Abstract 3085
Background
AXL and transforming growth factor β (TGF-β) signalling pathways play a key role in modulating tumour microenvironment by promoting epithelial to mesenchymal transition (EMT), stromal activation and regulating immune response in colorectal cancer (CRC). Here we have evaluated the effect of double blockade of TGF-β and AXL receptors, as an innovative therapeutic strategy for CRC.
Methods
We assessed the correlation of TGF-β and AXL by an in silico analysis of a human CRC gene expression profile database. Afterwards, an evaluation of AXL expression of in a panel of human CRC cell lines by Western Blot (WB) and Real time PCR was performed. The sensitivity of HCT116 and LOVO cells to treatment with galunisertib (LY21209761), a TGF-β R1 inhibitor, and R428, an AXL inhibitor, was assessed by MTT, cell migration, and colony forming assays. Furthermore we generated patient derived 3D spheroid cultures from primary CRC, and tested their susceptibility to galunisertib and R428 by MTT assay. Finally, in vivo experiments were done with HCT116 and LOVO tumour xenografts in immunodeficient mice.
Results
In silico analysis showed an association between high expression levels of AXL and TGF-β R1 in CMS4 CRC. AXL was differently expressed on cell lines, and interestingly it resulted increased in HCT116 and LOVO after TGF-β inhibition, probably representing a mechanism of cancer cell escape. Dual blockade with galunisertib and R428 determined a reduction in cell migration of 50% in HCT116 and 37% in LOVO cells, respectively, and colony formation of approximately 90 % in both cell lines. Moreover, combined treatment displayed a strong synergistic activity in 3D cultures derived from five human CRC samples, resulting in the inhibition of proliferation ranging from 80 to 90%. The in vivo experiments of HCT116 and LOVO subcutaneous xenograft models are currently on going and results will be presented.
Conclusions
Combined TGF-β and AXL inhibition showed a promising activity in preclinical models of CRC and could represent a novel potential therapeutic strategy for patients with CRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Università degli studi della Campania "Luigi Vanvitelli".
Funding
ICURE project, Università degli studi della Campania "Luigi Vanvitelli".
Disclosure
D. Melisi: Research grant/Funding (self): Lilly.
Resources from the same session
3345 - Escalation plans and DNACPR discussions in the unwell oncology patient
Presenter: Raghad Elghadi
Session: Poster Display session 1
Resources:
Abstract
4165 - The Relation between the Symptom Burden of Hospitalized Patients with Incurable Cancer and the Quality-of-Life of Their Family Caregivers
Presenter: Eman Tawfik
Session: Poster Display session 1
Resources:
Abstract
1784 - Clinical predictors for analgesic response to radiotherapy in patients with painful bone metastases
Presenter: Ragnhild Habberstad
Session: Poster Display session 1
Resources:
Abstract
5323 - 30-Day Mortality in Palliative Radiotherapy
Presenter: Shing Fung Lee
Session: Poster Display session 1
Resources:
Abstract
3942 - The relationship between Naldemedine administration and the maximum dose of oral opioids
Presenter: Shinya Kajiura
Session: Poster Display session 1
Resources:
Abstract
3698 - Exposure to low energy amplitude modulated radiofrequency electromagnetic fields (EMF) is associated with rapid improvement in quality of life (QoL) status in patients with advanced hepatocellular carcinoma (HCC), using various analyses of EORTC-C30.
Presenter: Elizabeth Santana
Session: Poster Display session 1
Resources:
Abstract
3885 - Olanzapine Combined with 5-HT3 RA Plus Dexamethasone for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in High and Moderate Emetogenic Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Presenter: Jian-Guo Zhou
Session: Poster Display session 1
Resources:
Abstract
5700 - Early Palliative care in advanced cancer, is it really effective?
Presenter: Raquel Gómez Bravo
Session: Poster Display session 1
Resources:
Abstract
5924 - Deprescribing Potentially Inappropriate Medication in Cancer Patients
Presenter: Simon Reuter
Session: Poster Display session 1
Resources:
Abstract
5314 - Spirituality and religious coping for Cancer patients and providers: An ‘Almighty’ belief for palliative care
Presenter: Vibhay Pareek
Session: Poster Display session 1
Resources:
Abstract