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Targeting NOTCH1 in T-cell acute lymphoblastic leukemia with a novel selective SERCA inhibitor
Universita degli Studi di Parma
Dipartimento di Medicina e Chirurgia Università degli Studi di Parma Azienda Ospedaliero Universitaria di Parma Via Gramsci, 14 43126 Parma, Italy
Type of Research Project
- Clinical Project with Laboratory work
What is the background of the project?
Acute Lymphoblastic Leukemia (ALL) is the first cause of cancer related death in childhood . Gain-of- function mutations in NOTCH1 are the most common genetic abnormalities in T-ALL (55-60%), an aggressive subgroup of ALL, and several studies strongly support the development of Notch1 inhibitors particularly for T-ALL where cancer dependency has been well established . SERCA emerged at the intersection of a chemical genomic NOTCH1 loss-of-function screen and a cell-based screen for cDNA enhancers of a NOTCH1 mutant allele . Thapsigargin selectively inhibits SERCA causing a depletion of the endoplasmic reticulum (ER) storage and sustained elevation of cytosolic Ca2+ leading to DNA fragmentation and programmed cell death. Our group previously demonstrated that thapsigargin treatment has on target NOTCH1 activity in vitro and in vivo . However, SERCA is critical to maintain intracellular Ca2+ homeostasis in all cell types; as such thapsigargin’s activity is unlikely to be tumor or cell type specific raising the question whether thapsigargin can be safely translated into a clinical application anticipating a potential Ca2+ related toxicity.
What is the aim of the project?
In this work we describe a new SERCA inhibitor to decouple Ca2+ off-target effects from NOTCH1 inhibitory properties through studying the anti-Notch properties of CAD204520 in vitro and in T-ALL murine models.
What techniques and methods are used?
1) We identify CAD204520 as potent and selective Ca 2+ ATPase inhibitor from a large 191000 small molecules screen targeting P-type ATPase. 2) We compare CAD204520 with different SERCA inhibitors to understand how the docking pose influences Ca 2+ off-target effects. 3) We move into preclinical studies to characterize anti-leukemia effect and assess cardiac toxicity in isolated cardiomyocyte exposed to CAD204520. 4) Finally we study the functional and biochemical correlation between SERCA and NOTCH1 to further optimize SERCA inhibitor for cancer therapies.
What is the role of the student?
- The student will mainly observe
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- If the project is clinical
- the student will be allowed to work with patients
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
To participate in collection of new patients and to perform some experiments in lab. In particular, student will be involved in patient enrollment (how to propose a clinical study and how to collect an informed consent). Student will learn the principles technique of pre-clinical laboratory: to perform a cell culture, protein extraction and western blot analysis. Moreover, student will improve their management skills of data base and statistical analysis
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The tutor or his collaborators will take a few (2 or 3) seminars about T-cell acute lymphoblastic leukemia and targeting NOTCH1.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a poster - The student will prepare a presentation - The student will prepare a scientific report
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Basic knowledge of biochemistry and molecular pathology. Previous experience with: if possible, previous laboratory experience.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months)
- 1. Weng AP; Ferrando AA; Lee W; Morris JPt; Silverman LB; Sanchez-Irizarry C; et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science (New York; NY). 2004;306(5694):269-71.
- 2. Minowada J; Kohno K; Matsuo Y; Drexler HG; Ohnuma T; Tax WJ; et al. Characteristics of 27 human T-cell leukemia cell lines with/without T-cell receptors of T3-Ti alpha beta or T3-Ti gamma delta complex. Haematology and blood transfusion. 1989;32:233-6.
- 3. Roti G; Qi J; Kitara S; Sanchez-Martin M; Saur Conway A; Varca AC; et al. Leukemia-specific delivery of mutant NOTCH1 targeted therapy. The Journal of experimental medicine. 2018;215(1):197-216.
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