Combined Therapies for Neuroblastoma Based on the Activation of the Calcium- Sensing Receptor

dc.contributor
Universitat de Barcelona. Facultat de Medicina
dc.contributor.author
Gonçalves Alves, Eliana Carolina
dc.date.accessioned
2023-07-12T08:49:06Z
dc.date.available
2023-07-12T08:49:06Z
dc.date.issued
2021-01-15
dc.identifier.uri
http://hdl.handle.net/10803/688643
dc.description
Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut de Recerca Sant Joan de Déu (IRSJD)
ca
dc.description.abstract
[eng] Neuroblastoma (NB) is the most common extracranial solid childhood tumour. Its clinical and histological manifestations range from benign tumours that spontaneously regress to highly aggressive metastatic tumours (Matthay et al -2016). In spite of the advances in treatment and the multidisciplinary approaches, almost half of high-risk NB patients do not survive (Whittle et al – 2017). The Calcium-sensing receptor (CaSR) is a G-protein coupled receptor (GPCR) that was found to be expressed in good prognosis NB tumour (de Torres et al – 2009). Activation of this receptor using cinacalcet (CIN), a positive allosteric modulator of CaSR, in a xenograft NB animal model, reduced tumour growth. In addition, it was described that in NB cell lines with an overexpression of CaSR, CIN induced ER-stress mediated apoptosis (Rodríguez-Hernández et al – 2016). However, efficacy of CIN in the treatment of NB is limited by the low expression of CaSR in high-risk NB. Furthermore, CIN acts mainly in the CaSR present in the parathyroid glands, inducing hypocalcemia. This work addresses these two limitations of using CIN in the treatment of NB patients. We demonstrate that the active compound of vitamin D, 1,25-dihydroxyde vitamin D (1,25-D3) and the retinoids all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cis-RA) increase the expression of CaSR in two NB cell lines. Unfortunately, in vitro anti-tumorigenic capacities of CIN are not increased by its combination with 1,25-D3. Moreover, we show that the strong in vitro and in vivo anti-tumorigenic capacities of retinoids are unaltered by its combination with CIN. On the other hand, we identify another positive allosteric modulator of CaSR, AC-265347, with NB anti-tumorigenic properties which does not induce hypocalcemia in mouse animal models. In these models each calcimimetic induce a differential protein and gene expression pattern, suggesting a different mechanism of action in the inhibition of tumour growth. Additionally, in vitro studies show that CIN and AC-265347 induce different stages of differentiation in NB cell lines. Altogether, our data shows that the combination of CIN with different drugs that induce an increase in the expression levels of CaSR do not potentiate the anti-tumorigenic effect of CIN. More importantly, this work identifies a new calcimimetic that shows a potential neuroblastoma specific effect, AC-265347 inhibits NB tumour growth while maintaining plasma calcium levels. Our results strongly suggest that AC-265347 may be and effective therapeutic agent against NB, alone or in combination with other potentially synergistic treatments.
ca
dc.format.extent
179 p.
ca
dc.language.iso
eng
ca
dc.publisher
Universitat de Barcelona
dc.rights.license
ADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.
ca
dc.source
TDX (Tesis Doctorals en Xarxa)
dc.subject
Cèl·lules canceroses
ca
dc.subject
Células cancerosas
ca
dc.subject
Cancer cells
ca
dc.subject
Canals de calci
ca
dc.subject
Canales de calcio
ca
dc.subject
Calcium channels
ca
dc.subject
Teràpia cel·lular
ca
dc.subject
Terapia celular
ca
dc.subject
Cellular therapy
ca
dc.subject
Química combinatòria
ca
dc.subject
Química combinatoria
ca
dc.subject
Combinatorial chemistry
ca
dc.subject
Proteïnes G
ca
dc.subject
Proteínas G
ca
dc.subject
G Proteins
ca
dc.subject.other
Ciències de la Salut
ca
dc.title
Combined Therapies for Neuroblastoma Based on the Activation of the Calcium- Sensing Receptor
ca
dc.type
info:eu-repo/semantics/doctoralThesis
dc.type
info:eu-repo/semantics/publishedVersion
dc.subject.udc
577
ca
dc.contributor.director
Lavarino, Cinzia
dc.contributor.director
Mateo Lozano, Silvia
dc.contributor.tutor
Menéndez Buján, Pablo
dc.embargo.terms
cap
ca
dc.rights.accessLevel
info:eu-repo/semantics/openAccess


Documentos

ECGA_PhD_THESIS.pdf

6.873Mb PDF

Este ítem aparece en la(s) siguiente(s) colección(ones)