Individual projects

Research project

DC9 GATA3 Inhibition as a therapy for T-cell Acute Lymphoblastic Leukemia

GAIN4ALL

GAIN4ALL aims to improve current therapies in T-cell Acute Lymphoblastic Leukemia (T-ALL), where conventional chemotherapy regimens have limited success, particularly in relapsed adult patients. By targeting the critical NOTCH-GATA3-MYC axis, a pivotal regulatory circuit in T-ALL, the project aims to identify novel compounds capable of disrupting its activity as a new therapeutic strategy for T-ALL treatment.

Keywords: GATA3, T-ALL, small-molecule inhibitors, molecular modeling, experimental therapeutics 

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STATE-OF-THE-ART

T-ALL treatment and prognosis

Intensive multiagent chemotherapy is still the backbone of T-ALL treatment. While this therapeutic approach is curative in up to 90% of pediatric cases, the survival rate in adults remains at 50%, dropping to under 10% in patients with relapsed disease. This dismal landscape speaks to the urgent need for providing novel targeted therapies that improve the outcome of these patients.

The NOTCH-GATA3-MYC axis in T-ALL

Approximately 60% of T-ALL patients present oncogenic activating mutations in the NOTCH1 gene. These mutations initiate a broad transcriptional program that is dominated by the upregulation of the MYC oncogene, which is indispensable for NOTCH1-induced T-ALL leukemogenesis (Belver and Ferrando, Nature Reviews in Cancer, 2016). The mechanism by which the activation of NOTCH1 triggers the expression of MYC was only elucidated with the discovery of the NOTCH-MYC enhancer (N-Me) by our group (Adolfo Ferrando’s lab at Columbia University). We demonstrated that N-Me is essential for NOTCH-induced T-ALL transformation and progression in vivo (Herranz et al, Nature Medicine, 2014), and that the binding of the transcription factor GATA3 to N-Me is strictly required for the oncogenic activity of this enhancer (Belver et al, Cancer Discovery, 2023). Moreover, we found that GATA3 knock-out mice are protected against the development of NOTCH-induced T-ALL (unpublished data).

HIPOTHESIS

The molecular crosstalk between NOTCH1, GATA3 and MYC highlights the potential of this regulatory circuit as a therapeutic target in T-ALL. However, while the NOTCH pathway is critical for the development and homeostasis of most tissues, and MYC controls a broad range of essential cellular functions, GATA3 is only crucial during embryonic development and its activity is restricted to a few cell types postnatally, including breast epithelia, adipocyte precursors and the T-cell compartment. In this context, the working hypothesis of GAIN4ALL is that GATA3 represents a safe therapeutic target to disrupt the NOTCH-GATA3-MYC axis that sustains T-ALL progression.

OBJECTIVES

The main aim of GAIN4ALL is to identify small-molecule compounds (SMCs) that provide antileukemic effects in T-ALL through the inhibition of GATA3. Thus, the specific objectives of this research program are:

Objective 1 (O1). To identify SMC candidates as potential GATA3 inhibitors.

Objective 2 (O2). To evaluate the inhibitory effects of GATA3 SMC candidates on T-ALL cell lines in vitro.

Objective 3 (O3). To validate the therapeutic effect of inhibitory GATA3 SMCs in vivo.

SCIENTIFIC APPROACH

O1. To identify SMC candidates as potential GATA3 inhibitors

To identify SMCs that can potentially inhibit the activity of GATA3 in T-ALL, we will collaborate with Dr. Katarina Nikolić at the University of Belgrade (Serbia). With the help of Dr. Nikolić and using computational approaches, we will perform a virtual screening on GATA3 of SMCs. This screening will include different methods to assess ligand-based similarity, molecular docking, and toxicity. From this analysis, we will select an array of 100-150 GATA3 SMC candidates that will be screened in O2.

O2. To evaluate the inhibitory effects of GATA3 SMC candidates on T-ALL cell lines in vitro

To assess the inhibitory potential of the SMC array, we will conduct in vitro screenings on six distinct T-ALL cell lines using MTT assays. Through these analyses, we will determine the half maximal inhibitory concentration (IC50) for each SMC. The top-performing three compounds identified in these assays will then be chosen for further in vivo evaluation in O3.

O3. To validate the therapeutic effect of inhibitory GATA3 SMCs in vivo

To evaluate the therapeutic value of the three selected GATA3 SMCs, we will first determine their maximum tolerated dose (MTD) in healthy animals. Then, cohorts of mice transplanted with human T-ALL patient-derived xenografts (PDXs) will be treated with the SMCs at the MTD or with vehicle (negative control). The impact of the SMC treatments will be determined by monitoring leukemia progression (in vivo bioimaging) and by analyzing the differences in survival among experimental groups.

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Secondment

University of Belgrade (Serbia)