Overcoming drug resistance in relapsed T-ALL patients

This technology identifies a mutation in the NT5C2 gene of relapsed T-cell acute lymphoblastic leukemia (T-ALL) patients which may be targeted by inhibitors to overcome first-line drug resistance.

Unmet Need: Method to overcome resistance to common antitumor drugs in T-ALL treatments

T-ALL is an aggressive hematological malignancy. Even after receiving intensive chemotherapy regimens, 20% of pediatric and 50% of adult patients with T-ALL will show only transient responses to treatment and will eventually die of the disease. Currently, T-ALL is treated using nucleoside analogs such as cytarabine, but the efficacy of this treatment is reduced in relapsed patients. This may be due to mutations in the cytosolic 5’ – nucleotidase II (NT5C2) gene that dephosphorylate these nucleoside analogs, rendering them ineffective and leading to increased drug resistance.

The Technology: Mutated NT5C2 as target for inhibition in relapsed T-ALL

This technology identifies a mutation in the NT5C2 gene, which encodes an enzyme capable of inactivating nucleoside analog antitumor drugs. This mutation allows tumor cells to continue to replicate and progress disease despite treatment with first-line therapies, such as cytarabine. By inhibiting identified sites in the mutant NT5C2 gene or enzyme, it may be possible to overcome resistance to nucleoside analog chemotherapy and effectively treat relapsed T-ALL with first-line therapies.

This technology has been validated with human DNA from leukemic ALL blasts at relapse.

Applications:

• Treatment for relapsed T-ALL patients with mutations in the NT5C2 gene
• Treatment for other nucleoside analog-resistant diseases such as myeloid leukemia, non-Hodgkins lymphoma, and hepatitis B and C
• Diagnostic for predicting resistance to nucleoside therapies
• Drug development for NT5C2 inhibitors to overcome nucleoside analog resistance

Advantages:

• Identifies targetable mutation in both gene and corresponding enzyme
• Allows continued use of first-line chemotherapies, such as cytarabine
• Common shared T-ALL mutation allows large populations of patients to benefit from developed treatments

Lead Inventor:

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

Patent Information:

Patent Status

Related Publications:

• Barz MJ, Hof J, Groeneveld-Krentz S, Loh JW, Szymansky A, Astrahantseff K, von Stackelberg A, Khiabanian H, Ferrando AA, Eckert C, Kirschner-Schwabe R. “Subclonal NT5C2 mutations are associated with poor outcomes after relapse of pediatric acute lymphoblastic leukemia.” Blood. 2020 Mar 19; 135(12): 921-933.

• Dieck CL, Tzoneva G, Forouhar F, Carpenter Z, Ambesi-Impiombato, 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, Dieck CL, Oshima K, Ambesi-Impiombato A, Sánchez-Martín M, Madubata CJ, Khiabanian H, Yu J, Waanders E, Iacobucci I, Sulis ML, Kato M, Koh K, Paganin M, Basso G, Gastier-Foster JM, Loh ML, Kirschner-Schwabe R, Mullighan CG, Rabadan R, Ferrando AA. “Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia” Nature. 2018 Jan 25; 553(7689): 511-514.

• 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 Feb 3; 19(3): 368-371.

Tech Ventures Reference:

• IR CU13051, CU16271, CU17081, CU18358, CU19220

• Licensing Contact: Joan Martinez