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Use of rad18 inhibitors in the treatment of tumors

a tumor and inhibitor technology, applied in the field of tumor treatment, can solve the problems of no available effective tools to fight acquired tumors, major challenge in the actual treatment of cancers, etc., and achieve the effects of reducing the risk of cancer recurrence, reducing the self-renewal of cancer stem cells, and reducing the growth of said cells

Inactive Publication Date: 2017-12-21
CENT NAT DE LA RECHERCHE SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent relates to using an inhibitor of a protein called Rad18 to treat tumors and reduce the risk of cancer relapse. The inhibitor can kill cancer stem cells, which are the cells that give rise to most tumors, and also reduce their self-renewal and growth. The treatment involves combining the inhibitor with other chemotherapy drugs that damage DNA. This approach can enhance the effects of traditional cancer treatment and improve patient outcomes. The invention is particularly useful for patients with tumors that have cancer stem cells. The inhibitor can be used as a sole antitumor agent.

Problems solved by technology

However certain tumors are resistant from the start to therapy and manage to escape from the treatment.
This constitutes a major challenge in the actual treatment of cancers.
To date there are no available efficient tools to fight against the acquired resistance of cancer to the therapy which is responsible for cancer recurrence.

Method used

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  • Use of rad18 inhibitors in the treatment of tumors
  • Use of rad18 inhibitors in the treatment of tumors
  • Use of rad18 inhibitors in the treatment of tumors

Examples

Experimental program
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Effect test

example 1

Association of Rad18 with the Stem Cell State of Cancerous Cells Materials and Methods

[0131]Xenopus Egg Extracts Preparation and Use

[0132]Interphasic and cycling Xenopus egg extracts were prepared and used as described (Murray et al, 1991; Recolin et al, 2012). UV-irradiation of sperm chromatin and isolation of chromatin fractions was as described (Recolin et al, 2012). For experiments performed at low N / E ratio, sperm nuclei (1000 nuclei / μl) were diluted 10-fold in XB buffer (100 mM KCl; 10 mM Hepes-KOH, pH 7.7; 2 mM MgCl2; 0.1 mM CaCl2; 50 mM sucrose, pH 7.7) supplemented with proteases inhibitors (leupeptin, aprotinin and pepstatin, 5 μg / ml each) on ice, and added to the same volume of cytoplasm as for the high N / E ratio condition.

[0133]Immunodepletion and Immunoprecipitation Procedures

[0134]Rad18 was removed from egg extracts by two rounds of depletion with affinity-purified Rad18 antibodies coupled to DyneBeads (Invitrogene). This procedure allows minimal dilution of the extrac...

example 2

Rad18 Downregulation Affects the Proliferation of Glioblastoma Cancer Stem Cells in the Absence of External Damage

[0163]Materials and Methods

[0164]Glioblastoma cancer stem cells (Gliospheres, Gb4 and Gb7 cell lines) were isolated from patients as described in Clarion et al, 2014.

[0165]Cells were maintained in DMEM-F12 (Lonza, Levallois-Perret, France) supplemented with B27 and N2 (Invitrogen, LifeTechnologies, Saint Aubin, France), 25 ng / ml of FGF-2 and EGF (Peprotech, Neuilly sur Seine, France) at 37° C. in 5% CO2 humidified incubators.

[0166]Results Gb4 glioblastoma cancer stem cells extracts, treated with control siRNA or a Rad18-specific siRNA (SEQ ID NO:3) were analysed 72 hours post-treatment. Extracts were probed with anti-Rad18 or anti-PCNA antibodies, the Western Blot is shown on FIG. 6(A).

[0167]FIG. 6(B) shows phase contrast microscopy images of the gliospheres. Downregulation of Rad18 expression was shown to affect the proliferation of gliospheres (see also FIG. 6C, for qu...

example 3

The USP7 Inhibitor P2207 Sensitizes Glioblastoma to Cisplatin Treatment

[0168]Materials and Methods

[0169]Cell Viability Experiments

[0170]Cells were plated at 1.0×104 cells / well in 12-well plates and exposed to the indicated amount of P2207 inhibitor (Sigma) or DMSO as control. 48 h post-treatment, cell viability was determined using the CellTiter-Glo luminescent cell viability assay (Promega).

[0171]Results

[0172]Cell viability of U87-MG glioblastoma cells treated with USP7 inhibitor P2207 was assessed.

[0173]As shown on FIG. 7, the USP7 inhibitor P2207 sensitizes glioblastoma to cisplatin treatment.

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Abstract

The present invention relates to the use of an inhibitor of Rad18 expression or activity, in treating a tumor or in sensitizing a patient affected with a tumor, to a treatment with an antineoplastic agent that is a DNA damaging chemotherapeutic agent so to both reduce the self renewal of cancer stem cells and increase the DNA damage response thus boosting apoptotic cell death.

Description

[0001]The present invention relates to the use of an inhibitor of Rad18 expression or activity, in treating a tumor that is resistant to a treatment with a DNA damaging antineoplastic agent, by sensitization of cancer cells resistant to the said treatment and / or by eradicating cancer stem cells of the said tumor. More particularly, the invention is based on reducing self-renewal of cancer stem cells through targeting Rad18.BACKGROUND OF THE INVENTION:[0002]Treatment of cancer is mainly based on the use of DNA damaging agents that generate DNA lesions. The mechanism of action of this treatment is to produce a large amount of DNA damage that cannot be efficiently repaired by the tumor cells so as to fully boost a programmed cell death pathway, such as apoptosis, mainly mediated by the genome surveillance mechanisms (checkpoints). ATR, ATM, Chk1, and Chk2 protein kinases comprise main regulators of this signaling pathway (Ciccia and Elledge, 2010).[0003]These kinases in turn phosphoryl...

Claims

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Application Information

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IPC IPC(8): C12N15/113A61K31/381G01N33/574A61K31/713C12Q1/68A61K33/243
CPCC12N15/1137C12Y203/02A61K31/713A61K31/381G01N33/57496G01N2333/9108C12N2310/14C12Q2600/106C12Q2600/158G01N2800/52C12Q1/6886C07K16/18C12N15/113C12N2320/31A61K31/255A61K31/4745A61K31/555A61K31/7105C12Y603/02C12N9/93C07K16/40A61K33/243
Inventor MAIORANO, DOMENICO
Owner CENT NAT DE LA RECHERCHE SCI
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