FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4Citation formats

  • External authors:
  • Lana McClements
  • Stephanie Annett
  • Anita Yakkundi
  • Martin O'Rourke
  • Andrea Valentine
  • Nermeen Moustafa
  • Abdelrahim Alqudah
  • Fiona Furlong
  • Amy Short
  • Stuart A. McIntosh
  • Helen O. McCarthy
  • Tracy Robson

Standard

FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. / McClements, Lana; Annett, Stephanie; Yakkundi, Anita; O'Rourke, Martin; Valentine, Andrea; Moustafa, Nermeen; Alqudah, Abdelrahim; Simões, Bruno M.; Furlong, Fiona; Short, Amy; McIntosh, Stuart A.; McCarthy, Helen O.; Clarke, Robert B.; Robson, Tracy.

In: BMC Cancer, Vol. 19, No. 1, 351, 2019.

Research output: Contribution to journalArticle

Harvard

McClements, L, Annett, S, Yakkundi, A, O'Rourke, M, Valentine, A, Moustafa, N, Alqudah, A, Simões, BM, Furlong, F, Short, A, McIntosh, SA, McCarthy, HO, Clarke, RB & Robson, T 2019, 'FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4' BMC Cancer, vol. 19, no. 1, 351. https://doi.org/10.1186/s12885-019-5500-0

APA

McClements, L., Annett, S., Yakkundi, A., O'Rourke, M., Valentine, A., Moustafa, N., ... Robson, T. (2019). FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. BMC Cancer, 19(1), [351]. https://doi.org/10.1186/s12885-019-5500-0

Vancouver

Author

McClements, Lana ; Annett, Stephanie ; Yakkundi, Anita ; O'Rourke, Martin ; Valentine, Andrea ; Moustafa, Nermeen ; Alqudah, Abdelrahim ; Simões, Bruno M. ; Furlong, Fiona ; Short, Amy ; McIntosh, Stuart A. ; McCarthy, Helen O. ; Clarke, Robert B. ; Robson, Tracy. / FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. In: BMC Cancer. 2019 ; Vol. 19, No. 1.

Bibtex

@article{a50ef75fba184f06bc5af3a8ed87988b,
title = "FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4",
abstract = "Background: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. Results: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n ≥ 3, p < 0.05) and invasion (n ≥ 3, p < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n ≥ 3, p < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p < 0.05) or 21 days (p < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.",
keywords = "AD-01, ALM201, Breast cancer stem cells, DLL4, Endocrine therapy, Estrogen receptor, FKBPL, Letrozole, Metastasis, Notch4, Tamoxifen, Triple negative breast cancer",
author = "Lana McClements and Stephanie Annett and Anita Yakkundi and Martin O'Rourke and Andrea Valentine and Nermeen Moustafa and Abdelrahim Alqudah and Sim{\~o}es, {Bruno M.} and Fiona Furlong and Amy Short and McIntosh, {Stuart A.} and McCarthy, {Helen O.} and Clarke, {Robert B.} and Tracy Robson",
year = "2019",
doi = "10.1186/s12885-019-5500-0",
language = "English",
volume = "19",
journal = "B M C Cancer",
issn = "1471-2407",
publisher = "Springer Nature",
number = "1",

}

RIS

TY - JOUR

T1 - FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

AU - McClements, Lana

AU - Annett, Stephanie

AU - Yakkundi, Anita

AU - O'Rourke, Martin

AU - Valentine, Andrea

AU - Moustafa, Nermeen

AU - Alqudah, Abdelrahim

AU - Simões, Bruno M.

AU - Furlong, Fiona

AU - Short, Amy

AU - McIntosh, Stuart A.

AU - McCarthy, Helen O.

AU - Clarke, Robert B.

AU - Robson, Tracy

PY - 2019

Y1 - 2019

N2 - Background: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. Results: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n ≥ 3, p < 0.05) and invasion (n ≥ 3, p < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n ≥ 3, p < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p < 0.05) or 21 days (p < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.

AB - Background: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. Results: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n ≥ 3, p < 0.05) and invasion (n ≥ 3, p < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n ≥ 3, p < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p < 0.05) or 21 days (p < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.

KW - AD-01

KW - ALM201

KW - Breast cancer stem cells

KW - DLL4

KW - Endocrine therapy

KW - Estrogen receptor

KW - FKBPL

KW - Letrozole

KW - Metastasis

KW - Notch4

KW - Tamoxifen

KW - Triple negative breast cancer

UR - http://www.scopus.com/inward/record.url?scp=85064227574&partnerID=8YFLogxK

U2 - 10.1186/s12885-019-5500-0

DO - 10.1186/s12885-019-5500-0

M3 - Article

VL - 19

JO - B M C Cancer

JF - B M C Cancer

SN - 1471-2407

IS - 1

M1 - 351

ER -