Dorothy Sipkins

Positions:

Associate Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Associate Research Professor in Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1999

Stanford University, School of Medicine

Ph.D. 1999

Stanford University, School of Medicine

Internship and Residency, Internal Medicine

Massachusetts General Hospital

Hematology-Oncology Fellowship, Hematology Oncology

Dana-Farber Cancer Institute

Grants:

Targeting sphingosine kinase 2 for the treatment of multiple myeloma

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

Defining the Rules of Breast Cancer Cell Traffic Through Bone

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

Targeting Dormant Breast Cancer Micrometastases to Prevent Disease Relapse

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
American Cancer Society, Inc.
Role
Principal Investigator
Start Date
End Date

Role of Osteopontin in Induction of Leukemia Dormancy in the Bone Marrow

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
American Cancer Society, Inc.
Role
Principal Investigator
Start Date
End Date

Studying the Effects of Combined E-Selectin/CXCR4 Inhibition on Breast Cancer Cell Metastasis, Growth and Immune Regulation

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
GlycoMimetics, Inc
Role
Principal Investigator
Start Date
End Date

Publications:

Stem cell factor expression in B cell malignancies is influenced by the niche.

Our group has previously demonstrated that expression of the cytokine stem cell factor (SCF) by leukemic blasts is a frequent finding in pre-B acute lymphoblastic leukemia (ALL). Whether SCF expression is a feature of other B cell malignancies and whether cross-talk from the local microenvironment modulates malignant cell SCF production are, however, unknown. Here we show using immunohistochemistry that SCF is expressed by a wide variety of indolent and aggressive B cell malignancies involving the bone marrow (BM) or lymph nodes (LNs). In diseases such as follicular lymphoma (FL), however, where lymphoma cells uniquely associate with the BM endosteal niche, BM lymphoma does not express SCF, while LN involvement is SCF positive. In contrast, cases of FL with high-grade transformation in the BM are SCF positive. These data suggest that lymphoma cell interaction with the endosteal niche inhibits SCF production, and that FL cells become independent of this microenvironment effect following transformation.
Authors
Fox, MF; Pontier, A; Gurbuxani, S; Sipkins, DA
MLA Citation
Fox, Matthew F., et al. “Stem cell factor expression in B cell malignancies is influenced by the niche.Leuk Lymphoma, vol. 54, no. 10, Oct. 2013, pp. 2274–80. Pubmed, doi:10.3109/10428194.2013.777067.
URI
https://scholars.duke.edu/individual/pub1025908
PMID
23418895
Source
pubmed
Published In
Leuk Lymphoma
Volume
54
Published Date
Start Page
2274
End Page
2280
DOI
10.3109/10428194.2013.777067

ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging.

The expression of leukocyte adhesion molecules in the intact brains of mice with experimental autoimmune encephalitis (EAE) was visualized by Magnetic Resonance Imaging (MRI) through the use of a new, target-specific MR contrast agent. Antibody-conjugated paramagnetic liposomes (ACPLs) were designed to achieve in vivo targeting of molecules expressed on vascular endothelium, while providing sufficient signal enhancement at these sites for detection by MRI. ACPLs targeted to intercellular adhesion molecule-1 (ICAM-1), an endothelial leukocyte receptor upregulated on cerebral microvasculature during EAE, were administered to diseased mice. Fluorescence microscopy confirmed that fluorescently-tagged ACPLs were localized to central nervous system (CNS) microvasculature in a pattern consistent with ICAM-1 upregulation described immunohistochemically. High resolution MRI of mouse brains ex vivo demonstrated that ACPL binding conferred significant enhancement of signal intensity (SI) as compared to control images. These results suggest that ACPLs can be used as MRI contrast agents to visualize specific molecules expressed on vascular endothelium during disease.
Authors
Sipkins, DA; Gijbels, K; Tropper, FD; Bednarski, M; Li, KC; Steinman, L
MLA Citation
Sipkins, D. A., et al. “ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging.J Neuroimmunol, vol. 104, no. 1, Apr. 2000, pp. 1–9. Pubmed, doi:10.1016/s0165-5728(99)00248-9.
URI
https://scholars.duke.edu/individual/pub1025892
PMID
10683508
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
104
Published Date
Start Page
1
End Page
9
DOI
10.1016/s0165-5728(99)00248-9

Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy.

Malignant cells may evade death from cytotoxic agents if they are in a dormant state. The host microenvironment plays important roles in cancer progression, but how niches might control cancer cell dormancy is little understood. Here we show that osteopontin (OPN), an extracellular matrix molecule secreted by osteoblasts, can function to anchor leukemic blasts in anatomic locations supporting tumor dormancy. We demonstrate that acute lymphoblastic leukemia (ALL) cells specifically adhere to OPN in vitro and secrete OPN when localized to the endosteal niche in vivo. Using intravital microscopy to perform imaging studies of the calvarial bone marrow (BM) of xenografted mice, we show that OPN is highly expressed adjacent to dormant tumor cells within the marrow. Inhibition of the OPN-signaling axis significantly increases the leukemic cell Ki-67 proliferative index and leads to a twofold increase in tumor burden in treated mice. Moreover, using cell-cycle-dependent Ara-C chemotherapy to produce minimal residual disease (MRD) in leukemic mice, we show that OPN neutralization synergizes with Ara-C to reduce detectable BM MRD. Taken together, these data suggest that ALL interacts with extracellular OPN within the malignant BM, and that this interaction induces cell cycle exit in leukemic blasts, protecting them from cytotoxic chemotherapy.
Authors
Boyerinas, B; Zafrir, M; Yesilkanal, AE; Price, TT; Hyjek, EM; Sipkins, DA
MLA Citation
Boyerinas, Benjamin, et al. “Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy.Blood, vol. 121, no. 24, June 2013, pp. 4821–31. Pubmed, doi:10.1182/blood-2012-12-475483.
URI
https://scholars.duke.edu/individual/pub1025904
PMID
23589674
Source
pubmed
Published In
Blood
Volume
121
Published Date
Start Page
4821
End Page
4831
DOI
10.1182/blood-2012-12-475483

Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging.

Angiogenesis, the formation of new blood vessels, is a requirement for malignant tumor growth and metastasis. In the absence of angiogenesis, local tumor expansion is suppressed at a few millimeters and cells lack routes for distant hematogenous spread. Clinical studies have demonstrated that the degree of angiogenesis is correlated with the malignant potential of several cancers, including breast cancer and malignant melanoma. Moreover, the expression of a specific angiogenesis marker, the endothelial integrin alphaVbeta3, has been shown to correlate with tumor grade. However, studies of tumor angiogenesis such as these have generally relied on invasive procedures, adequate tissue sampling and meticulous estimation of histologic microvessel density. In the present report, we describe a novel approach to detecting angiogenesis in vivo using magnetic resonance imaging (MRI) and a paramagnetic contrast agent targeted to endothelial alphaVbeta3 via the LM609 monoclonal antibody. This approach provided enhanced and detailed imaging of rabbit carcinomas by directly targeting paramagnetic agents to the angiogenic vasculature. In addition, angiogenic 'hot spots' not seen by standard MRI were detected. Our strategy for MR imaging of alphaVbeta3 thus represents a non-invasive means to assess the growth and malignant phenotype of tumors.
Authors
Sipkins, DA; Cheresh, DA; Kazemi, MR; Nevin, LM; Bednarski, MD; Li, KC
MLA Citation
Sipkins, D. A., et al. “Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging.Nat Med, vol. 4, no. 5, May 1998, pp. 623–26. Pubmed, doi:10.1038/nm0598-623.
URI
https://scholars.duke.edu/individual/pub1025891
PMID
9585240
Source
pubmed
Published In
Nature Medicine
Volume
4
Published Date
Start Page
623
End Page
626
DOI
10.1038/nm0598-623

Polycythemia Vera and Chronic Idiopathic Myelofibrosis CD34+ Cells Preferentially Traffic to Splenic Niches

<jats:title>Abstract</jats:title> <jats:p>Abstract 1750</jats:p> <jats:sec> <jats:title>Background:</jats:title> <jats:p>Polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF) are both clonal disorders of CD34+ hematopoietic stem and progenitor cells (HSPC) that undergo inappropriate expansion. The pathological CD34+ clones from both disorders are found at increased levels in the peripheral blood of patients, indicating that the interactions between these CD34+ cells and tissue HSPC niches are different from normal HSPC. Other studies have implicated deficiencies in the CXCR4 signaling axis as a possible reason for the abnormal trafficking of HSPCs in PV and CIMF. We set out to functionally test the importance of CXCR4 for the interactions of HSPCs collected from peripheral blood of patients with PV and CIMF with the bone marrow and other tissue microenvironments.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>We purified CD34+ cells from peripheral blood of patients with PV or CIMF, labeled them with fluorescent trackers, and engrafted them into unmanipulated SCID mice. Using video rate, scanning confocal microscopy we tracked CD34+ cell interactions with bone marrow, spleen and liver. To functionally test the role of CXCR4 in the homing of patient CD34+ cells to different microenvironments, we treated CD34+ cells with a blocking antibody prior to engraftment.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Flow cytometry revealed that PV CD34+ cells had significantly lower surface expression of CXCR4 than control HSPCs (PV mean: 32.93% positive, range: 14.8–55.1; Control mean: 58.85% positive, range: 33.5–78.7; p value = 0.018) while CIMF samples had scattered CXCR4 expression (mean 61.2% positive range: 0.6–95.4) PV CD34+ cells migrated toward SDF-1 in migration assays, demonstrating that although they had lower surface CXCR4 expression, they were still able to respond to signals from the environment through this receptor. In vivo imaging of mice after engraftment revealed that PV and CIMF CD34+ cells had decreased BM homing compared to control HSPCs. However, CD34+ cells from PV and CIMF patients homed to similar areas of bone marrow vasculature as control cells. Treating CD34+ cells with a blocking antibody against CXCR4 before engraftment significantly reduced the number of PV and CIMF cells that homed to the bone marrow, indicating that their bone marrow homing still relied on CXCR4. Interestingly, there were an increased number of PV and CMF cells that homed to the spleen at baseline compared to control HSPC, suggesting that a distinct homing mechanism favored PV and CMF cell trafficking to the spleen over the BM. The number of cells that homed to the spleen increased upon antibody blockade of CXCR4, indicating that splenic homing of CD34+ cells did not depend on CXCR4/SDF-1 interactions.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>CD34+ HSPC from PV and CIMF patients and controls homed to similar areas of the BM, although PV and CIMF cells had significantly decreased BM homing. Conversely, PV and CIMF CD34+ cells homed to the spleen in significantly higher numbers than control cells. PV, CIMF and control CD34+ cells were all dependent on CXCR4 for maximal BM homing. Splenic homing was not CXCR4 dependent, however, and PV and CIMF cells homed to the spleen in higher numbers when BM homing was inhibited by CXCR4 blockade. Taken together, we conclude that unique signaling mechanisms regulate trafficking of CD34+ cells to the BM vs. the splenic microenvironments. PV and CIMF CD34+ cells have an abnormal response to these tissue signals, resulting in their preferential homing to the spleen. Molecularly targeted therapies with the Jak2 inhibitors significantly decrease splenomegaly in CIMF patients, although they do not reverse the BM disease process. Recent evidence in a mouse model suggests that the BM is in fact a sanctuary site for disease during treatment with these agents. Whether PV and CIMF CD34+ cells in patients can escape apoptosis during treatment by trafficking to more favorable microenvironments is unknown. Our study suggests that an increased understanding of the mechanisms that these cells use to engage different tissue niches could aid the treatment of these diseases.</jats:p> </jats:sec> <jats:sec> <jats:title>Disclosures:</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec>
Authors
Horton, B; Zafrir, M; Wales, P; Pontier, A; Tefferi, A; Sipkins, DA
MLA Citation
Horton, Brendan, et al. “Polycythemia Vera and Chronic Idiopathic Myelofibrosis CD34+ Cells Preferentially Traffic to Splenic Niches.” Blood, vol. 120, no. 21, American Society of Hematology, 2012, pp. 1750–1750. Crossref, doi:10.1182/blood.v120.21.1750.1750.
URI
https://scholars.duke.edu/individual/pub1025898
Source
crossref
Published In
Blood
Volume
120
Published Date
Start Page
1750
End Page
1750
DOI
10.1182/blood.v120.21.1750.1750