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

Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety of afatinib, an irreversible ErbB family inhibitor, alone and in combination with vinorelbine in patients with HER2-positive IBC. This trial included prospectively planned exome analysis before and after afatinib monotherapy. METHODS AND FINDINGS: HER2-positive IBC patients received afatinib 40 mg daily until progression, and thereafter afatinib 40 mg daily and intravenous vinorelbine 25 mg/m2 weekly. The primary endpoint was clinical benefit; secondary endpoints were objective response (OR), duration of OR, and progression-free survival (PFS). Of 26 patients treated with afatinib monotherapy, clinical benefit was achieved in 9 patients (35%), 0 of 7 trastuzumab-treated patients and 9 of 19 trastuzumab-naïve patients. Following disease progression, 10 patients received afatinib plus vinorelbine, and clinical benefit was achieved in 2 of 4 trastuzumab-treated and 0 of 6 trastuzumab-naïve patients. All patients had treatment-related adverse events (AEs). Whole-exome sequencing of tumour biopsies taken before treatment and following disease progression on afatinib monotherapy was performed to assess the mutational landscape of IBC and evolutionary trajectories during therapy. Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. Planned exploratory analysis revealed that trastuzumab-naïve patients with tumours harbouring somatic activation of PI3K/Akt signalling had significantly shorter PFS compared to those without (p = 0.03). High genomic concordance between biopsies taken before and following afatinib resistance was observed with stable clonal structures in non-responding tumours, and evidence of branched evolution in 8 of 9 tumours analysed. Recruitment to the trial was terminated early following the LUX-Breast 1 trial, which showed that afatinib combined with vinorelbine had similar PFS and OR rates to trastuzumab plus vinorelbine but shorter overall survival (OS), and was less tolerable. The main limitations of this study are that the results should be interpreted with caution given the relatively small patient cohort and the potential for tumour sampling bias between pre- and post-treatment tumour biopsies. CONCLUSIONS: Afatinib, with or without vinorelbine, showed activity in trastuzumab-naïve HER2-positive IBC patients in a planned subgroup analysis. HER2-positive IBC is characterized by frequent TP53 gain-of-function mutations and a high mutational burden. The high mutational load associated with HER2-positive IBC suggests a potential role for checkpoint inhibitor therapy in this disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01325428.
Authors
Goh, G; Schmid, R; Guiver, K; Arpornwirat, W; Chitapanarux, I; Ganju, V; Im, S-A; Kim, S-B; Dechaphunkul, A; Maneechavakajorn, J; Spector, N; Yau, T; Afrit, M; Ahmed, SB; Johnston, SR; Gibson, N; Uttenreuther-Fischer, M; Herrero, J; Swanton, C
MLA Citation
Goh, Gerald, et al. “Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine.Plos Med, vol. 13, no. 12, Dec. 2016, p. e1002136. Pubmed, doi:10.1371/journal.pmed.1002136.
URI
https://scholars.duke.edu/individual/pub1168835
PMID
27923043
Source
pubmed
Published In
Plos Medicine
Volume
13
Published Date
Start Page
e1002136
DOI
10.1371/journal.pmed.1002136

What can we learn from the age- and race/ethnicity- specific rates of inflammatory breast carcinoma?

Inflammatory Breast Carcinoma (IBC), the most aggressive type of breast tumor with unique clinicopathological presentation, is hypothesized to have distinct etiology with a socioeconomic status (SES) component. Using the Surveillance, Epidemiology and End Results (SEER) Program data for 2004-2007, we compare incidence rates of IBC to non-inflammatory locally advanced breast cancer (LABC) among racial/ethnic groups with different SES. The analysis includes women 20-84 years of age. To examine evidence for the distinct etiology of IBC, we analyzed age-distribution patterns of IBC and non-inflammatory LABC, using a mathematical carcinogenesis model. Based on the Collaborative Staging Extension codes, 2,942 incident IBC cases (codes 71 and 73) and 5,721 non-inflammatory LABC cases (codes 40-62) were identified during the four-year study period. Age-adjusted rates of IBC among non-Hispanic White and Hispanic women were similar (2.5/100,000 in both groups). Similar rates were also found in non-inflammatory LABC in these two groups (4.8/100,000 and 4.2/100,000, respectively). In African-American women, the IBC (3.91/100,000) and non-inflammatory LABC (8.47/100,000) rates were greater compared with other ethnic/racial sub-groups. However, the ratio of rates of IBC/non-inflammatory LABC was similar among all the racial/ethnic groups, suggesting that African-American women are susceptible to aggressive breast tumors in general but not specifically to IBC. The mathematical model successfully predicted the observed age-specific rates of both examined breast tumors and revealed distinct patterns. IBC rates increased until age 65 and then slightly decreased, whereas non-inflammatory LABC rates steadily increased throughout the entire age interval. The number of critical transition carcinogenesis stages (m-stages) predicted by the model were 6.3 and 8.5 for IBC and non-inflammatory LABC, respectively, supporting different etiologies of these breast tumors.
Authors
Il'yasova, D; Siamakpour-Reihani, S; Akushevich, I; Akushevich, L; Spector, N; Schildkraut, J
MLA Citation
Il’yasova, Dora, et al. “What can we learn from the age- and race/ethnicity- specific rates of inflammatory breast carcinoma?Breast Cancer Res Treat, vol. 130, no. 2, Nov. 2011, pp. 691–97. Pubmed, doi:10.1007/s10549-011-1719-4.
URI
https://scholars.duke.edu/individual/pub737973
PMID
21850396
Source
pubmed
Published In
Breast Cancer Res Treat
Volume
130
Published Date
Start Page
691
End Page
697
DOI
10.1007/s10549-011-1719-4

Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells.

The human EGF receptor (HER) 2 receptor tyrosine kinase is a survival factor for human cardiomyocytes, and its inhibition may explain the increased incidence of cardiomyopathy associated with the anti-HER2 monoclonal antibody trastuzumab (Genentech, South San Francisco, CA), particularly in patients with prior exposure to cardiotoxic chemotherapies e.g., anthracyclines. Here, we show that GW2974 (HER2/EGF receptor tyrosine kinase inhibitor), but not trastuzumab, activates AMP-activated protein kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNFalpha-induced cell death. GW2974 stimulates calcium dependent fatty acid oxidation in vitro and in the myocardium of GW2974-treated rodents. Calcium chelation or siRNA-targeted AMPK knockdown blocks GW2974 induced fatty acid oxidation. In addition, inhibition of AMPK by a specific inhibitor resulted in increased killing of cardiomyocytes. Elucidating the effects of HER2-targeted therapies on AMPK may predict for risk of cardiomyopathy and provide a novel HER2-targeted strategy designed to protect myocardium from the pro-apoptotic effects of pro-inflammatory cytokines released in response to cardiac injury by chemotherapy or acute ischemia.
Authors
Spector, NL; Yarden, Y; Smith, B; Lyass, L; Trusk, P; Pry, K; Hill, JE; Xia, W; Seger, R; Bacus, SS
MLA Citation
Spector, Neil L., et al. “Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells.Proc Natl Acad Sci U S A, vol. 104, no. 25, June 2007, pp. 10607–12. Pubmed, doi:10.1073/pnas.0701286104.
URI
https://scholars.duke.edu/individual/pub697906
PMID
17556544
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
104
Published Date
Start Page
10607
End Page
10612
DOI
10.1073/pnas.0701286104

Tumor selective G2/M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine.

Two distinct benzodiazepine binding sites have been identified, (i) a central site restricted to brain and (ii) a ubiquitously expressed mitochondrial binding site, the so-called peripheral-type benzodiazepine receptor (PBR). In this paper, we show that a benzazepine referred to as BBL22 (2-amino 9-chloro-7-(2-fluorophenyl)-5H-pyrimidol[5,4-d][2]benzazepine), which is classified as a PBR ligand based on structure, induces arrest in G(2)/M phase of the cell cycle in human tumor cell lines of both epithelial and hematopoietic cellular origin. After G(2)/M arrest, several tumor types, notably prostate and certain breast cancer lines exhibited significant apoptosis. Ideally, cancer therapies should selectively target tumor cells while sparing normal cell counterparts. BBL22 exhibited such selectivity, as it did not affect the growth and survival of nonmalignant breast and prostate epithelial lines. Moreover, BBL22 demonstrated structural requirements for this selective antitumor activity as 11 structurally related PBR ligands, including high-affinity ligands Ro5-4864 and PK11195, failed to induce tumor cell growth arrest or apoptosis. The in vivo antitumor activity of BBL22 was examined in a human xenograft model of androgen-independent prostate cancer where BBL22 significantly reduced the growth of PC3 prostate tumors without eliciting overt toxicity. Identification of BBL22 represents a tumor selective therapeutic strategy for a variety of human tumors.
Authors
Xia, W; Spector, S; Hardy, L; Zhao, S; Saluk, A; Alemane, L; Spector, NL
MLA Citation
Xia, W., et al. “Tumor selective G2/M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine.Proc Natl Acad Sci U S A, vol. 97, no. 13, June 2000, pp. 7494–99. Pubmed, doi:10.1073/pnas.97.13.7494.
URI
https://scholars.duke.edu/individual/pub697918
PMID
10861014
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
97
Published Date
Start Page
7494
End Page
7499
DOI
10.1073/pnas.97.13.7494