Methods and pharmaceutical compositions for treating lymphoid malignancy

a technology of lymphoid malignancy and compositions, applied in the direction of instruments, biocides, transferases, etc., can solve the problems of limited information regarding the role of pi3k in thymocyte survival, and achieve the effect of lowering tumor burden

Inactive Publication Date: 2014-07-31
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]Another embodiment of the present invention is a method for lowering tumor burden in a subject suffering from T-ALL. This method comprises administering to the subject an effective amount of a pharmaceutical composition comprising a PI3Kδ inhibitor and a PI3Kγ inhibitor.

Problems solved by technology

To date, limited information exists regarding the role of PI3K in thymocyte survival.
However, over-expression of specific PI3K isoforms has not been reported for T-ALL and mutations in PI3Kα are rare, thus suggesting that they are not a major contributor to pathogenesis (Gutierrez et al., 2009; Lo et al., 2009).

Method used

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  • Methods and pharmaceutical compositions for treating lymphoid malignancy
  • Methods and pharmaceutical compositions for treating lymphoid malignancy
  • Methods and pharmaceutical compositions for treating lymphoid malignancy

Examples

Experimental program
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example 1

Materials and Methods

Mice and Animal Procedures.

[0115]All mice were kept in a specific pathogen-free facility at Columbia University Medical Center. All mice studies and breeding were carried out under the approval of the Institutional Animal Care and Use Committee of Columbia University.

[0116]Mice (p110δ− / − and p110γ− / −) on a mixed B6 / 129 background were described previously (Sasaki et al., 2000; Clayton et al., 2002). Animals were bred to generate a deficiency in both p110 catalytic subunits, the p110γδ− / − mice. Other names for the mouse include p110γδko and Pik3cg− / −; Pik3cd− / −, because p110γ is encoded by Pik3cg and p110δ is encoded by Pik3cd.

[0117]NOD.Cg-Prkdcscid II2rgtm1Wjl / Sz mice for xenograft experiments and Gt(ROSA)26Sortm1(Luc)Kael / J for bioimaging studies were obtained from The Jackson Laboratory (Bar Harbor, Me.). Mice deficient for PTEN in the T cell lineage were generated by crossing Lck-cre with floxed Pten (Hennet et al., 1995; Trotman et al., 2003). P110γ− / − and p...

example 2

Abnormal Thymus Size and Structure in p110γδ− / − Mice

[0152]The absence of p110δ and p110γ catalytic subunits in 4-week-old mice resulted in a significant reduction in thymus size compared with either age-matched WT littermate controls (FIG. 1Ai-ii) or singly deficient animals (FIG. 7). Consequently, total cell counts in p110γδ− / − thymi were significantly reduced compared with WT control (approximately 27-fold) or p110γ-deficient (approximately 10-fold) animals. No defect in thymus size or total cell count, however, was observed for mice deficient in p110δ. Strikingly, thymic sections from p110γδ− / − mice revealed a unique phenotype, that is, a lack of corticomedullary differentiation (FIG. 1Aiv-v). This was confirmed by the disorganized pattern of K5+ medullary epithelial cells (ECs), a finding consistent with disorders in T-cell development (FIG. 1Aviii) (Anderson et al., 2001). Moreover, this defect in corticomedullary differentiation was corrected on the reconstitution of p110γδ− / −...

example 3

Depletion of DP Thymocytes but Intact TCRB Expression Define p110γδ− / − Thymi

[0153]To determine the thymocyte population(s) most affected by the absence of PI3Kδ and PI3Kγ, flow cytometry analyses were performed to detect markers associated with thymocyte differentiation. Although the total number of CD4+ and CD8+ SP and DP cells were reduced overall, the absence of catalytic subunits had the greatest effect on the number of DP cells, typically the largest population of thymocytes in WT mice (FIG. 2A). In contrast, DN cells were the preponderant population in p110γδ− / − thymi, as occurs, for instance, in RAG2− / − mice (FIG. 8). In the latter, TCRB selection cannot occur at the DN3 stage, resulting in thymocyte death by apoptosis. Although a percentage of the DN3 population (CD44− CD25+) increased in thymi of p110γδ− / − mice, these cells were still capable of differentiating to the DN4 stage (CD44−CD25−) (FIG. 2B). The populations of DN3 and DN4 thymocytes developing in p110γδ− / − mice, h...

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Abstract

The present invention provides, inter alia, methods for treating, preventing, or ameliorating the effects of a lymphoid malignancy, such as those associated with a mutated phosphatase and tensin homolog (PTEN) gene, or T-cell acute lymphoblastic leukemia (T-ALL). These methods include administering to a subject an effective amount of a phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor and a phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitor. The present invention also provides pharmaceutical compositions for treating the effects of a lymphoid malignancy. This invention further provides a method for identifying a subject who may benefit from co-treatment with a PI3Kδ inhibitor and a PI3Kγ inhibitor. This method includes determining from a sample of the subject whether the subject has a mutated PTEN gene. Additionally, this invention provides methods for identifying a compound that has both PI3Kδ and PI3Kγ inhibitory activity.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present invention claims benefit to U.S. provisional application Ser. No. 61 / 450,341 filed Mar. 8, 2011, the entire contents of which are incorporated by reference.GOVERNMENT FUNDING[0002]This invention was made with government support under grant no. PR093714 from the Department of Defense. The government has certain rights in the invention.FIELD OF INVENTION[0003]The present invention relates to, inter alia, methods and pharmaceutical compositions to treat, prevent, or ameliorate the effects of a lymphoid malignancy, such as T-cell acute lymphoblastic leukemia (T-ALL) or T-cell acute lymphoblastic lymphoma. Methods for identifying a subject who may benefit from co-treatment with a phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor and a phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitor and for identifying a compound that has both PI3Kδ and PI3Kγ inhibitory activity are also provided.BACKGROUND OF THE INVENTION[0004]Thymocyte developm...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/52A61K31/573G01N33/50C12Q1/68G01N33/573A61K31/713C12N15/113
CPCC12N9/1205C12Y207/01137C12Y207/01153A61K31/52A61K31/573A61K31/713C12N15/1137C12Q1/6886G01N33/5041G01N33/573
Inventor DIACOVO, THOMAS
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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