Small molecule therapeutics to treat treatment-resistant ALL and T-ALL

This technology describes the synthesis and characterization of small molecule NT5C2 inhibitors for the treatment of relapsed and chemotherapy-resistant acute lymphoblastic leukemia (ALL) and T-cell acute lymphoblastic leukemia (T-ALL).

Unmet Need: Targeted therapies for aggressive, relapsed blood cancers

ALL and T-ALL are aggressive blood cancers in which relapse is common and resistance to therapy remains a substantial challenge. Gain-of-function mutations in the cytosolic nucleotidase 2 gene (NT5C2) have been identified as a major contributor to this resistance through inactivation of nucleoside-analog chemotherapy drugs. In view of this, a method of inhibiting NT5C2 activity will be needed to improve treatment outcomes for chemotherapy-resistant patients.

The Technology: Compounds that inhibit NT5C2

This technology identifies HTP-2 as a potent inhibitor of NT5C2 and describes the synthesis and characterization of HTP-2 analogues for treatment of chemotherapy-resistant and relapsed ALL and T-ALL. In a dose-dependent manner, these NT5C2 inhibitors potentiate the ability of 6-MP, a chemotherapy agent, to eliminate NT5C2-mutant mouse lymphoblasts. As such, this technology can be used in combination with existing chemotherapies to more efficaciously treat resistant cases of ALL and T-ALL.

This technology has been validated in NT5C2 R367Q mutant mouse lymphoblasts.

Applications:

• Treatment for T-ALL and ALL in combination with chemotherapy
• Treatment of relapsed T-ALL and ALL
• Prophylactic to prevent chemotherapy resistance
• Research tool for studying NT5C2 function

Advantages:

• Targets a clinically-relevant mutation
• Acts synergistically with chemotherapies
• Potential for both prophylactic and treatment indications

  Lead Inventor:

Adolfo Ferrando, M.D., Ph.D.

Patent Information:

Patent Status

Related Publications:

• Dieck CL, Tzoneva G, Forouhar F, Carpenter Z, Ambesi-Impiombato A, Sánchez-Martín M, Kirschner-Schwabe R, Lew S, Seetharaman J, Tong L, Ferrando AA. “Structure and mechanisms of NT5C2 mutations driving thiopurine resistance in relapsed lymphoblastic leukemia” Cancer Cell. 2018 Jul 9; 34(1): 136-147.

• Tzoneva G, Perez-Garcia A, Carpenter Z, Khiabanian H, Tosello V, Allegretta M, Paietta E, Racevskis J, Rowe JM, Tallman MS, Paganin M, Basso G, Hof J, Kirschner-Schwabe R, Palomero T, Rabadan R, Ferrando A. “Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL” Nat Med. 2013 Mar; 19(3): 368-371.

Tech Ventures Reference:

• IR CU18358, CU19220

• Licensing Contact: Joan Martinez