Synthetic lethality and the treatment of cancer
Inventors
Berthiaume, Luc G. • Beauchamp, Erwan • Perinpanayagam, Conganige Maneka Anne • Yap, Chuiyee
Assignees
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Publication Number
US-11135218-B2
Publication Date
2021-10-05
Expiration Date
Abstract
Described herein are compounds, compositions and methods for treatment of cancer. Also described are methods and uses for identifying subject with cancer that are suitable for treatment with the compounds, composition and methods are described herein. In one aspect of the present invention, there is provided a method of treating a subject having a cancer deficient in NMT2, comprising: administering to said subject an NMT inhibitor.
Core Innovation
The invention relates to treating cancers, including Burkitt’s lymphoma and other B-cell lymphoma types, by exploiting synthetic lethality associated with loss of N-myristoyltransferase 2 (NMT2) protein activity or level relative to normal human B cells. The treated subjects express an N-myristoyltransferase 1 (NMT1) protein and comprise a loss of NMT2 protein activity or level as compared to normal human B cells. In this context, the invention administers an inhibitor of NMT1 protein activity.
The NMT1 inhibitor is described as DDD85646 or a derivative thereof, where the NMT1 inhibitor inhibits NMT1 protein activity. The invention further describes companion approaches for identifying suitable patients by measuring NMT2 deficiency, including NMT2 expression/activity and biomarkers associated with myristoylated proteins and protein acylation.
The disclosure includes experimental support that B-cell lymphoma cells show near-complete absence or reduction of NMT2 relative to NMT1, and that these cells are sensitive to NMT inhibitors in vitro. The document further reports that ectopic NMT2 expression in Ramos increases resistance to Tris-DBA, and that qRT-PCR indicates reduced NMT2 versus NMT1 mRNA in B-cell lymphoma cell lines.
Claims Coverage
The provided set contains 2 independent claims, both centered on treating Burkitt’s lymphoma by administering DDD85646 or a derivative to subjects characterized by NMT1 expression and loss of NMT2 protein activity or level, with patient identification addressed in one independent claim.
Treating Burkitt’s lymphoma with DDD85646 or derivative in NMT1+/NMT2-loss subjects
Administering a therapeutically effective amount of an inhibitor of NMT1 protein, where the NMT1 inhibitor inhibits NMT1 protein activity, the NMT1 inhibitor is DDD85646 or a derivative thereof, to a human subject having Burkitt’s lymphoma that expresses an NMT1 protein and comprises a loss of NMT2 protein activity or level as compared to normal human B cells.
Identified Burkitt’s lymphoma patient treatment with DDD85646 or derivative
Administering DDD85646 or a derivative thereof to a human subject identified as having Burkitt’s lymphoma that expresses an NMT1 protein and comprises a loss of NMT2 protein activity or level as compared to normal human B cells.
Across the two independent claims, the core inventive coverage is limited to Burkitt’s lymphoma treatment using DDD85646 or a derivative as an NMT1 inhibitor for subjects expressing NMT1 and exhibiting loss of NMT2 protein activity or level versus normal human B cells; one independent claim also recites that the subject is identified as having the specified lymphoma and biomarker pattern.
Stated Advantages
Synthetic lethality is exploited by targeting NMT1 in subjects with NMT2 deficiency (loss of NMT2 protein activity or level).
The document reports inhibition of NMT activity and sensitivity of B-cell lymphoma cells to NMT inhibitors in vitro.
Documented Applications
Treating Burkitt’s lymphoma in a human subject expressing NMT1 and exhibiting loss of NMT2 protein activity or level compared to normal human B cells, using an NMT1 inhibitor that is DDD85646 or a derivative thereof.
Patient selection and diagnostics to identify suitable subjects by assessing NMT2 deficiency, including NMT2 expression or activity and biomarkers related to myristoylated proteins and protein acylation.
Treating cancers including B-cell lymphomas, including follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, B-CLL/SLL, immunocytoma or Waldenstrom’s, MALT-type or monocytoid B cell lymphoma, and anaplastic large cell lymphoma, by targeting synthetic lethality associated with NMT2 loss using NMT inhibition.
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