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Methods for diagnosis prognosis and methods of treatment

a diagnostic prognosis and treatment technology, applied in the field of diagnostic prognosis and treatment methods, can solve the problems of short survival time of patients resistant to therapy, inability to accurately identify and inability to accurately diagnose the molecular events underlying these transformations

Inactive Publication Date: 2009-04-16
NODALITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]Other objects, features and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Problems solved by technology

These disruptions are often caused by changes in the activity of molecules participating in cellular pathways.
Despite the increasing evidence that disruption in cellular pathways mediate the detrimental transformation, the precise molecular events underlying these transformations have not been elucidated.
As a result, therapeutics may not be effective in treating conditions involving cellular pathways that are not well understood.
Patients who are resistant to therapy have very short survival times, regardless of when the resistance occurs.
While various staging systems have been developed to address this clinical heterogeneity, they cannot accurately predict whether an early or intermediate stage patient will experience an indolent or aggressive course of disease.

Method used

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  • Methods for diagnosis prognosis and methods of treatment
  • Methods for diagnosis prognosis and methods of treatment
  • Methods for diagnosis prognosis and methods of treatment

Examples

Experimental program
Comparison scheme
Effect test

example 1

Signaling Pathways in CLL Samples

[0337]Signals propagated through the B cell receptor (BCR) guide the maturation and survival of B cells and might factor in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). In this example, BCR signaling in CLL cells was investigated at the single-cell level using multiparametric flow cytometry. Concurrent analysis was performed using fluorochrome-conjugated antibodies specific for B-cell surface antigens and a panel of antibodies recognizing specific phospho-peptide epitopes within a selected group of intracellular signaling proteins. CLL samples from patients (N=6) showed weak or minimal signaling activity at p72SYK / p70ZAP, Erk1 / 2, B-Cell linker protein (BLNK) and phospholipase-Cγ-2, (PLCγ2) when stimulated only at the BCR with anti-μ crosslinking, whereas a robust signal was observed in a control Ramos B cell line. The low-level signaling in CLL cells could be accounted for by either a defect in activation of a key protein r...

example 2

CLL Patients Display Distinguishable Patterns

[0368]Isolation, storage, thawing, and equilibration of primary cells. PBMC were isolated using density gradient separation (Ficoll-Paque Plus; Amersham Biosciences). In some embodiments, PBMC were pelleted by low-speed centrifugation, resuspended in medium composed of 90% FCS (HyClone)+10% DMSO (Sigma-Aldrich), frozen slowly in the vapor phase of liquid nitrogen in multiple cryotubes, and stored in liquid nitrogen. For signaling analysis of frozen samples, an individual cryotube was thawed into 5 ml of RMPI +1% serum, counted, pelleted, and resuspended at 3.3×106 cells / ml. Thawed PBMC were allowed to rest at 37° C. in a CO2 incubator for 2 h before stimulation.

Modulation

[0369]At least half an hour before stimulation, 300 μl of medium containing 1×106 PBMC was aliquoted into flow cytometry tubes (Falcon 2052; BD Biosciences) and allowed to rest at 37° C. in a CO2 incubator. Cross-linking of B cell receptors was achieved using goat polyclo...

example 3

Evaluation of Apoptosis Pathways in CLL Patient Samples

[0373]Current therapeutic approaches for CLL involve fludarabine-based regimens combined with monoclonal antibodies such as rituximab. Fludarabine, a purine analog, inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. Rituximab is a chimeric CD20 specific antibody and has mechanistically been shown to bind complement, induce antibody-dependent cellular cytotoxicity (ADCC) and, in some situations, rituximab binding to CD20 inhibits proliferation and induces cellular apoptosis (for a discussion of apoptosis see U.S. Ser. No. 61 / 085,789).

[0374]Cellular apoptosis in response to therapeutic agents, including but not limited to, DNA damaging agents such as Fludarabine or biological agents such as Rituximab, can be measured by multiparameter flow cytometry using fluorophore-conjugated antibodies that recognize intracellular protein components or nodes of the apoptotic machinery. Such nodes may include...

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Abstract

This invention is directed to methods and compositions for diagnosis, prognosis and for determining methods of treatment. The physiological status of cells present in a sample (e.g. clinical sample) can be used in diagnosis or prognosis of a condition (e.g. Chronic Lymphocytic Leukemia), in patient selection for therapy, to monitor treatment and to modify or optimize therapeutic regimens. The physiological status of a cell can be determined by comparing the intracellular status of one or more activation elements (e.g. the phosphorylation status of a signaling molecule) in a cell (e.g. a cancer cell) to that of another cell (e.g. a normal cell). The physiological status of a cell can be further classified by adding one or more modulators (e.g. an inhibitor or activator) to the cell in question. In some embodiments, the invention is directed to methods of determining a phenotypic profile of a population of cells.

Description

CROSS-REFERENCE[0001]This application claims the benefit of the filing date of U.S. Ser. No. 60 / 957,160 filed Aug. 21, 2007 and U.S. Ser. No. 61 / 048,920 filed Apr. 29, 2008 and each of these provisional applications are hereby expressly incorporated by reference in their entirety.BACKGROUND OF THE INVENTION[0002]Many conditions are characterized by disruptions in cellular pathways that lead, for example, to aberrant control of cellular processes, or to uncontrolled growth and proliferation of cells. These disruptions are often caused by changes in the activity of molecules participating in cellular pathways. For example, specific signaling pathway alterations have been described for many cancers. Despite the increasing evidence that disruption in cellular pathways mediate the detrimental transformation, the precise molecular events underlying these transformations have not been elucidated. As a result, therapeutics may not be effective in treating conditions involving cellular pathw...

Claims

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Application Information

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IPC IPC(8): C12Q1/02
CPCG01N33/5041G01N33/57426G01N33/5047G01N2333/4703G01N2333/7051G01N2333/70514G01N2333/70517G01N2333/70596G01N2333/912
Inventor FANTL, WENDY J.PUTTA, SANTOSH K.PEREZ, OMAR D.FRANCIS-LANG, HELEN L.COHEN, AILEEN C.
Owner NODALITY
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