 17 endoscopic tissue biopsies using the nanophotonics technology our group has developed, termed the inverse molecular sentinel (iMS) nanobiosensor, with surface-enhanced Raman scattering (SERS) detection. The potential of this label-free, homogeneous biosensor for cancer diagnosis without the need for target amplification was demonstrated by discriminating esophageal cancer and Barrett's esophagus from normal tissue with notable diagnostic accuracy. This work establishes the potential of the iMS nanobiosensor for cancer diagnostics via miRNA detection in clinical samples without the need for target amplification, validating the potential of this assay as part of a new diagnostic strategy. Combining miRNA diagnostics with the nanophotonics technology will result in a paradigm shift in achieving a general molecular analysis tool that has widespread applicability for cancer research as well as detection of cancer. We anticipate further development of this technique for future use in point-of-care testing as an alternative to histopathological diagnosis as our method provides a quick result following RNA isolation, allowing for timely treatment.
Authors
Crawford, BM; Wang, H-N; Stolarchuk, C; von Furstenberg, RJ; Strobbia, P; Zhang, D; Qin, X; Owzar, K; Garman, KS; Vo-Dinh, T
MLA Citation
Crawford, Bridget M., et al. “Plasmonic nanobiosensors for detection of microRNA cancer biomarkers in clinical samples.Analyst, vol. 145, no. 13, July 2020, pp. 4587–94. Pubmed, doi:10.1039/d0an00193g.
URI
https://scholars.duke.edu/individual/pub1441616
PMID
32436503
Source
pubmed
Published In
Analyst
Volume
145
Published Date
Start Page
4587
End Page
4594
DOI
10.1039/d0an00193g