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Methods for Treating Cancer with a WEE1 Inhibitor

a technology of wee1 inhibitor and cancer, applied in the field of gene mutations, can solve the problems that p53-deficient tumors treated with gsub>2 /sub>checkpoint abrogators may be particularly susceptible to dna damag

Inactive Publication Date: 2017-04-06
MERCK SHARP & DOHME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a new way to identify patients who may benefit from treatment with a special type of inhibitor called WEE1. The invention is based on the discovery of specific mutations in a gene called TP53, which can make p53, a protein that helps protect cells from damage, non-functional. The patent describes using these mutations to predict which patients may respond to WEE1 treatment, and to develop a method for treating patients with WEE1-inhibitors based on the presence of these mutations. Overall, this invention provides a better way to identify and target cancer cells for treatment, potentially improving the effectiveness of WEE1 inhibitors and other cancer therapies.

Problems solved by technology

Many commonly used anti-cancer drugs indiscriminately target DNA in dividing cells and ultimately cause DNA damage.
Thus, p53-deficient tumors treated with G2 checkpoint abrogators may be particularly susceptible to DNA damage (Kawabe, T., Mol.

Method used

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  • Methods for Treating Cancer with a WEE1 Inhibitor
  • Methods for Treating Cancer with a WEE1 Inhibitor
  • Methods for Treating Cancer with a WEE1 Inhibitor

Examples

Experimental program
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Effect test

example 1

[0125]Thirty-one cell lines were treated with various DNA-damaging agents with or without WEE1-1 in a cell growth assay. Immediately after cells were plated, each drug was added at four concentrations for a total of 16 treatment conditions per combination (4×4 dose grid). Ninety-six hours following treatment, cell growth was evaluated with CellTiter-Glo (Promega) in treated samples relative to vehicle (DMSO) treated samples. Synergy was quantitated as the predicted additive growth inhibition of the two drugs (using the Bliss additivity model) subtracted from the observed growth inhibition of the two drugs. Therefore, a larger positive net difference indicates greater synergy, a negative difference indicates antagonism, and values at or close to 0 indicate additivity predicted by the Bliss model. The scale is displayed in the upper left corner of FIG. 1; darkest grey denotes strong synergy, light grey denotes moderate synergy, and darker grey denotes values that are considered additi...

example 2

[0128]A Phase II study was conducted with WEE1-1 Inhibitor combined with carboplatin in patients with p53 mutated epithelial ovarian cancer that show early relapse (<3 months) or progression during standard first line treatment with carboplatin—paclitaxel combination therapy. Patients were enrolled based on the tumor's TP53 gene sequence as determined in the AmpliChip p53 assay.

[0129]AmpliChip p53 test reagents are used to amplify products encompassing the coding regions of the p53 gene in two reactions (A and B) for all samples including a reference wildtype DNA. Exons 2, 5, 8, and 10; exon 4 upstream sequence; and internal control are in the Primer Mix A. Primer Mix B is designed and contained primers for exons 3, 6, 7, 9, and 11; exon 4 downstream sequence; and internal control. After thermal cycling, the products from Primer Mixes A and B are combined. The products generated from the A and B reactions are cleaved by a mix containing DNase I. Fragmentation is performed by recombi...

example 4

[0135]In a randomized, Phase II study evaluating WEE1-1 in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in adult patients with platinum sensitive p53 mutant ovarian cancer, patient enrollment was based on the presence of one or more mutations in Table 3. If the specimen has no mutations in the TP53 gene, or if it contains a mutation not listed on the Mutation Lookup Table 3, the patient will not be eligible for the study. If the specimen had at least one mutation that is listed in the Mutation Lookup Table 3, the patient was eligible for enrollment in the study.

[0136]Analysis of patient tumor tissue samples using the AmpliChip p53 assay was performed by Caris Life Sciences (Phoenix, Ariz.). The AmpliChip p53 assay characterized each specimen as ‘Mutation Not Detected,’ Mutation Detected′ or ‘Test Invalid’. A base change to a synonymous codon is treated as a Mutation Not Detected call, since it does not alter the amino acid. There are seven sing...

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Abstract

The present invention relates generally to the use of gene mutations, whose presence or absence are useful for predicting a patient's response to treatment with an anti-proliferative agent, in particular a WEE1 inhibitor. The presence or absence of a mutation to the TP53 gene, can be used to predict response to treatment with a WEE1 inhibitor in a patient presenting with a cancerous condition.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to the use of gene mutations, whose presence or absence are useful for predicting a patient's response to treatment with an anti-proliferative agent, in particular a WEE1 inhibitor. The presence or absence of a mutation to the TP53 gene, can be used to predict response to treatment with a WEE1 inhibitor in a patient presenting with a cancerous condition.BACKGROUND OF THE INVENTION[0002]Many commonly used anti-cancer drugs indiscriminately target DNA in dividing cells and ultimately cause DNA damage. This, in turn, triggers activation of cell cycle checkpoints which arrest progression of the cell cycle (at the G1, S, or G2 / M phases) with the purpose of allowing time for the DNA to be repaired before the cell undergoes DNA replication or division. From a therapeutic standpoint, inhibition of checkpoint kinases that mediate cell cycle arrest could force tumor cells to continue cell division before chemically-induced DN...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61K31/337C12Q1/68A61K31/555
CPCA61K31/519A61K31/555A61K31/337C12Q2600/106C12Q2600/156C12Q2600/158C12Q1/6886A61K45/06A61K31/407A61K31/4188A61K31/4745A61K31/513A61K31/704A61K31/7048A61K31/7068A61P11/00A61P15/08A61P35/00A61P43/00A61K2300/00
Inventor MARTON, MATTHEW J.BENITA, YAIR
Owner MERCK SHARP & DOHME CORP