H2020Индивидуална стипендия2021–2024

MITHAML · Exploring the role of Metabolic IntraTumoral Heterogeneity in drug resistance of Acute Myeloid Leukemia in vivo

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

Период: 2021-02-01 → 2024-01-31
Финансиране от ЕС: 257 620 €
Участници: 2
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Метаболитните разлики между раковите клетки при остра миелоидна левкемия определят как те реагират на лекарства като веनेटклоксас. Разбирането на тези процеси помага за откриване на по-ефективни комбинации от терапии и биомаркери за персонализирано лечение.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

MITHAML – Exploring the role of Metabolic IntraTumoral Heterogeneity in drug resistance of Acute Myeloid Leukemia in vivo

Acute Myeloid Leukemia (AML) patient prognosis remains dramatic with a 5-year overall survival of only 28%. However, several new-drugs have been approved by the FDA during the last 2 years. This includes venetoclax (VEN), a selective inhibitor of the anti-apoptotic protein BCL2, which showed 62% of overall clinical response in combination with conventional chemotherapy cytarabine (AraC) in Phase 2/3 clinical trials. However, several mechanisms of resistance have already been reported. Different subpopulations coexist within the same tumor and differ in their ability to acquire, or because they already possess, features to resist treatments. Thus, intratumoral heterogeneity may underlie innate or acquired resistance, and disease relapses. Sources of intratumoral heterogeneity are diverse and lead to different metabolic status at the cellular level. Indeed, metabolism plays a critical role in AML relapse by conferring unique drug-resistant properties. In order to therapeutically impact the incidence of AML relapse, we must understand the metabolic intratumoral heterogeneity (MITH). Our project aimed to develop a novel approach using mass cytometry (CyTOF) for single-cell proteomics to explore MITH in AML at diagnosis and following treatment with VEN alone or in combination with AraC or hypomethylating agent azacytidine (AZA) ex vivo. This could help better understand the mechanisms of resistance to these new regimens already approved in clinic and identify complementary drug combinations able to circumvent them. Moreover, the identification of biomarkers of response to the different therapies is a crucial point to make progress towards precision medicine. The main conclusions of the project so far are: 1/AML patients present a high metabolic heterogeneity which is not restrained to developmental state. 2/Adult and pediatric AML patients display distinct and unique features, in particular metabolic ones, which could lead to different response to metabolic inhibitors. 3/VEN treatment abrogates immature clusters but spares other clusters, monocytic or not, with specific metabolic features which represent promising targets for more efficient combinations.

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

Цел на проекта

Drug resistance is a major barrier in acute myeloid leukemia (AML) for which prognosis remains unfavorable. We and others have shown the importance of metabolism in the response to therapies in AML, leading to the development of several drugs targeting mitochondrial functions such as BCL2 inhibitor Venetoclax or Electron Transfer Chain Complex I inhibitor IACS-010759. Tumors are composed of genetically and phenotypically heterogeneous cell populations, not all cells being equal in their ability to respond to treatment. Tremendous advances in single-cell technologies like mass cytometry (CyTOF) have demonstrated a fantastic potential to decipher this phenotypic and signaling heterogeneity. However, metabolic features are mostly measured in bulk, impeding the assessment of the metabolic cellular heterogeneity. We propose to investigate the role of metabolic intratumoral heterogeneity in AML at diagnosis and after new drugs in vivo through 2 aims. First we will determine the relationship between metabolic, signaling and developmental states in healthy and leukemic myeloid bone marrow cells and its link with chemoresistance (Aim 1). Then we will focus on the impact of Venetoclax and IACS on MITH in vivo using patient-derived xenograft mice models to identify specific features related to resistance to these drugs that we will finally therapeutically target with new combinations in vivo (Aim 2). The skills of the experienced researcher (ER) on metabolism and omic technologies and the complementary expertise of the 2 laboratories are key for the success of MITHAML. Indeed, the ER will be trained for 2 years in Dr Davis’s lab (Stanford University, USA), highly recognized in the study of intratumoral heterogeneity especially with CyTOF. She will then bring back these skills in Dr Sarry’s lab (Inserm, France), expert in in vivo AML resistance. This fellowship will be key to help the ER develop the scientific, technological and management skills required for her independence.

Оригинален текст от CORDIS (на английски).

Участници

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisКоординаторФранция
BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY · STANFORDСъединени щати