Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

Area of Science:

• Oncology
• Hematology
• Molecular Biology

Background:

• T- and NK-cell lymphomas (TCL) are aggressive lymphoid malignancies with limited preclinical models, hindering therapeutic development.
• Existing research in B-cell and myeloid malignancies contrasts with the scarcity of effective models for TCL.
• Poor prognosis associated with TCL underscores the urgent need for novel therapeutic strategies and preclinical research.

Purpose of the Study:

• To establish and characterize preclinical models for T- and NK-cell lymphomas (TCL).
• To identify targetable vulnerabilities within TCL using these novel models.
• To evaluate the efficacy of novel therapeutic agents, including ALRN-6924, in preclinical TCL models.

Main Methods:

• Development and characterization of patient-derived xenograft (PDX) models for TCL.
• In vitro and in vivo testing of targeted agents, including JAK2 and IKZF1 inhibitors.
• Assessment of ALRN-6924, a p53-MDM2/MDMX interaction inhibitor, against multiple PDX models.
• Clinical evaluation of ALRN-6924 in a patient with angioimmunoblastic T-cell lymphoma.

Main Results:

• Multiple targetable vulnerabilities were identified in TCL, including JAK2, IKZF1, MDM2, and MDMX.
• ALRN-6924 demonstrated potent in vitro and superior in vivo efficacy across 8 PDX models compared to romidepsin.
• A patient with TP53-wild-type angioimmunoblastic T-cell lymphoma achieved complete remission with ALRN-6924 treatment.

Conclusions:

• Established preclinical models provide a platform for discovering TCL vulnerabilities and testing therapeutics.
• MDM2 and MDMX are identified as targetable vulnerabilities in TP53-wild-type TCL.
• ALRN-6924 shows significant therapeutic potential for TCL, with rapid clinical translation demonstrated.