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:

Immunolight 2019 Renewal

Administered By
Biomedical Engineering
Role
Co-Principal Investigator
Start Date
End Date

Circumventing Therapeutic Resistance and the Emergency of Disseminated Breast Cancer Cells through Non-Invasive Optical

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
End Date

The Role of HER2 Signaling Networks in Early Stage Breast Cancer Initiation and Resistance to Tamoxifen Prevention

Administered By
Medicine, Medical Oncology
Role
Co Investigator
Start Date
End Date

ACOSOG Competing Renewal

Administered By
Duke Clinical Research Institute
Awarded By
National Institutes of Health
Role
Committee Chair
Start Date
End Date

Quantitative and Qualitative Differential Expression Proteomics

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

Publications:

Perspectives on Inflammatory Breast Cancer (IBC) Research, Clinical Management and Community Engagement from the Duke IBC Consortium.

Inflammatory breast cancer (IBC) is an understudied and aggressive form of breast cancer with a poor prognosis, accounting for 2-6% of new breast cancer diagnoses but 10% of all breast cancer-related deaths in the United States. Currently there are no therapeutic regimens developed specifically for IBC, and it is critical to recognize that all aspects of treating IBC - including staging, diagnosis, and therapy - are vastly different than other breast cancers. In December 2014, under the umbrella of an interdisciplinary initiative supported by the Duke School of Medicine, researchers, clinicians, research administrators, and patient advocates formed the Duke Consortium for IBC to address the needs of patients in North Carolina (an ethnically and economically diverse state with 100 counties) and across the Southeastern United States. The primary goal of this group is to translate research into action and improve both awareness and patient care through collaborations with local, national and international IBC programs. The consortium held its inaugural meeting on Feb 28, 2018, which also marked Rare Disease Day and convened national research experts, clinicians, patients, advocates, government representatives, foundation leaders, staff, and trainees. The meeting focused on new developments and challenges in the clinical management of IBC, research challenges and opportunities, and an interactive session to garner input from patients, advocates, and community partners that would inform a strategic plan toward continuing improvements in IBC patient care, research, and education.
Authors
Devi, GR; Hough, H; Barrett, N; Cristofanilli, M; Overmoyer, B; Spector, N; Ueno, NT; Woodward, W; Kirkpatrick, J; Vincent, B; Williams, KP; Finley, C; Duff, B; Worthy, V; McCall, S; Hollister, BA; Palmer, G; Force, J; Westbrook, K; Fayanju, O; Suneja, G; Dent, SF; Hwang, ES; Patierno, SR; Marcom, PK
MLA Citation
Devi, Gayathri R., et al. “Perspectives on Inflammatory Breast Cancer (IBC) Research, Clinical Management and Community Engagement from the Duke IBC Consortium.J Cancer, vol. 10, no. 15, 2019, pp. 3344–51. Pubmed, doi:10.7150/jca.31176.
URI
https://scholars.duke.edu/individual/pub1395729
PMID
31293637
Source
pubmed
Published In
Journal of Cancer
Volume
10
Published Date
Start Page
3344
End Page
3351
DOI
10.7150/jca.31176

Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.

PURPOSE: The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors. EXPERIMENTAL DESIGN: Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor. RESULTS: In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers. CONCLUSION: Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION: NCT00359190.
Authors
Spector, NL; Robertson, FC; Bacus, S; Blackwell, K; Smith, DA; Glenn, K; Cartee, L; Harris, J; Kimbrough, CL; Gittelman, M; Avisar, E; Beitsch, P; Koch, KM
MLA Citation
Spector, Neil L., et al. “Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.Plos One, vol. 10, no. 11, 2015, p. e0142845. Pubmed, doi:10.1371/journal.pone.0142845.
URI
https://scholars.duke.edu/individual/pub1111413
PMID
26571496
Source
pubmed
Published In
Plos One
Volume
10
Published Date
Start Page
e0142845
DOI
10.1371/journal.pone.0142845

Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.

The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress, suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab- and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific antiserum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine-induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific antiserum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted.
Authors
Morse, MA; Wei, J; Hartman, Z; Xia, W; Ren, X-R; Lei, G; Barry, WT; Osada, T; Hobeika, AC; Peplinski, S; Jiang, H; Devi, GR; Chen, W; Spector, N; Amalfitano, A; Lyerly, HK; Clay, TM
MLA Citation
Morse, Michael A., et al. “Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.Int J Cancer, vol. 126, no. 12, June 2010, pp. 2893–903. Pubmed, doi:10.1002/ijc.24995.
URI
https://scholars.duke.edu/individual/pub726619
PMID
19856307
Source
pubmed
Published In
Int J Cancer
Volume
126
Published Date
Start Page
2893
End Page
2903
DOI
10.1002/ijc.24995

Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers.

In breast cancer, overexpression of ErbB2 or aberrant regulation of survivin, a member of the inhibitor of apoptosis family, is associated with resistance to chemo/hormone therapy and predicts for a poor clinical outcome. A functional link between the two predictive factors has not been previously shown. Here, using genetic and pharmacologic approaches to block ErbB2 signaling, we show that ErbB2 regulates survivin protein expression in ErbB2-overexpressing breast cancer cells. Selective knockdown of ErbB2 using small interfering RNA markedly reduced survivin protein, resulting in apoptosis of ErbB2-overexpressing breast cancer cell lines such as BT474. Alternatively, inhibition of ErbB2 signaling using lapatinib (GW572016), a reversible small-molecule inhibitor of ErbB1/ErbB2 tyrosine kinases, at pharmacologically relevant concentrations, leads to marked inhibition of survivin protein with subsequent apoptosis. The effect of lapatinib on survivin seems to be predominantly posttranslational, mediated by ubiquitin-proteosome degradation as lactacystin, a proteosome inhibitor, reverses these effects. Furthermore, lapatinib down-regulated the expression of His-tagged survivin, which was under the transcriptional control of a heterologous promoter, providing additional evidence supporting a posttranslational mechanism of regulation. In contrast, trastuzumab and gefitinib failed to down-regulate survivin in ErbB2-overexpressing breast cancer cells. Importantly, the clinical relevance of these findings was illustrated in patients with ErbB2-overexpressing breast cancer whose clinical response to lapatinib was associated with marked inhibition of survivin in their tumors. These findings shed new light on the mechanism by which ErbB2 overexpression protects against apoptotic stimuli in breast cancer and identifies therapeutic interventions to improve clinical outcomes in these aggressive tumors.
Authors
Xia, W; Bisi, J; Strum, J; Liu, L; Carrick, K; Graham, KM; Treece, AL; Hardwicke, MA; Dush, M; Liao, Q; Westlund, RE; Zhao, S; Bacus, S; Spector, NL
MLA Citation
Xia, Wenle, et al. “Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers.Cancer Res, vol. 66, no. 3, Feb. 2006, pp. 1640–47. Pubmed, doi:10.1158/0008-5472.CAN-05-2000.
URI
https://scholars.duke.edu/individual/pub697915
PMID
16452223
Source
pubmed
Published In
Cancer Research
Volume
66
Published Date
Start Page
1640
End Page
1647
DOI
10.1158/0008-5472.CAN-05-2000

Analysis of the value of empiric vancomycin administration in febrile neutropenia occurring after autologous peripheral blood stem cell transplants.

We conducted a retrospective review of 125 patients undergoing high-dose therapy and stem cell rescue in order to evaluate the incidence of documented infection and the utility of the administration of vancomycin empirically. All patients received prophylactic oral quinolone therapy. Because neutropenia in this setting is relatively brief, 21 patients never manifested fever, and no patient died of infection. Of the remaining 104 patients, positive blood cultures were obtained in only 10, nine with a gram stain positive and one with a gram stain negative organism. Sixty-two patients without any evidence of gram positive infection received vancomycin according to the existing algorithm for care of neutropenic fevers. In this population of patients, empiric administration of vancomycin for neutropenic fevers without culture documentation appears to be unnecessary, could be discontinued safely and at substantial cost savings, and might slow the appearance of vancomycin-resistant organisms.
Authors
Koya, R; Andersen, J; Fernandez, H; Goodman, M; Spector, N; Smith, R; Hanlon, J; Cassileth, PA
MLA Citation
Koya, R., et al. “Analysis of the value of empiric vancomycin administration in febrile neutropenia occurring after autologous peripheral blood stem cell transplants.Bone Marrow Transplant, vol. 21, no. 9, May 1998, pp. 923–26. Pubmed, doi:10.1038/sj.bmt.1701201.
URI
https://scholars.duke.edu/individual/pub799715
PMID
9613785
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
21
Published Date
Start Page
923
End Page
926
DOI
10.1038/sj.bmt.1701201