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Biomarkers for HEDGEHOG inhibitor therapy

A technology of biomarkers and inhibitors, applied in the field of personalized therapy

Inactive Publication Date: 2014-02-26
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, aberrant activity of the HEDGEHOG signaling pathway due to, for example, mutations that constitutively activate said pathway can have pathological consequences

Method used

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  • Biomarkers for HEDGEHOG inhibitor therapy
  • Biomarkers for HEDGEHOG inhibitor therapy

Examples

Experimental program
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Effect test

Embodiment 1

[0092] The multigene Hedgehog signature was originally developed by analyzing 40FFPE medulloblastoma (MB) samples. Matched fresh-frozen samples from the same cases were profiled previously as described by Y-J Cho and colleagues (Y-J Cho et al., JCO, 2010), and each individual case was identified as Hedgehog activated or non-Hedgehog activated based on its gene expression profile. A set of 32 candidate genes differentially expressed in hedgehog-positive (Hh+) versus hedgehog-negative (Hh-) tumors were selected from a comprehensive database of available profiling studies and an additional 22 potential normalizing genes. All candidate genes showing differential Hh+ versus Hh- expression were consistent across all profiling studies evaluated. RT-PCR assays for these candidate genes were developed and optimized for use with FFPE samples. Candidate genes that do not show robust expression within FFPE sample types are removed in further applications. In terms of 10 up- and 8 down-r...

Embodiment 2

[0106] Recruitment of adult cancer patients, including medulloblastoma, into an ongoing study of methyl-4'-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl -Morpholin-4-yl)-pyridin-3-yl]-amide Phase I dose escalation trial to evaluate methyl-4'-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis -2,6-Dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide safety and tolerability and evaluation of methyl-4'-trifluoromethoxy in adult patients - Maximum tolerated dose of biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide. Archived FFPE tumor samples collected prior to the start of the trial were available for analysis by the method of the present invention from 3 medulloblastoma patients recruited into this trial. A daily dose of 200 mg methyl-4'-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridine-3- Base]-amide-treated patients achieved a RECIST-criteria partial response (PR) after 2 months of treatmen...

Embodiment 3

[0109] The method of the present invention was used to confirm Hedgehog activation status on another group of 40 medulloblastomas with a pathologically confirmed diagnosis. Of the 40 cases, 26 had classic medulloblastoma histology, 12 had nodular / desmoplastic histology, and 1 had large cell / undifferentiated histology. No other demographic data related to these cases were available. The Hedgehog activation status of these tumors was previously characterized by the affymetric gene expression profiling method as described by Y-J Cho and colleagues (YJ Cho et al. JCO, 2010). Hedgehog activation in 15 cases and non-Hedgehog activation in the remaining 25 cases were determined by the method of the present invention according to the 8-gene model, 5-gene model and each single gene SPHK1, OTX2, SFRP1, PDLIM3 or SHROOM2 in FFPE tumor samples Confirm in .

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Abstract

A method of selecting a subject having cancer for treatment with a Hedgehog signaling inhibitor by determining the level of expression of at least one biomarker in a biological sample derived from the subject.

Description

technical field [0001] The present invention relates to methods of personalizing therapy. Background of the invention [0002] HEDGEHOG signaling is known to regulate a wide range of biological processes such as cell proliferation, differentiation and organ formation in a tissue-specific and dose-dependent manner. Normally, HEDGEHOG signaling is tightly regulated during cell proliferation, differentiation and embryonic patterning. However, aberrant activity of the HEDGEHOG signaling pathway due to, for example, mutations that constitutively activate the pathway can have pathological consequences. For example, loss-of-function mutations in Patched are found in Gorlin syndrome (an inherited syndrome with high risk of skin and brain cancer, also known as basal cell nevus syndrome (BCNS)); gain-of-function mutations in Smo and GIi Mutations are associated with basal cell carcinoma and glioblastoma. Basal cell carcinoma (BCC) is the most common form of skin cancer, affecting m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/574G01N33/50
CPCG01N33/5041G01N33/57407G01N2800/60G01N33/5023G01N2800/52C12Q1/6886G01N33/6803C12Q2600/158C12Q2600/106A61P1/18A61P11/00A61P13/08A61P15/00A61P19/00A61P21/00A61P35/00A61P35/02A61P43/00G01N33/574G01N33/50G01N33/68A61K31/5377C12Q1/6881
Inventor R·班达鲁A·海德D·M·罗宾逊K·L·罗斯T·T·夏普寿亚平
Owner NOVARTIS AG
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