H2020Индивидуална стипендия2019–2021

UNBRACE · Investigating the Role of the Unfolded Protein Response as a Novel Targetable Pathway in BRAF Mutant Colorectal Cancer

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2019-02-01 → 2021-01-31
Финансиране от ЕС: 187 866 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Стресът в клетките на панкреаса активира механизъм за справяне с неправилно сгънатите протеини. Разбирането на този процес помага за разработването на вещества, които да блокират растежа на тумора.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Investigating the Role of the Unfolded Protein Response as a Novel Targetable Pathway in BRAF Mutant Colorectal Cancer

Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of all cases of pancreatic cancer. Pancreatic stellate cells (PSCs) are the most prominent cell type in the PDAC stroma, accounting for around 50% of the tumour microenvironment. Interestingly, PSCs show chronic cellular stress as seen by the persistent activity of the unfolded protein response (UPR). The UPR is a cellular pathway that is triggered by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), a condition known as ER stress. The UPR is normally a transient adaptive response mechanism that aims at resolving the ER stress and returning the cell to an unstressed state. However, when it is persistently active in cancer, the UPR can promote tumour growth and progression. Modulating UPR signalling using small molecule inhibitors is therefore an attractive approach for intervention in pancreatic cancer. The overall aim of this project was to understand the role the UPR in cancer and to develop novel compounds that can switch it off. This was addressed through two objectives; (a) investigation into the role of UPR in PDAC and its tumour microenvironment, and (b) develop tools to test novel small molecule inhibitors to target the UPR in these cells. These scientific aims were underpinned by the cross-cutting objectives of training and transfer of knowledge between the fellow and the host organisation. Thus the fellow gained training from the expertise of the host in UPR biology and cancer, and integrated it with his own expertise in immune cells and inflammatory responses. Conclusions of the action: Through the course of the UNBRACE project we were able to understand possible roles for UPR in the PDAC and the associated TME. We have further developed tools to test small molecule inhibitors to target the UPR as a potential future therapeutic target. The extrapolation of the undergone work will hypothetically delineate impactful publications, and tools to develop cancer therapeutics.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

BRAF mutant (MT) colorectal cancer (CRC) accounts for 10-15% of CRC and represents the subgroup with the worst overall survival. There is an urgent need to identify strategies that hit the 'Achilles Heel' in poor prognostic BRAFMT CRC. Preliminary data from the host lab have shown that BRAFMT CRC cells are vulnerable to disturbances in the Endoplasmic Reticulum (ER)-specific Unfolded Protein Response (UPR) machinery. The overall aim of the proposal is to identify whether the ER stress activator ONC201 in combination with MAPKi (MEK1/2i or BRAFi) will be a novel treatment strategy for BRAFMT CRC. Specific objectives of the proposal are1. Investigate the effect of ONC201 combined with MAPKi in BRAFMT CRC in vitro.2. Investigate the in vivo effect of ONC201 with MAPKi using BRAFMT CRC syngeneic and patient derived xenograft models.3. Assess prognostic/predictive role of ER stress proteins in CRC.UNBRACE will go beyond the current state-of-the-art by (i) developing a novel treatment strategy targeting the biology of poor prognostic BRAFMT CRC; (ii) using relevant pre-clinical models and clinical available datasets to underpin a novel stratified solution for BRAFMT CRC with poor clinical outcome. UNBRACE adopts the concept “personalized medicine strategy” through applying a novel approach targeting BRAFMT CRC. This fellowship will provide the researcher, through mobility, an increased set of excellent skills (e.g. molecular pathology; patient derived xenografts, 3D organoids), which will give him the opportunity to become a future leader in experimental cancer medicine. The fellowship will result in a strong collaborative network between the host and partner institute, transfer of knowledge between academia and industry, ultimately resulting in a phase I clinical trial in BRAFMT CRC. The fellowship can form the basis to attract other scientists internationally, from other disciplines and sectors to receive training in these unique R&I skills.

Оригинален текст от CORDIS (на английски).

Участници

CELL STRESS DISCOVERIES LIMITED · GalwayКоординаторИрландия