US-12616673-B2 - Compounds for use in the treatment of leukemia

US12616673B2US 12616673 B2US12616673 B2US 12616673B2US-12616673-B2

Abstract

The present invention belongs to the field of cancer therapy and relates to a composition or product comprising at least one retinoid compound, at least one arsenic compound and at least one proteasome inhibitor, for use in the treatment of acute myeloid leukemia (AML) where the tumor cells are positive for the FLT3-ITD mutation.

Inventors

Francesco FAZI
Silvia MASCIARELLI

Assignees

Universita' Degli Studi Di Roma “La Sapienza”

Dates

Publication Date: 20260505
Application Date: 20210128
Priority Date: 20200129

Claims (7)

1 . A method for treating acute myeloid leukemia in a patient having tumor cells which are FLT3-ITD mutation positive, comprising administering: a) all-trans retinoic acid (ATRA) and/or pharmaceutically acceptable salts thereof; b) arsenic trioxide (ATO); and c) a proteasome inhibitor, wherein the proteasome inhibitor is Bortezomib; to a patient in need thereof, wherein all-trans retinoic acid (ATRA) is administered at 70 mg/kg, bortezomib is administered at 0.5 mg/kg and arsenic trioxide (ATO) is administered at 3 mg/kg.
2 . The method of claim 1 , wherein said method is used in sequence, or in combination, with other anticancer therapies.
3 . The method according to claim 2 , wherein the other anticancer therapies are selected from idarubicin, daunorubicin, cytarabine, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin and/or specific inhibitors of the FLT3 tyrosine kinase receptor.
4 . The method of claim 1 , wherein the all-trans retinoic acid (ATRA) and/or pharmaceutically acceptable salt thereof; the arsenic trioxide (ATO); and the proteasome inhibitor are administered as a combined preparation.
5 . The method of claim 1 , wherein the all-trans retinoic acid (ATRA) and/or pharmaceutically acceptable salt thereof; the arsenic trioxide (ATO); and the proteasome inhibitor are administered concurrently.
6 . The method of claim 1 , wherein the all-trans retinoic acid (ATRA) and/or pharmaceutically acceptable salt thereof; the arsenic trioxide; and the proteasome inhibitor are administered sequentially.
7 . The method of claim 1 , wherein the ATRA, bortezomib, and ATO are administered for a period of 3 weeks.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a 371 of PCT/IB2021/050674, filed Jan. 28, 2021, which claims the benefit of Italian Patent Application No. 102020000001732, filed Jan. 29, 2020. REFERENCE TO A SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB The content of the electronically submitted sequence listing, file name: 128-1262_SeqListing.txt; size: 4 KB; and date of creation Jul. 5, 2022, filed herewith, is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present invention belongs to the field of cancer therapy and relates to a composition or product comprising at least one retinoid compound, at least one arsenic compound and at least one proteasome inhibitor, for use in the treatment of acute myeloid leukemia (AML) where the tumor cells are positive for the FLT3-ITD mutation (FLT3-ITD+ AML). Preferably, the composition or product of the invention comprises: a) all-trans retinoic acid (ATRA) and/or derivatives thereof and/or pharmaceutically acceptable salts thereof,b) arsenic trioxide (ATO) andc) the proteasome inhibitor Bortezomib (Btz). BACKGROUND OF THE INVENTION Acute myeloid leukemia (AML) is the most frequent non-paediatric acute leukemia. At present, first-line therapy is based on chemotherapy, whether or not associated with bone marrow transplantation, with 40-50% and 10-15% cure rates in adult and older patients, respectively. It is therefore clear that more effective innovative therapeutic approaches are needed. The endoplasmic reticulum (ER) is the cellular organelle responsible for the maturation and correct folding of proteins that travel through the secretory pathway, i.e., secreted proteins and membrane-residing proteins. Disruption in the balance of this organelle (for example, due to the presence of mutated proteins, alterations in the cell's redox balance or physiological calcium concentrations) results in accumulation of non-properly matured proteins in the ER. This phenomenon is called ER stress. The cellular response to ER stress, defined as “Unfolded Protein Response” (UPR), plays a fundamental role in maintaining cellular protein homeostasis (proteostasis). The idea of interfering with proteostasis to promote cancer cell death has been widely described in the case of multiple myeloma (MM)1. In fact, the success of the proteasome inhibitors currently used in MM therapy can be attributed, at least in part, to the fact that the secretory pathway, whose function strictly depends on an efficient proteasome system, is very active in plasma cells2. The present authors therefore hypothesized that a similar strategy could be used to target AML cells. AMLs make up a group of heterogeneous diseases caused by an arrest of myeloid progenitor differentiation due to numerous and different genetic alterations, which result in the production of mutant proteins or fusions of different proteins. Cells of a particular type of AML, i.e., acute promyelocytic leukemia (APL), can be induced to complete granulocyte differentiation by pharmacological doses of all-trans retinoic acid (ATRA). This differentiation requires an increase in the production of secretory proteins, thereby generating a physiological ER stress. The present authors have previously demonstrated that this increase in the level of ER activity is sufficient to make differentiation-induced APL cells sensitive to doses of a drug, i.e., Tunicamycin (Tm), that impairs the maturation ability of the ER proteins, which instead do not cause lethal effects in the same cells not treated with ATRA3. Tunicamycin is a mixture of homologous nucleoside antibiotics which inhibits the UDP-HexNAc:polyprenol-P HexNAc-1-P enzyme family. In eukaryotes, this includes the GlcNAc phosphotransferase (GPT) enzyme, which catalyzes the transfer of N-acetylglucosamine-1-phosphate from UDP-N-acetylglucosamine to dolichol phosphate in the first step of glycoprotein synthesis. Tunicamycin blocks N-linked glycosylation (N-glycans), and treatment of cultured human cells with tunicamycin in high doses causes cell cycle arrest in the G1 phase. Furthermore, the addition of Arsenic Trioxide (ATO), which causes oxidative stress, to the combination of ATRA and Tm significantly increases the lethal effect on APL cells3. At present, ATRA and ATO are the first-line therapy for particular APL subgroups4; the most important feature of the present authors' previous work3 is that the synergistic effect of the three drugs, i.e., ATRA, Tm and ATO, allows the use of low doses of each of them, possibly reducing the risk of a generic toxicity. In fact, in support of this hypothesis, the present authors have shown that the triple combination is capable of reducing the clonogenic ability of primary APL cells isolated from the bone marrow of patients and treated in culture ex vivo, without however affecting the proliferation ability of hematopoietic progenitors isolated from healthy donors3. Later, the goal was to try to apply this strategy