H2020Индивидуална стипендия2018–2020

Proteasome in cancer · Identification of the proteasome machinery targets in human cancer

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

Период: 2018-05-01 → 2020-04-30
Финансиране от ЕС: 146 462 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Протезомният механизъм, който разгражда протеини в клетките, се изследва при рак на белите дробове, панкреаса и дебелото черво. Разбирането на това как раковите клетки компенсират липсата на неговата активност помага за разработването на нови терапевтични подходи.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Identification of the proteasome machinery targets in human cancer

Cancer remains one of the primary causes of death in western countries. Tendencies allow to predict that in the upcoming decade the cancers of lung, colon/rectum and pancreas will be the primary causes of neoplasia-related deaths in the EU. The proteasome machinery – consisting of 20S Proteasome, 26S Proteasome and immunoproteasome - is the major protein degradation factor in human cells. It is also strongly upregulated in most human neoplasias of various tissues, including the above-mentioned most deadly cancer types, being one of the most universal oncogenic drivers in human cancer. Proteasome inhibitors Bortezomib (1st generation) and Carflizomib (2nd generation) are clinically approved for multiple myeloma clinical treatment. Even though the proteasome has been reported as a vulnerability in multiple types of cancers, the resistance mechanisms in humans have not yet allowed the proteasome inhibitor-based solid tumor therapies to progress beyond clinical trials. Thus, the main objective of the project was to understand the oncogenic contribution of the proteasome machinery to the reprogramming of human cancer cells and to use this knowledge to discover anti-cancer therapeutic approaches targeting the proteasome downstream effectors. Addressing this objective is bringing a detailed knowledge of the general proteasome effect in human cells, on how these cells compensate for the lack of the proteasome activity, and how this compensation can be prevented specifically in cancer cells. This has a meaning for designing new therapeutic approaches for some of the most dangerous cancer types listed above, as well as is bringing basic, academic knowledge on the action of one of the indispensable components of human cells – the proteasome machinery.

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

Цел на проекта

The 26S/20S proteasome and immunoproteasome machinery is the major protein degradation system in human cells and a strongly oncogenic factor upregulated in most human neoplasias of various tissues. Thus, it is a target of clinically approved treatment protocols in human multiple myeloma and mantle cell lymphoma. However, clinical trials have shown a limited effect of proteasome inhibitors in solid tumors and their metastases, despite initial encouraging results in vitro and in xenografts. The main objective of the following project is to understand the oncogenic contribution of the human proteasome machinery to the proteome and transcriptome of human cancer cells and to use this knowledge to improve the anti-cancer therapeutic approaches targeting the proteasome and its downstream effectors, in human cancer types causing most deaths in the European Union – lung, colon/rectum and pancreatic cancers.The main research hypothesis is that the unknown mechanisms downstream of the human proteasome machinery are critical for cancer progression and will be effective as drug targets in the treatment of the solid tumors and their metastasis. Discovering these mechanisms using proteome-scale mass spectrometry analysis combined with RNA-sequencing will allow in this project to: (i) identify novel proteasome targets and understand reprogramming of human neoplastic cells by the proteasome machinery on the basic level in multiple myeloma, lung, colon and pancreatic cancer cultured cells, (ii) understand the reason for the exceptionally efficient therapeutic effect of the proteasome inhibitor carfilzomib in multiple myeloma compared to solid tumor cancer cells, and (iii) test in frozen/fixed tumor material, cell cultures the functional validity of the discovered proteasome targets as therapeutic target candidates in lung, colon and pancreatic cancers – which could increase efficiency or bypass targeting of the proteasome machinery by carfilzomib in the solid tumors

Оригинален текст от CORDIS (на английски).

Участници

INSTYTUT MEDYCYNY DOSWIADCZALNEJ I KLINICZNEJ IM MIROSLAWA MOSSAKOWSKIEGO POLSKIEJ AKADEMII NAUK · WARSZAWAКоординаторПолша