Diagnostic markers for treating cell proliferative disorders with telomerase inhibitors

A telomerase inhibitor, cancer cell technology, applied in the treatment of these individuals, can solve the problem of cancer patients not getting benefits, exposure to toxic effects, etc.

Inactive Publication Date: 2015-09-23
GERON CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Unfortunately, many cancer patients do not gain benefit from cytotoxic agents or targeted therapies such as telomerase inhibitors, but are still exposed to their toxic effects

Method used

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  • Diagnostic markers for treating cell proliferative disorders with telomerase inhibitors
  • Diagnostic markers for treating cell proliferative disorders with telomerase inhibitors
  • Diagnostic markers for treating cell proliferative disorders with telomerase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] Embodiment 1: Oligonucleotide N3'→P5'phosphoramidate (NP) or N3'→P5'thiophosphoramidate (NPS) preparation and lipid conjugation

[0169] This example shows how to synthesize lipid-conjugated oligonucleotides N3'→P5' phosphoramidate (NP) or N3'→P5' phosphorothioate (NPS).

[0170] Materials and methods

[0171] starting compound

[0172] These compounds can be prepared as described, for example, in McCurdy et al., Tetrahedron Letters 38:207-210 (1997) or Pongracz & Gryaznov, Tetrahedron Letters 49:7661-7664 (1999). The starting 3'- Amino nucleoside monomers.

[0173] lipid attachment

[0174] Depending on the nature of the linkage chosen, a variety of synthetic methods can be used to conjugate the lipid moiety L to oligonucleotides; see, e.g., Mishra et al., Biochim. et Biophys. Acta 1264:229-237 (1995), Shea et al. al., Nucleic Acids Res. 18:3777-3783 (1995), or Rump et al., Bioconj. Chem. 9:341-349 (1995). Typically, conjugation is achieved through the use of...

Embodiment 2

[0183] Example 2: Analysis of formalin-fixed, paraffin qPCR of embedded samples

[0184] This example demonstrates the performance of quantitative polymerase chain reaction for the determination of relative telomere length of FFPE NSC Phase II (CP14B-012) research tissue samples.

[0185] Materials and methods

[0186] clinical trial design

[0187] The purpose of the NSC Phase II (CP14B-012) study was to evaluate the efficacy and safety of imetelostat (GRN163L) as maintenance therapy in patients with advanced-stage NSCLC who have not progressed after 4 cycles of platinum-based therapy . Participants were randomized in a 2:1 ratio to imelastat and standard of care versus standard of care alone. Participants who received bevacizumab along with their induction chemotherapy continued to receive bevacizumab in this study.

[0188] The primary outcome measure was progression-free survival, defined as the time from randomization to documented disease progression or death, wh...

Embodiment 3

[0211] Example 3: Analysis of formalin-fixed, paraffin-embedded samples from the NSC Phase II (CP14B) study Telo-FISH

[0212] Samples were obtained from 61 of 116 patients enrolled in the NSC Phase II (CP14B-012) study described above. Of these 61 patient samples, 59 yielded evaluable Telo-FISH assay results for PFS analysis. Each assay yielded data from 7-14545 foci in 6 regions ("fields") on the slide. Area and fluorescence intensity were recorded for each focus.

[0213] Materials and methods

[0214] Unstained FFPE tissue slides (5 μm thick tissue sections) were prepared by conventional histological methods. Tissue slides were preheated at 65°C for 6 minutes to melt the paraffin before loading onto slide holders. Immerse the loaded slide rack in 100 mL of xylene in the staining jar for 2 times for 3 minutes (3 minutes x 2) to remove paraffin.

[0215] Slides were then hydrated in 3 minute increments via a graded ethanol series: 100% EtOH (3 minutes x2), 95% EtOH ...

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Abstract

Provided herein are methods for identifying individuals diagnosed with a cell proliferative disorder that will benefit from treatment with a telomerase inhibitor compound. Also provided herein are methods for treating these individuals with telomerase inhibitor compounds. The methods comprise identifying individuals who will benefit from said treatment based on the average relative length of telomeres in cancer cells from said individuals.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Patent Application No. 61 / 732,263, filed November 30, 2012, U.S. Provisional Patent Application No. 61 / 780,851, filed March 13, 2013, U.S. Patent Application No. 61 / 780,851, filed March 13, 2013 Priority to U.S. Provisional Patent Application No. 13 / 802,035, U.S. Provisional Patent Application No. 61 / 798,478, filed March 15, 2013, and U.S. Provisional Patent Application No. 61 / 809,228, filed April 5, 2013, which are incorporated by reference The full disclosure content is included in this article. field of invention [0003] The present invention relates to methods for identifying individuals with or suspected of having cancer who would benefit from treatment with telomerase inhibitor compounds and methods for treating such individuals. Background of the invention [0004] Cancer is a leading cause of death worldwide. Despite significant advances in the field of chemotherapy, ...

Claims

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Application Information

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IPC IPC(8): C12Q1/68G01N33/533
CPCC12Q1/68C12Q2600/156G01N33/533C12Q1/6886C12Q2600/106G01N33/574G01N2333/9128A61K45/06A61K31/7125A61P1/04A61P1/16A61P11/00A61P13/10A61P15/00A61P21/00A61P25/00A61P35/00A61P35/02A61P43/00A61K2300/00A61K31/7088
Inventor E·巴塞特B·伯林顿H·王K·恩格
Owner GERON CORPORATION
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