Paraneoplastic Limbic Encephalitis with NMDA Receptor (NR1) Antibodies in Breast Cancer (S08.007)

Will, Andrea; Akalin, M

doi:10.1212/wnl.78.1_meetingabstracts.s08.007

Cited by 3 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While all of these findings support the potential use of anti-GluN1 therapeutics, concerns could arise from reports of anti-GluN1 encephalitis occurring in patients through centrally present anti-GluN1 antibodies and immune inflammation, as found in responses to ovarian teratomas, small-cell lung cancer, breast cancer, or to autoimmunity of unknown etiology. 9 – 11 While several of these cases are documented, only one of these was in a patient with small-cell lung cancer, one in a patient with breast cancer, and most in patients with ovarian teratoma of germinal cell origin. However, we have previously shown that all small-cell lung cancers and all breast cancers express functional NMDARs, 7 , 8 as do apparently all ovarian cancers (from our IHC studies), and only approximately 0.5% of ovarian cancers are represented by teratomas of germ-cell origin.…”

Section: Discussionmentioning

confidence: 99%

NMDA receptors are expressed in human ovarian cancer tissues and human ovarian cancer cell lines

North¹,

Liu²,

Tian³

et al. 2015

CPAA

View full text Add to dashboard Cite

We have earlier demonstrated that breast cancer and small-cell lung cancer express functional NMDA receptors that can be targeted to promote cancer cell death. Human ovarian cancer tissues and human ovarian cancer cell lines (SKOV3, A2008, and A2780) have now been shown to also express NMDA-receptor subunit 1 (GluN1) and subunit 2B (GluN2B). Seventeen ovarian cancers in two arrays were screened by immunohistochemistry using polyclonal antibodies that recognize an extracellular moiety on GluN1 and on GluN2B. These specimens comprised malignant tissue with pathology diagnoses of serous papillary cystadenocarcinoma, endometrioid adenocarcinoma, and clear-cell carcinoma. Additionally, archival tissues defined as ovarian adenocarcinoma from ten patients treated at this institute were also evaluated. All of the cancerous tissues demonstrated positive staining patterns with the NMDA-receptor antibodies, while no staining was found for tumor-adjacent normal tissues or sections of normal ovarian tissue. Human ovarian adenocarcinoma cell lines (A2008, A2780, SKOV3) were demonstrated to express GluN1 by Western blotting, but displayed different levels of expression. Through immunocytochemistry utilizing GluN1 antibodies and imaging using a confocal microscope, we were able to demonstrate that GluN1 protein is expressed on the surface of these cells. In addition to these findings, GluN2B protein was demonstrated to be expressed using polyclonal antibodies against this protein. Treatment of all ovarian cell lines with antibodies against GluN1 was found to result in decreased cell viability (P<0.001), with decreases to 10%–25% that of untreated cells. Treatment of control HEK293 cells with various dilutions of GluN1 antibodies had no effect on cell viability. The GluN1 antagonist MK-801 (dizocilpine maleate) and the GluN2B antagonist ifenprodil, like antibodies, dramatically decreased the viability of A2780 ovarian tumor cells (P<0.01). Treatment of A2780 tumor xenografts with ifenprodil (2.5 mg/kg body weight/day) significantly reduced tumor growth in nu/nu mice. Our findings suggest that both GluN1 and GluN2B proteins as membrane components could be readily available targets for the treatment of most ovarian cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

NMDA receptors are expressed in human ovarian cancer tissues and human ovarian cancer cell lines

North¹,

Liu²,

Tian³

et al. 2015

CPAA

View full text Add to dashboard Cite

show abstract

“…However, both antagonists readily cross the blood–brain barrier. While a potential complication in the use of tumor NMDA receptor blockade could be expected from the reports of autoimmune encephalitis that can occur in some cancer patients through the generation of antibodies against the GluN1 protein of NMDA receptors,14,15 this malady seems to be principally due to a rare central inflammatory reaction 16. Moreover, the NMDA antagonists used here have been successfully introduced for therapy in the treatment of conditions such as post-traumatic stress disorder and Alzheimer’s disease, without serious side effects 17,18.…”

Section: Introductionmentioning

confidence: 99%

<p>Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy</p>

North

Liu

Dragnev

et al. 2019

CPAA

View full text Add to dashboard Cite

BackgroundSmall-cell lung cancer (SCLC) has a poor prognosis since there is currently no effective therapy for commonly recurring disease. In our previous study, both primary and recurrent human tumors have been shown to express functional N-methyl-D-aspartate (NMDA) receptors, and blockade of these receptors with GluN1 and GluN2B antagonists decreased tumor cell viability in vitro, and growth of tumor xenografts in nu/nu mice.Materials and methodsIn this study, we examine the influence of the GluN2B antagonist ifenprodil and the channel-blocker antagonist memantine, on cell viability and growth of tumor xenografts of recurrent SCLC (rSCLC) in mice.ResultsBoth antagonists significantly reduced cell viability and levels of components of the ERK1/2 pathway, increased apoptosis, and at very safe levels significantly reduced the growth of tumors in mice. Each antagonist and topotecan had additive effects to reduce cell viability with significant synergy demonstrated for the case of memantine. More significantly, combination treatments of xenografts in mice with ifenprodil and the chemotherapeutic agent topotecan produced clear additive effects that completely stopped tumor growth. Moreover, the ifenprodil and topotecan combination showed excellent supra-addition or synergy of inhibition for tumors ≤300 mm in size (P=4.7E−4). Combination treatment of memantine with topotecan also showed clear addition but, unlike ifenprodil, no synergy for the doses chosen.ConclusionSince topotecan is a drug of choice for treatment of rSCLC, our findings suggest that combining this agent with NMDA receptor blockade using the GluN2B antagonist, ifenprodil, will significantly improve patient outcomes.

show abstract

“…We earlier reported NMDA receptors are commonly expressed by human neuroblastoma, breast cancer, small-cell lung cancer, and ovarian cancer, and blockade of these receptors inhibit tumor growth 12–15. A potential complication in the use of such NMDA receptor blockade could be expected from reports of autoimmune encephalitis that can occur in some cancer patients through the generation of antibodies to NMDA receptors 16–18. However, this malady seems to be principally due to a rare central inflammatory reaction, and NMDA antagonists has been successfully introduced for therapy in the treatment of Alzheimer’s disease and post traumatic stress disorder, without serious side effects 19–21.…”

Section: Introductionmentioning

confidence: 99%

“… 12 – 15 A potential complication in the use of such NMDA receptor blockade could be expected from reports of autoimmune encephalitis that can occur in some cancer patients through the generation of antibodies to NMDA receptors. 16 – 18 However, this malady seems to be principally due to a rare central inflammatory reaction, and NMDA antagonists has been successfully introduced for therapy in the treatment of Alzheimer’s disease and post traumatic stress disorder, without serious side effects. 19 – 21 Additionally, During et al 22 performed oral vaccination against GluN1 in mice and found there were no noticeable pathological effects induced through this treatment.…”

Section: Introductionmentioning

confidence: 99%

NMDA receptors are important regulators of pancreatic cancer and are potential targets for treatment

North¹,

Liu²,

Lin³

et al. 2017

CPAA

View full text Add to dashboard Cite

Pancreatic cancer, particularly adenocarcinoma of the pancreas, is a common disease with a poor prognosis. In this study, the importance of N-methyl-D-aspartate (NMDA) receptors for the growth and survival of pancreatic cancer was investigated. Immunohistochemistry performed with antibodies against GluN1 and GluN2B revealed that all invasive adenocarcinoma and neuroendocrine pancreatic tumors likely express these two NMDA receptor proteins. These proteins were found to be membrane components of pancreatic cancer cell lines, and both channel-blocker antagonist and GluN2B antagonist significantly reduced cell viability in vitro. Both types of antagonists caused an internalization of the receptors. Dizocilpine maleate (MK-801) and ifenprodil hemitartrate both significantly inhibited the growth of pancreatic tumor xenografts in nu/nu mice. These findings predict that, as for other solid tumors investigated by us, pancreatic cancer could be successfully treated, alone or in combination, with NMDA receptor antagonists or other receptor-inhibiting blocking agents.

show abstract

Paraneoplastic Limbic Encephalitis with NMDA Receptor (NR1) Antibodies in Breast Cancer (S08.007)

Cited by 3 publications

References 0 publications

NMDA receptors are expressed in human ovarian cancer tissues and human ovarian cancer cell lines

NMDA receptors are expressed in human ovarian cancer tissues and human ovarian cancer cell lines

<p>Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy</p>

NMDA receptors are important regulators of pancreatic cancer and are potential targets for treatment

Contact Info

Product

Resources

About