FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer

被引：50

作者：

Annett, Stephanie ^{[1
,2
]}

Moore, Gillian ^{[1
]}

Short, Amy ^{[2
]}

Marshall, Andrea ^{[3
]}

McCrudden, Cian ^{[2
]}

Yakkundi, Anita ^{[2
]}

Das, Sudipto ^{[1
]}

McCluggage, W. Glenn ^{[4
]}

Nelson, Laura ^{[2
]}

Harley, Ian ^{[5
]}

Moustafa, Nermeen ^{[2
]}

Kennedy, Catherine J. ^{[6
,7
]}

Defazio, Anna ^{[6
,7
,8
]}

Brand, Alison ^{[6
,8
]}

Sharma, Raghwa ^{[8
,9
]}

Brennan, Donal ^{[10
]}

O'Toole, Sharon ^{[11
]}

O'Leary, John ^{[12
]}

Bates, Mark ^{[11
,12
]}

O'Riain, Ciaran ^{[13
]}

O'Connor, Darran ^{[1
]}

Furlong, Fiona ^{[2
]}

McCarthy, Helen ^{[2
]}

Kissenpfennig, Adrien ^{[14
]}

McClements, Lana ^{[14
,15
]}

Robson, Tracy ^{[1
,2
]}

机构：

[1] Royal Coll Surgeons Ireland, Sch Pharm & Biomol Sci, Irish Ctr Vasc Biol, Dublin, Ireland

[2] Queens Univ Belfast, Sch Pharm, Belfast, Antrim, North Ireland

[3] Univ Warwick, Warwick Clin Trials Unit, Coventry, W Midlands, England

[4] Belfast Hlth & Social Care Trust, Dept Pathol, Belfast, Antrim, North Ireland

[5] Belfast Hlth & Social Care Trust, Northern Ireland Gynaecol Canc Ctr, Belfast, Antrim, North Ireland

[6] Westmead Hosp, Dept Gynaecol Oncol, Sydney, NSW, Australia

[7] Westmead Inst Med Res, Ctr Canc Res, Sydney, NSW, Australia

[8] Univ Sydney, Sydney, NSW, Australia

[9] Univ Western Sydney, Westmead Hosp, ICPMR, NSW Hlth Pathol, Westmead, NSW, Australia

[10] Univ Coll Dublin, UCD Sch Biomol & Biomed Sci, Dublin, Ireland

[11] Trinity Coll Dublin, Sch Med, Dept Obstet & Gynaecol, Dublin, Ireland

[12] Trinity Coll Dublin, Dept Histopathol, Dublin, Ireland

[13] St James Hosp, Dept Histopathol, Dublin, Ireland

[14] Queens Univ Belfast, Wellcome Wolfson Inst Expt Med, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland

[15] Univ Technol Sydney, Fac Sci, Sch Life Sci, Sydney, NSW, Australia

来源：

BRITISH JOURNAL OF CANCER | 2020年 / 122卷 / 03期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

LIVER METASTASES; TUMOR-GROWTH; IDENTIFICATION; EXPRESSION; GENERATION; RESISTANCE; REGULATOR; MORTALITY; RECEPTOR; THERAPY;

D O I：

10.1038/s41416-019-0649-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BACKGROUND: ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. METHODS: In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). RESULTS: ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. CONCLUSION: FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.

引用

页码：361 / 371

页数：11

共 50 条

[1] Targeting cancer stem cells in the clinic: Current status and perspectives [J].

Annett, Stephanie ;

Robson, Tracy .

PHARMACOLOGY & THERAPEUTICS, 2018, 187 :13-30

[2]

[Anonymous], ACCEPTS GENENTECHS S

[3]

[Anonymous], 2014, Journal of Clinical Oncology

[4]

[Anonymous], PHASE OPEN LABEL MUL

[5] Tumor Microvessel Density as a Potential Predictive Marker for Bevacizumab Benefit: GOG-0218 Biomarker Analyses [J].

Bais, Carlos ;

Mueller, Barbara ;

Brady, Mark F. ;

Mannel, Robert S. ;

Burger, Robert A. ;

Wei, Wei ;

Marien, Koen M. ;

Kockx, Mark M. ;

Husain, Amreen ;

Birrer, Michael J. .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2017, 109 (11)

[6] RALA-mediated delivery of FKBPL nucleic acid therapeutics [J].

Bennett, Rachel ;

Yakkundi, Anita ;

McKeen, Hayley D. ;

McClements, Lana ;

McKeogh, Thomas J. ;

McCrudden, Cian M. ;

Arthur, Kenneth ;

Robson, Tracy ;

McCarthy, Helen O. .

NANOMEDICINE, 2015, 10 (19) :2989-3001

[7] Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer [J].

Bowtell, David D. ;

Boehm, Steffen ;

Ahmed, Ahmed A. ;

Aspuria, Paul-Joseph ;

Bast, Robert C., Jr. ;

Beral, Valerie ;

Berek, Jonathan S. ;

Birrer, Michael J. ;

Blagden, Sarah ;

Bookman, Michael A. ;

Brenton, James D. ;

Chiappinelli, Katherine B. ;

Martins, Filipe Correia ;

Coukos, George ;

Drapkin, Ronny ;

Edmondson, Richard ;

Fotopoulou, Christina ;

Gabra, Hani ;

Galon, Jerome ;

Gourley, Charlie ;

Heong, Valerie ;

Huntsman, David G. ;

Iwanicki, Marcin ;

Karlan, Beth Y. ;

Kaye, Allyson ;

Lengyel, Ernst ;

Levine, Douglas A. ;

Lu, Karen H. ;

McNeish, Iain A. ;

Menon, Usha ;

Narod, Steven A. ;

Nelson, Brad H. ;

Nephew, Kenneth P. ;

Pharoah, Paul ;

Powell, Daniel J., Jr. ;

Ramos, Pilar ;

Romero, Iris L. ;

Scott, Clare L. ;

Sood, Anil K. ;

Stronach, Euan A. ;

Balkwill, Frances R. .

NATURE REVIEWS CANCER, 2015, 15 (11) :668-679

[8] Constitutive Activation of STAT3 Signaling Regulates hTERT and Promotes Stem Cell-Like Traits in Human Breast Cancer Cells [J].

Chung, Seyung S. ;

Aroh, Clement ;

Vadgama, Jaydutt V. .

PLOS ONE, 2013, 8 (12)

[9] Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia [J].

Conley, Sarah J. ;

Gheordunescu, Elizabeth ;

Kakarala, Pramod ;

Newman, Bryan ;

Korkaya, Hasan ;

Heath, Amber N. ;

Clouthier, Shawn G. ;

Wicha, Max S. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (08) :2784-2789

[10] Evaluating cell lines as tumour models by comparison of genomic profiles [J].

Domcke, Silvia ;

Sinha, Rileen ;

Levine, Douglas A. ;

Sander, Chris ;

Schultz, Nikolaus .

NATURE COMMUNICATIONS, 2013, 4

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