Neil Spector

Positions:

Sandra Coates Associate Professor

Medicine, Medical Oncology
School of Medicine

Associate Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Associate Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1982

University of Medicine and Dentistry of New Jersey

Intern, Medicine

University of Texas at Dallas

First Year Neurology Resident, Neurology

University of Texas at Dallas

Medical Resident, Medicine

University of Texas at Dallas

Grants:

Publications:

Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow.

PURPOSE: Acute and chronic graft-versus-host disease (GVHD) continues to be the major causes of morbidity and mortality after allogeneic bone marrow transplantation (BMT). In this study, we have evaluated the clinical effects of selective in vitro T-cell depletion of donor allogeneic bone marrow by using a single monoclonal antibody ([MoAb] anti-T12, CD6) and rabbit complement. This antibody recognizes mature T cells, but not other cellular elements such as natural-killer (NK) cells, B cells, and myeloid precursors. PATIENTS AND METHODS: From August 1983 to April 1991, 112 consecutive adult patients with hematologic malignancies underwent BMT with bone marrow from HLA-identical sibling donors. Marrow was harvested and depleted of mature T lymphocytes ex vivo by the use of three rounds of incubation with an anti-T12 antibody and rabbit complement. The preparative regimen consisted of cyclophosphamide and fractionated total body irradiation (TBI) in 108 patients. No patients received prophylactic immune suppression post-BMT. Purgation by anti-T12 was used as the only method for the prevention of GVHD. RESULTS: Twenty patients (18%) developed acute GVHD (grade 2 to 4); only eight patients developed chronic GVHD. The incidence of GVHD did not increase significantly with age. Only three of 112 patients (2.7%) exhibited acute graft failure. One patient developed late graft failure that was associated with cytomegalovirus (CMV) infection. Within the subset of 50 patients who had not previously undergone unsuccessful conventional therapy (acute leukemia in first remission or chronic myelogenous leukemia [CML] in stable phase), we estimated by the Kaplan-Meier method that the probability of disease-free survival was 50% at 3 years post-BMT, with a median follow-up of 44 months. The treatment-related mortality rate in this group was only 14% and was independent of patient age. CONCLUSIONS: We conclude that selective in vitro T-cell depletion with an anti-T12 monoclonal antibody effectively reduces the incidence of both acute and chronic GVHD after allogeneic BMT without compromising engraftment. Moreover, depletion of CD6-positive cells from donor marrow obviates the need to administer immune suppressive medications to the majority of patients. This approach reduces the morbidity and mortality of allogeneic BMT and permits the BMT of older patients.
Authors
Soiffer, RJ; Murray, C; Mauch, P; Anderson, KC; Freedman, AS; Rabinowe, SN; Takvorian, T; Robertson, MJ; Spector, N; Gonin, R
MLA Citation
Soiffer, R. J., et al. “Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow.J Clin Oncol, vol. 10, no. 7, July 1992, pp. 1191–200. Pubmed, doi:10.1200/JCO.1992.10.7.1191.
URI
https://scholars.duke.edu/individual/pub799729
PMID
1607923
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
10
Published Date
Start Page
1191
End Page
1200
DOI
10.1200/JCO.1992.10.7.1191

A role for the androgen receptor in the treatment of male breast cancer.

Male breast cancer (BC) is relatively rare, making up less than 1% of all breast cancer cases in the United States. Treatment guidelines for male BC are derived from studies on the treatment of female BC, and are based molecular and clinical characteristics, such as hormone receptor positivity. For female estrogen receptor positive (ER+) breast cancers, the standard of care includes three classes of endocrine therapies: selective estrogen receptor modulators, aromatase inhibitors, and pure anti-estrogens. In contrast to female ER+ breast cancers, there is less known about the optimal treatment for male ER+ BC. Furthermore, in contrast to ER, less is known about the role of the androgen receptor (AR) in male and female BC. We report here the treatment of a 28-year-old man with metastatic AR+, ER+ breast cancer otherwise refractory to chemotherapy, who has had a durable clinical response to hormonal suppression with the combination of aromatase inhibition (Letrozole) in conjunction with a GnRH agonist (Leuprolide).
Authors
Zhu, J; Davis, CT; Silberman, S; Spector, N; Zhang, T
MLA Citation
Zhu, Jason, et al. “A role for the androgen receptor in the treatment of male breast cancer.Crit Rev Oncol Hematol, vol. 98, Feb. 2016, pp. 358–63. Pubmed, doi:10.1016/j.critrevonc.2015.11.013.
URI
https://scholars.duke.edu/individual/pub1110983
PMID
26669267
Source
pubmed
Published In
Crit Rev Oncol Hematol
Volume
98
Published Date
Start Page
358
End Page
363
DOI
10.1016/j.critrevonc.2015.11.013

Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors.

ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically those expressed in tumor cell nuclei, to the development of therapeutic resistance to ErbB2 TKIs has not been previously shown. Here, we show that expression of a 95-kDa tyrosine phosphorylated form of ErbB2, herein referred to as p95L (lapatinib-induced p95) was increased in ErbB2(+) breast cancer cells treated with potent ErbB2 TKIs (lapatinib, GW2974). Expressed in tumor cell nuclei, tyrosine phosphorylation of p95L was resistant to inhibition by ErbB2 TKIs. Furthermore, the expression of p95L was increased in ErbB2(+) breast cancer models of acquired therapeutic resistance to lapatinib that mimic the clinical setting. Pretreatment with proteasome inhibitors blocked p95L induction in response to ErbB2 TKIs, implicating the role of the proteasome in the regulation of p95L expression. In addition, tyrosine phosphorylated C-terminal fragments of ErbB2, generated by alternate initiation of translation and similar in molecular weight to p95L, were expressed in tumor cell nuclei, where they too were resistant to inhibition by ErbB2 TKIs. When expressed in the nuclei of lapatinib-sensitive ErbB2(+) breast cancer cells, truncated ErbB2 rendered cells resistant to lapatinib-induced apoptosis. Elucidating the function of nuclear, truncated forms of ErbB2, and developing therapeutic strategies to block their expression and/or activation may enhance the clinical efficacy of ErbB2 TKIs.
Authors
Xia, W; Liu, Z; Zong, R; Liu, L; Zhao, S; Bacus, SS; Mao, Y; He, J; Wulfkuhle, JD; Petricoin, EF; Osada, T; Yang, X-Y; Hartman, ZC; Clay, TM; Blackwell, KL; Lyerly, HK; Spector, NL
MLA Citation
Xia, Wenle, et al. “Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors.Mol Cancer Ther, vol. 10, no. 8, Aug. 2011, pp. 1367–74. Pubmed, doi:10.1158/1535-7163.MCT-10-0991.
URI
https://scholars.duke.edu/individual/pub760962
PMID
21673090
Source
pubmed
Published In
Mol Cancer Ther
Volume
10
Published Date
Start Page
1367
End Page
1374
DOI
10.1158/1535-7163.MCT-10-0991

HER2 therapy. Small molecule HER-2 tyrosine kinase inhibitors

Overexpression of the human epidermal growth factor receptor (HER)-2 oncogenic receptor tyrosine kinase, which occurs in 25% of breast cancers, portends poor clinical outcome and consequently represents an attractive target for therapeutic intervention. Small molecule tyrosine kinase inhibitors that compete with ATP binding at the cytoplasmic catalytic kinase domain of HER-2 block autophosphorylation and activation of HER-2, resulting in inhibition of downstream proliferation and survival signals. These agents have exhibited clinical activity in patients with HER-2 overexpressing breast cancers. Here we review the development of HER-2 tyrosine kinase inhibitors, their mechanisms of action, their biological and clinical activities, their safety profile, and combination strategies including conventional cytotoxics and other targeted agents. © 2007 BioMed Central Ltd.
Authors
Spector, N; Xia, W; El-Hariry, I; Yarden, Y; Bacus, S
MLA Citation
Spector, N., et al. “HER2 therapy. Small molecule HER-2 tyrosine kinase inhibitors.” Breast Cancer Research, vol. 9, no. 2, Mar. 2007. Scopus, doi:10.1186/bcr1652.
URI
https://scholars.duke.edu/individual/pub697911
Source
scopus
Published In
Breast Cancer Research : Bcr
Volume
9
Published Date
DOI
10.1186/bcr1652

Sensitization of tumor cells to fas killing through overexpression of heat-shock transcription factor 1.

Activation of the heat-shock or stress response is generally considered a cytoprotective response to heat or other proteotoxic stresses. In mammalian cells, stress-induced transcription of heat-shock genes is regulated by heat-shock transcription factor 1 (HSF1). We now show that activation of the Fas death receptor transactivates HSF1 in HeLa cells, a Fas-expressing cervical carcinoma line. Whereas HSF1 is constitutively expressed in a non-DNA-binding, transcriptionally inactive state, activation of Fas leads to enhanced transcription of a heat-shock reporter gene. The effects of Fas on heat-shock-gene transcription do not appear to be a consequence of cell death as they (1) precede apoptotic changes and (2) are not abrogated by YVAD-CMK, an inhibitor of Fas apoptosis that acts by blocking downstream effector proteases. Despite expressing Fas, HeLa cells are relatively insensitive to Fas-mediated killing, indicating that Fas expression alone, although necessary, is not sufficient for apoptosis. By overexpressing a constitutively activated form of HSF1, we sensitize HeLa cells to Fas-mediated killing. These findings shed new light on the interaction between two of the most evolutionarily conserved cell programs in nature, the Fas death pathway and the heat-shock response. Strategies designed to upregulate HSF1 in tumor cells, either through pharmacologic or gene-therapy approaches will hopefully provide a means with which to sensitize tumors to the killing effects of cancer therapies operating through the Fas receptor.
Authors
Xia, W; Voellmy, R; Spector, NL
MLA Citation
Xia, W., et al. “Sensitization of tumor cells to fas killing through overexpression of heat-shock transcription factor 1.J Cell Physiol, vol. 183, no. 3, June 2000, pp. 425–31. Pubmed, doi:10.1002/(SICI)1097-4652(200006)183:3<425::AID-JCP16>3.0.CO;2-M.
URI
https://scholars.duke.edu/individual/pub697884
PMID
10797318
Source
pubmed
Published In
Journal of Cellular Physiology
Volume
183
Published Date
Start Page
425
End Page
431
DOI
10.1002/(SICI)1097-4652(200006)183:3<425::AID-JCP16>3.0.CO;2-M