Sandeep Dave

Positions:

Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1999

Northwestern University

Medical Resident, Medicine

Northwestern University

Fellow in Hematology-Oncology, Medicine

National Institutes of Health

Grants:

Clinico-Genomic Assessment of Performance Status in Elderly AML Patients

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Co-Mentor
Start Date
End Date

Genetic and genomic signatures of long-term radiation exposure in non-human primates

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Wake Forest University School Of Medicine
Role
Principal Investigator
Start Date
End Date

Understanding the context-dependent roles of mutations in lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Phase 1 Trial of Panobinostat + Ruxolitnib for Relapsed/Refactory Diffused Large B Cell Lymphoma (DLBCL)

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Lymphoma Research Foundation of America
Role
Mentor
Start Date
End Date

Understanding the Context-Dependent Roles of Mutations in Lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that typically causes asymptomatic infection but can promote B lymphoid tumors in the immune suppressed. In vitro, EBV infection of primary B cells stimulates glycolysis during immortalization into lymphoblastoid cell lines (LCLs). Lactate export during glycolysis is crucial for continued proliferation of many cancer cells-part of a phenomenon known as the "Warburg effect"- and is mediated by monocarboxylate transporters (MCTs). However, the role of MCTs has yet to be studied in EBV-associated malignancies, which display Warburg-like metabolism in vitro. Here, we show that EBV infection of B lymphocytes directly promotes temporal induction of MCT1 and MCT4 through the viral proteins EBNA2 and LMP1, respectively. Functionally, MCT1 was required for early B cell proliferation, and MCT4 up-regulation promoted acquired resistance to MCT1 antagonism in LCLs. However, dual MCT1/4 inhibition led to LCL growth arrest and lactate buildup. Metabolic profiling in LCLs revealed significantly reduced oxygen consumption rates (OCRs) and NAD+/NADH ratios, contrary to previous observations of increased OCR and unaltered NAD+/NADH ratios in MCT1/4-inhibited cancer cells. Furthermore, U-<sup>13</sup>C<sub>6</sub>-glucose labeling of MCT1/4-inhibited LCLs revealed depleted glutathione pools that correlated with elevated reactive oxygen species. Finally, we found that dual MCT1/4 inhibition also sensitized LCLs to killing by the electron transport chain complex I inhibitors phenformin and metformin. These findings were extended to viral lymphomas associated with EBV and the related gammaherpesvirus KSHV, pointing at a therapeutic approach for targeting both viral lymphomas.
Authors
Bonglack, EN; Messinger, JE; Cable, JM; Ch'ng, J; Parnell, KM; Reinoso-Vizcaíno, NM; Barry, AP; Russell, VS; Dave, SS; Christofk, HR; Luftig, MA
MLA Citation
Bonglack, Emmanuela N., et al. “Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas.Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 25, June 2021. Epmc, doi:10.1073/pnas.2022495118.
URI
https://scholars.duke.edu/individual/pub1485641
PMID
34161263
Source
epmc
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
118
Published Date
DOI
10.1073/pnas.2022495118

Phase 1 study of belinostat (PXD-101) and bortezomib (Velcade, PS-341) in patients with relapsed or refractory acute leukemia and myelodysplastic syndrome.

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation.
Authors
Holkova, B; Shafer, D; Yazbeck, V; Dave, S; Bose, P; Tombes, MB; Shrader, E; Wan, W; Bandyopadhyay, D; Weir, C; Collins, EB; Garnett, A; Kmieciak, M; Roberts, JD; Garcia-Manero, G; Grant, S
MLA Citation
Holkova, Beata, et al. “Phase 1 study of belinostat (PXD-101) and bortezomib (Velcade, PS-341) in patients with relapsed or refractory acute leukemia and myelodysplastic syndrome.Leuk Lymphoma, vol. 62, no. 5, May 2021, pp. 1187–94. Pubmed, doi:10.1080/10428194.2020.1861270.
URI
https://scholars.duke.edu/individual/pub1471146
PMID
33356689
Source
pubmed
Published In
Leuk Lymphoma
Volume
62
Published Date
Start Page
1187
End Page
1194
DOI
10.1080/10428194.2020.1861270

Non-Hodgkin Lymphomas: Malignancies Arising from Mature B Cells.

Non-Hodgkin lymphomas (NHLs) are a diverse group of entities, both clinically and molecularly. Here, we review the evolution of classification schemes in B-cell lymphoma, noting the now standard WHO classification system that is based on immune cell-of-origin and molecular phenotypes. We review how lymphomas arise throughout the B-cell development process as well as the molecular and clinical features of prominent B-cell lymphomas. We provide an overview of the major progress that has occurred over the past decade in terms of our molecular understanding of these diseases. We discuss treatment options available and focus on a number of the diverse research tools that have been employed to improve our understanding of these diseases. We discuss the problem of heterogeneity in lymphomas and anticipate that the near future will bring significant advances that provide a measurable impact on NHL outcomes.
Authors
Shingleton, J; Wang, J; Baloh, C; Dave, T; Davis, N; Happ, L; Jadi, O; Kositsky, R; Li, X; Love, C; Panea, R; Qin, Q; Reddy, A; Singhi, N; Smith, E; Thakkar, D; Dave, SS
MLA Citation
Shingleton, Jennifer, et al. “Non-Hodgkin Lymphomas: Malignancies Arising from Mature B Cells.Cold Spring Harb Perspect Med, vol. 11, no. 3, Mar. 2021. Pubmed, doi:10.1101/cshperspect.a034843.
URI
https://scholars.duke.edu/individual/pub1435031
PMID
32152246
Source
pubmed
Published In
Cold Spring Harbor Perspectives in Medicine
Volume
11
Published Date
DOI
10.1101/cshperspect.a034843

Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma.

BACKGROUND: Significant racial differences have been observed in the incidence and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) in the United States, but to the authors' knowledge it remains unclear whether genomic differences contribute to these disparities. METHODS: To understand the influences of genetic ancestry on tumor genomic alterations, the authors estimated the genetic ancestry of 1001 previously described patients with DLBCL using unsupervised model-based Admixture global ancestry analysis applied to exome sequencing data and examined the mutational profile of 150 DLBCL driver genes in tumors obtained from this cohort. RESULTS: Global ancestry prediction identified 619 patients with >90% European ancestry, 81 patients with >90% African ancestry, and 50 patients with >90% Asian ancestry. Compared with patients with DLBCL with European ancestry, patients with African ancestry were aged >10 years younger at the time of diagnosis and were more likely to present with B symptoms, elevated serum lactate dehydrogenase, extranodal disease, and advanced stage disease. Patients with African ancestry demonstrated worse overall survival compared with patients with European ancestry (median, 4.9 years vs 8.8 years; P = .04). Recurrent mutations of MLL2 (KMT2D), HIST1H1E, MYD88, BCL2, and PIM1 were found across all ancestry groups, suggesting shared mechanisms underlying tumor biology. The authors also identified 6 DLBCL driver genes that were more commonly mutated in patients with African ancestry compared with patients with European ancestry: ATM (21.0% vs 7.75%; P < .001), MGA (19.7% vs 5.33%; P < .001), SETD2 (17.3% vs 5.17%; P < .001), TET2 (12.3% vs 5.82%; P = .029), MLL3 (KMT2C) (11.1% vs 4.36%; P = .013), and DNMT3A (11.1% vs 4.52%; P = .016). CONCLUSIONS: Distinct prevalence and patterns of mutation highlight an important difference in the mutational landscapes of DLBCL arising in different ancestry groups. To the authors' knowledge, the results of the current study provide the first-ever characterization of genetic alterations among patients with African descent who are diagnosed with DLBCL.
Authors
Lee, MJ; Koff, JL; Switchenko, JM; Jhaney, CI; Harkins, RA; Patel, SP; Dave, SS; Flowers, CR
MLA Citation
Lee, Michelle J., et al. “Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma.Cancer, vol. 126, no. 15, Aug. 2020, pp. 3493–503. Pubmed, doi:10.1002/cncr.32866.
URI
https://scholars.duke.edu/individual/pub1443342
PMID
32469082
Source
pubmed
Published In
Cancer
Volume
126
Published Date
Start Page
3493
End Page
3503
DOI
10.1002/cncr.32866

Identifying transcriptional profiles and evaluating prognostic biomarkers of HIV-associated diffuse large B-cell lymphoma from Malawi.

Lymphoma incidence in sub-Saharan Africa (SSA) is increasing due to HIV and population aging. Diffuse Large B-cell lymphoma (DLBCL), the most common lymphoma in SSA and worldwide, is highly associated with HIV, but molecular studies of HIV-associated DLBCL are scarce globally. We describe profiling of DLBCL from Malawi, aiming to elucidate tumor biology and identify clinically meaningful biomarkers specifically for SSA. Between June 1, 2013 and June 1, 2016, 59 cases of DLBCL (32 HIV+/27 HIV-) enrolled in the Kamuzu Central Hospital Lymphoma Study were characterized, of which 54 (92%) were negative for Epstein-Barr virus. Gene expression profiling (GEP) by whole transcriptome sequencing was performed on the first 36 cases (22 HIV+/14 HIV-). Immunohistochemistry (IHC) and GEP results were compared with published data and correlated to clinical outcome and pathologic features. Unsupervised clustering strongly segregated DLBCL by HIV status (p = 0.0003, Chi-squared test), indicating a marked contribution of HIV to expression phenotype. Pathway analysis identified that HIV-associated tumors were enriched in hypoxia, oxidative stress, and metabolism related gene expression patterns. Cell-of-origin subtype, determined by sequencing and IHC, did not associate with differences in overall survival (OS), while Ki-67 proliferation index ≥80% was associated with inferior OS in HIV+ DLBCL only (p = 0.03) and cMYC/BCL2 co-expression by IHC was negatively prognostic across the entire cohort (p = 0.01). This study provides among the first molecular characterizations of DLBCL from SSA, demonstrates marked gene expression differences by HIV status, and identifies genomic and immunophenotypic characteristics that can inform future basic and clinical investigations.
Authors
Fedoriw, Y; Selitsky, S; Montgomery, ND; Kendall, SM; Richards, KL; Du, W; Tomoka, T; Mulenga, M; Parker, JS; Dave, SS; Gopal, S
MLA Citation
Fedoriw, Yuri, et al. “Identifying transcriptional profiles and evaluating prognostic biomarkers of HIV-associated diffuse large B-cell lymphoma from Malawi.Mod Pathol, vol. 33, no. 8, Aug. 2020, pp. 1482–91. Pubmed, doi:10.1038/s41379-020-0506-3.
URI
https://scholars.duke.edu/individual/pub1433143
PMID
32080349
Source
pubmed
Published In
Modern Pathology
Volume
33
Published Date
Start Page
1482
End Page
1491
DOI
10.1038/s41379-020-0506-3