H2020Индивидуална стипендия2022–2024

AML-SynergyX · Systematic identification of genetic modifiers in the response to targeted therapies in acute myeloid leukemia.

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

Период: 2022-09-01 → 2024-08-31
Финансиране от ЕС: 186 167 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Генетичните модификатори при острия миелоиден левкемия се анализират чрез проучване на молекулата CD70 и нейния ефект върху лекарствената резистентност. Това помага за разработването на по-ефективни комбинирани терапии при пациенти с мутация в гена FLT3.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Systematic identification of genetic modifiers in the response to targeted therapies in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a deadly blood cancer with a long-term survival below 30%. In last decades, treatment strategy has not changed substantially and consists of intensive chemotherapy and/or allogeneic stem cell transplantation. Novel targeted therapies exist and are very potent in the initial course of treatment, however, most patients unfortunately develop resistance. While it is widely accepted that turning oncogene-targeted therapeutics into curative therapies will require drug combinations, the pre-clinical and clinical development of rational combination therapies remains challenging at multiple levels. In AML-SynergyX project, we focused on the FLT3 gene that is one of the most frequently mutated genes in AML and has been associated with high relapse rate and poor survival prognosis. Although specific inhibitors of mutated FLT3 are effective in the initial treatment, patients eventually develop the drug-resistant disease. We anticipate that by providing e will uncover new entry points for rational combination therapies that are urgently needed to turn the recent clinical success of FLT3 inhibitors into the cure. Our work has identified a surface molecule CD70 as a top hit. CD70 is a member of the tumor necrosis factor (TNF) superfamily and the ligand for the cytokine receptor CD27. Interestingly, it has also been reported to be upregulated specifically on AML blasts and leukemia stem cells, but not on healthy stem cells, progenitors, or differentiated blood cells. Role of CD70 in the adaptation of leukemia cells has been described previously. In conclusion, while the project did not identify novel drug targets as initially hoped, it made significant contributions to the development of genetic screening tools, provided valuable insights into the transcriptional responses to FLT3 inhibition in AML, and supported the established role of CD70 as a potential target in AML.

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

Цел на проекта

In the last decade, we have witnessed tremendous progress in understanding the genetic landscape of acute myeloid leukemia (AML), which has been translated into several approved targeted therapies. Although these therapies are effective initially, most patients eventually develop resistance through a variety of genetic and/or epigenetic mechanisms that remain incompletely understood. While it is widely accepted that transient responses to oncogene-targeted therapeutics into cure will require drug combinations, the pre-clinical and clinical development of rational combination therapies remains challenging. The advent of high-throughput genetic screens and transcriptome profiling methods fundamentally changes the way we can address this problem. The overall goal of this proposal is to apply and integrate these innovative technologies to deeply investigate genetic and gene-regulatory mechanisms in the response to small-molecule inhibitors of FLT3 and the MLL-Menin interaction, which hold promise as targeted therapeutics for more than 50% of AML patients. Using advanced CRISPR/Cas9- and shRNA-based screening platforms, I will systematically identify genes that modify the response to FLT3 and MLL-Menin inhibition. Complementary to functional-genetic screens, I will apply SLAMseq, a scalable time-resolved mRNA profiling method co-developed by the host lab, to dynamically investigate transcriptional programs underlying the primary response and adaptation to FLT3 and MLL-Menin inhibition. Functional-genetic and time-resolved transcriptome profiles will be integrated to select promising candidates for validation and mechanistic follow-up studies in patient AML samples and genetically engineered mouse models. In summary, by providing deep insight into the response to FLT3- and MLL-Menin inhibition, I thrive to identify candidate targets and new concepts for rational combination therapies that would address an unmet clinical need with a clear path towards clinical translation.

Оригинален текст от CORDIS (на английски).

Участници

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH · WienКоординаторАвстрия