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Methods of treating cancer patients with farnesyl transferase inhibitors

A cancer, tipifarnib technology, applied in the field of molecular biology and cancer biology, can solve the problem of different patient response

Active Publication Date: 2018-03-09
KURA ONCOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients respond differently to FTI therapy

Method used

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  • Methods of treating cancer patients with farnesyl transferase inhibitors
  • Methods of treating cancer patients with farnesyl transferase inhibitors
  • Methods of treating cancer patients with farnesyl transferase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[1020] Identification of immunological biomarkers associated with clinical benefit of tipifarnib

[1021] Analysis of gene expression profiles in bone marrow samples from two AML studies and tipifarnib IC50 data in multiple cell lines showed that multiple immune-related genes, especially NK cell-related genes, correlated better with tipifarnib. Prognosis related. Although some of these genes do not appear to be specific for tipifarnib treatment, others including KIR2DS2, KIR2DL2, KIR2DS5, KIR2DL5, and GZMM are specifically associated with clinical benefit of tipifarnib but not other non-FTI chemotherapy Agents such as cytarabine and mitoxantrone are related.

[1022] The current study used microarray data generated by global gene expression analysis of bone marrow samples collected in two clinical studies investigating the efficacy and safety of the FTI tipifarnib. One clinical study was conducted in adult patients over 65 years of age with previously untreated AML and the...

Embodiment II

[1047] A. Stratification of AML patients in the tipifarnib clinical trial.

[1048] Clinical trials can be conducted that include KIR typing as part of the patient inclusion criteria. For example, studies of tipifarnib treatment can be conducted in AML patients older than 60 years or who are not candidates for standard chemotherapy, or who have refractory or relapsed AML.

[1049] Bone marrow samples or blood samples were obtained from patients with AML before they entered clinical trials. The samples were then subjected to microarray analysis. DNA was isolated from samples of Trizol-treated bone marrow according to the manufacturer's instructions (Qiagen). Samples were analyzed for global gene expression and quantitative polymerase chain reaction (QPCR) for specific genes, including KIR2DS2, KIR2DL2, KIR2DS5, and KIR2DL5. In addition, microarray analysis provides the genotype of the patient's KIR genes. Patients were allowed to be tested for tipifarnib if they were iden...

Embodiment III

[1069] Individualized treatment judgment for CMML patients

[1070] The following procedure can be used to determine whether a patient with CMML is a candidate for FTI treatment, eg, tipifarnib.

[1071] BM samples were collected from patients prior to treatment, and monocytes were processed in situ. Total RNA was extracted from cell samples using the Trizol kit (Qiagen, Santa Clarita, CA). RNA quality was determined by assessing the presence of ribosomal bands on an Agilent Bioanalyzer (Agilent, Palo Alto, CA). Good quality samples were further processed for microarray analysis.

[1072] For each sample, 1 g of total RNA (measured by OD260) was reverse transcribed using the High Capacity cDNA ReverseTranscription Kit (Applied Biosystems, Foster City, CA) according to the manufacturer's instructions. Samples can then be incubated at 25°C for 10 minutes followed by 37°C for 30 minutes for optimal RNA conversion. QPCR was performed using the ABI Prism 7900HT Sequence Detec...

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Abstract

The present invention relates to the field of molecular biology and cancer biology. Specifically, the present invention relates to methods of treating a subject with a farnesyltransferase inhibitor (FTI) that include determining whether the subject is likely to be responsive to the FTI treatment based on genotyping and expression profiling of certain immunological genes and RAS mutation status inthe subject.

Description

technical field [0001] The present invention relates to the fields of molecular biology and cancer biology. Provided herein are methods of using certain immune-related genes as biomarkers to predict clinical sensitivity and therapeutic response to farnesyltransferase inhibitor therapy in subjects with cancer. Further provided herein are kits for performing these methods. Background of the invention [0002] Stratification of patient populations to improve treatment response rates is increasingly valuable in the clinical management of cancer patients. Farnesyltransferase inhibitors (FTIs) are therapeutic agents useful in the treatment of cancers such as leukemias, lymphomas and certain solid tumors. However, patients respond differently to FTI therapy. Thus, methods of predicting the response of cancer patients to FTI therapy, or of selecting patients for FTI therapy, represent an unmet need. The methods and compositions of the present invention fulfill these needs and pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886A61K45/00A61P35/00A61P35/04A61P35/02
CPCA61K45/00A61P35/00C12Q1/6886A61P35/04A61P35/02C12Q2600/106C12Q2600/156C12Q2600/158A61K31/4709A61P43/00A61K31/4725A61K45/06
Inventor 安东尼奥·瓜尔贝托凯瑟琳·罗斯·肖尔兹
Owner KURA ONCOLOGY
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