Tailored Treatment Suitable for Different Forms of Mastocytosis

Abstract

The present invention relates to a method for a tailored treatment of mastocytosis comprising a) assessing whether or not a c-kit mutation at position 816 is detected in a sample of a patient and b) administering a specific 816 mutant c-kit inhibitor in case a mutation is detected in step a) or an inhibitor displaying efficacy on c-kit wild in case no mutation is detected in step a). The invention is more particularly suited 10 for treating category II, III and IV mastocytosis.

Description

EXAMPLE 2

Human c-kit 816 Harboring Mast Cells Are Resistant to the Antiproliferative Activity of STI-571

The following experiment has been performed in order to confirm that mast cells harboring the human kit 816 mutant are resistant to the antiproliferative activity of STI-571, an inhibitor of kit wild-type activity.

For this purpose, a mouse bone marrow-derived mast cell line (BMMC), factor-independent and expressing the mutant D816V form of the human c-kit (as assessed by RT-PCR with specific primers for the mutant form of the human c-kit) has been generated by long-term liquid culture of bone marrow-derived progenitors from mice transgenic for the mutant form of the human c-kit. This cell line (doubling time of around 48 hours) has then been treated with increasing concentrations of STI-571 (0 to 10⁻⁵ M) for 3 days. At 24, 48 and 72 hours, the number of viable cells was determined in each condition using the trypan blue exclusion assay. The proliferation of the BMMC line with the mutant D816V form of the human c-kit was not affected, at any time, by STI-571 under or equal to 1 microM (FIG. 2). By contrast, the proliferation of these BMMC was dose- and time-dependently inhibited by concentrations of STI-571 above 1 microM. At this concentration, it is not possible to use STI-571 for treating patients afflicted with proliferative mast expressing the ‘816’ mutant C-KIT. This result is also observed using the lymphoid BaF/3 murine cell line transfected with the D816V mutant form of the human c-kit.

In conclusion, the D816V mutant form of the human c-kit receptor is resistant to pharmacological doses of STI 571.

We then choose to screen other compounds for specifically treating patients afflicted with proliferative mast expressing the ‘816’ mutant C-KIT. In this regards, we have shown that compounds of formula III and

Claims

1. A method for a tailored treatment of mastocytosis comprising a) assessing whether or not a c-kit mutation at position 816 is detected in a sample of a patient in need of the treatment; andb) administering to the patient 816 c-kit mutant inhibitor in case the mutation is detected or an inhibitor displaying efficacy on c-kit wild and/or on juxtamembrane mutated c-kit in case the mutation is not detected.

2-9. (canceled)

10. The method of claim 1, wherein the mastocytosis is category I mastocytosis, category II mastocytosis, category III mastocytosis, category IV mastocytosis or a symptom associated thereof.

11. The method of claim 1, wherein the mastocytosis is urticaria pigmentosa, diffuse cutaneous mastocytosis, solitary mastocytoma in human, dog mastocytoma, bullous mastocytosis, erythrodermic mastcytosis, teleangiectatic mastocytosis, mastocytosis with an associated hematological disorder, myeloproliferative disorder associated with mastocytosis or mast cell leukemia.

12. The method of claim 1, wherein the mastocytosis is category IV mastocytosis and wherein the method further comprises administering to the patient a compound selected from a group consisting of 2-Chloro-2′-desoxyadenosine and analogs thereof.

13. A method of treating Category II, III or IV mastocytosis in a patient having a c-kit mutation at position 816, said method comprising administering to the patient a 816 c-kit mutant inhibitor.

14. The method of claim 13, wherein the 816 c-kit mutant inhibitor is a compound of formula III

15. A method of treating Category I, II, III or IV mastocytosis in a patient not bearing a c-kit mutation at position 816, said method comprising administering to the patient an inhibitor displaying efficacy on c-kit wild and/or on juxtamembrane mutated c-kit.

16. The method of claim 15, wherein the inhibitor is a compound of formula III:

17. The method of claim 15, wherein the inhibitor is a N-phenyl-2-pyrimidine-amine compound of formula II

18. A method of diagnosing mastocytosis in an individual, said method comprising a) reversing transcription of a RNA sample from a skin of the individual using oligo dT primers and random primers to obtain a cDNA;b) amplifying the cDNA using primers