ACHM-025 / The University of Auckland, UNSW Sydney - LARVOL DELTA

MAPPING THE AKR1C3 CIS-REGULOME IN ACUTE LYMPHOBLASTIC LEUKEMIA TO ENHANCE TARGETED THERAPY WITH A NEW AKR1C3-ACTIVATED PRODRUG (EHA 2025) - "This is the first study to map AKR1C3 cis-regulome in T-and B-ALL. The observed sensitivity of TCF3::HLF B-ALL to ACHM-025 provides a new targeted therapy option for a subtype that remains otherwise incurable. Importantly, we demonstrate that increasing AKR1C3 expression in low-AKR1C3 B-ALL enhances sensitivity to ACHM-025, paving the way for identifying rational drug combinations that mimic this effect and expand the clinical utility of ACHM-025 beyond T-ALL."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • AKR1C3 • TCF3

MOLECULAR DETERMINANTS OF SENSITIVITY AND RESISTANCE TO A NOVEL AKR1C3-ACTIVATED PRODRUG IN PEDIATRIC LEUKEMIA (EHA 2025) - "ACHM-025, a novel prodrug activated by AKR1C3 into a nitrogen mustard-based DNA alkylating agent, was previously demonstrated by our group to exhibit profound in vivo activity against T-ALL patient-derived xenografts (PDXs), suggesting its potential for T-ALL targeted therapy. This study identified novel genes and pathways underlying sensitivity and resistance to ACHM-025, providing insights for designing rational combination therapies to improve T-ALL treatment. Based on these findings, potential combination strategies could include KEAP1 inhibitors to enhance AKR1C3 expression and prodrug activation, DNA damage response inhibitors to impair repair and increase ACHM-025-induced DNA damage, and antioxidant pathway inhibitors to impair cellular defenses against oxidative stress, thereby increasing ACHM-025 efficacy."

Clinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • AKR1C3 • EP300 • GCLM • KEAP1

Exploring the therapeutic potential of ACHM-025, a novel AKR1C3-activated prodrug, in preclinical models of paediatric T-cell acute lymphoblastic leukaemia (LCC 2025) - "ACHM-025 is a third-generation prodrug that is selectively activated by AKR1C3 to a potent nitrogen mustard-based DNA alkylating agent. ACHM-025 exhibited profound in vivo activity against aggressive and chemoresistant T-ALL PDXs, synergistic interactions with several classes of drugs ex vivo, and shows strong potential as a novel targeted therapy for T-ALL."

Preclinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • AKR1C3

Understanding the genetic determinants regulating AKR1C3 expression in acute lymphoblastic leukaemia (LCC 2025) - "This study is the first to identify long-range CREs that control AKR1C3 expression, which are both B- and T-ALL specific. The identification of AKR1C3 master regulators provides an avenue for the development of rational drug combinations, extending the use of ACHM-025 to all leukemia patients."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • AKR1C3

Molecular determinants of sensitivity and resistance to a novel AKR1C3 activated prodrug in paediatric leukaemia (LCC 2025) - "ACHM-025, a novel prodrug activated by AKR1C3 into a nitrogen mustard-based DNA alkylating agent, was previously demonstrated by our group to exhibit profound in vivo activity against T-ALL patient-derived xenografts (PDXs), suggesting its potential for T-ALL targeted therapy. This study has identified novel genes and pathways that regulate sensitivity and resistance to ACHM-025, providing insights for designing rational combination therapies to improve T-ALL treatment."

Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • AKR1C3

The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia. (PubMed, Blood Cancer J) - "To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent...ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL."

Journal • Preclinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • AKR1C3

A NEW AKR1C3-ACTIVATED PRODRUG, ACHM-025, ERADICATES DISEASE IN PRECLINICAL MODELS OF AGGRESSIVE T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2024) - "ACHM-025 was designed to improve drug specificity and minimize toxicity observed with currently used DNAalkylating agents, such as cyclophosphamide (CPM), a prodrug which is activated systemically via liverenzymes...For the consolidation therapy comparison,ACHM-025 or CPM combined with cytarabine (and 6-mercaptopurine were assessed against a T-ALL PDXderived from a patient at relapse... ACHM-025 exerted profound in vivo efficacy against T-ALL PDXs and eradicated the disease in 7 aggressive T-ALL PDXs. ACHM-025 was significantly more effective than CPM and was curative when used in combinationwith nelarabine The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providinga predictive biomarker for response."

Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • AKR1C3 • PTPRC

The AKR1C3-Activated Prodrug, Achm-025, Eradicates Disease in Preclinical Models of Aggressive T-Cell Acute Lymphoblastic Leukemia (ASH 2023) - "ACHM-025 was designed to improve drug specificity and minimize toxicity observed with currently used DNA alkylating agents, such as cyclophosphamide (CPM), a prodrug which is activated systemically via liver enzymes...For the consolidation therapy comparison, ACHM-025 (IP Days 0, 7) or CPM (IP Days 0, 7) combined with cytarabine (Ara-C; IP Days 0-4, 7-11) and 6-mercaptopurine (6MP; IP Days 0-4, 7-11) were assessed against a T-ALL PDX derived from a patient at relapse... ACHM-025 exerted profound in vivo efficacy against T-ALL PDXs and eradicated the disease in 7 aggressive T-ALL PDXs. ACHM-025 was significantly more effective than CPM both as a single agent and when used in combination with Ara-C/6MP. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo."

Preclinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • AKR1C3 • PTPRC