WO2014001988A2 - USE OF CTBP1 siRNA FOR THE TREATMENT OF GASTRIC CANCER - Google Patents

USE OF CTBP1 siRNA FOR THE TREATMENT OF GASTRIC CANCER Download PDF

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Publication number
WO2014001988A2
WO2014001988A2 PCT/IB2013/055125 IB2013055125W WO2014001988A2 WO 2014001988 A2 WO2014001988 A2 WO 2014001988A2 IB 2013055125 W IB2013055125 W IB 2013055125W WO 2014001988 A2 WO2014001988 A2 WO 2014001988A2
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Prior art keywords
cancer
epirubicin
cisplatin
sirna
ctbp1
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PCT/IB2013/055125
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French (fr)
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WO2014001988A3 (en
Inventor
Manuel Gidekel
Carolina BIZAMA
Osvaldo Podhajcer
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Manuel Gidekel
Bizama Carolina
Osvaldo Podhajcer
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Application filed by Manuel Gidekel, Bizama Carolina, Osvaldo Podhajcer filed Critical Manuel Gidekel
Publication of WO2014001988A2 publication Critical patent/WO2014001988A2/en
Publication of WO2014001988A3 publication Critical patent/WO2014001988A3/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/31—Combination therapy

Definitions

  • This invention encompasses a novel composition comprising silenced CTBP-1 combined with a compound selected from among 5-FU, Cisplatin and Epirubicin.
  • the invention further relates to a method of treating gastric cancer with a combination of siRNA silenced CTBP-1 and a compound selected from among 5-FU, Cisplatin and Epirubicin.
  • gastric cancer is considered the fourth most common cancer and second most deadly cancer (Brenner et a!., 2009).
  • the survival of resected gastric cancer is estimated between 10-30% (Dicken et aL, 2005).
  • adjuvant therapy either chemotherapy or radiotherapy to improve the survival in advanced lesions after surgery, in spite of multiple schemes, only 30% of patients presented a clinical response, the main complications being recurrence and systemic involvement (Cataiano et aL, 2005).
  • 5-FU is known as an anti-metabolite that acts as an inhibitor of thymidyiate synthase
  • Epirubicin as an inhibitor of topoisomerase H
  • Cisplatin is a DNA intercalating compound that leads damage to DNA in cancer cells.
  • the limited benefit and high toxicity of this scheme makes necessary the continued search for new molecular therapeutic approaches designed to reverse or overcome resistance to drugs such as the use of siRNA.
  • CTBP1 encodes for a phosphoprotein that acts in the nucleus as a transcriptional repressor and In the cytoplasm in the maintenance of vesicular membranes (Birts et a!., 2010).
  • E1A loses its C-terminai through interaction with CTBP domain, which makes E1A it less effective in promoting cell transformation, when collaborating with the mutant RAS.
  • CTBP1 degradation depends on APC in these cells and APC mutation leads to increased CTBP1 resulting in the initiation of the formation of adenomas (Nadauld et aL, 2006).
  • CTBPs have also been implicated in the cellular response to chemotherapy.
  • a method of treating gastric cancer comprising the steps of:
  • a composition for treating gastric cancer comprising CTBP-1 gene silenced with siRNA combined with an anticancer compound selected from the group consisting of 5-FU, Cisplatin and Epirubicin or mixtures thereof.
  • the anti-cancer compound is 5-FU wherein the activity of the 5-FU against expressed cancer cell lines is enhanced by a factor of approximately 6; when the anticancer compound is Cisplatin the activity of Cisplatin against expressed cancer cell lines is enhanced by a factor of 4-5; and, when the anticancer compound is Epirubicin the activity of Epirubicin against expressed cancer cell lines is enhanced by a factor of 12-17.
  • RNA Small interfering RNA
  • siRNA small interfering RNA
  • FIGURES Figure 1 illustrates CTBP1 expression in gastric cancer ceil lines.
  • Figure 2 illustrates a validation by PGR in real silencing time of CTBP1 at different siRNA concentrations, 48hrs post-transfection with siRNA.
  • Figure 3 shows the CTBP1 silencing increases sensitivity to 5-FU, Cisplatin and Epirubicin in two gastric cancer cell lines.
  • the figures show the mean ⁇ standard deviation of the result of three separate experiments.
  • KN45 cell lines were grown in RPM1-1640 media and AGS cell lines in F12K, both media were supplemented with 10% characterized fetal bovine serum (FBS) (Hyclone, Logan, UT, USA) and 100 U/mi of Penicillin/Streptomycin (GibcoBRL Gaitbersburgh, MD, USA), Cells were grown in an incubator (NUAIRE, Madison, USA) at 37 °C with an atmosphere of 5% C0 2 and 90% humidity.
  • FBS fetal bovine serum
  • Penicillin/Streptomycin GibcoBRL Gaitbersburgh, MD, USA
  • the cells were transfected with a pool of 4 siRNAFiexitubeslRNACTBPI and siRNA control AHStars Negative Control (QIAGEN, Valencia, CA, USA) at a concentration of 5 nM with 2.5 ⁇ of Lipofectamine 2000 (inviirogen, Carlsbad, CA, USA). After 7h of incubation, the transfection medium was removed and replaced by the respective culture medium supplemented with 10% FBS (Hyclone., Logan, UT, USA) and 100 U/mL of Penicillin plus 100 g/mL of Streptomycin (GibcoBRL, Gaithersburgh. MD, USA).
  • FBS Hyclone., Logan, UT, USA
  • Penicillin 100 g/mL of Streptomycin
  • ceils were seeded in 96 well plates at a concentration of 10,000 ceils per well. After 24 hours, cells were faced with serial dilutions of each chemotherapeutic agent.
  • the cell proliferation assay was performed after waiting 72 hours of incubation with each drug and it was performed using MTS-based ceil proliferation assay (CeilTitre Aqueous One Cell Proliferation assay; Promega). Each experiment was performed in triplicate.
  • the IC 50 values were calculated using GraphPad 5.0 software. The results of the response to the drugs were expressed as mean ⁇ SD.
  • CTBP1 encodes for a phosphoprotein that acts in the nucleus as a transcriptional repressor and in the cytoplasm in the maintenance of vesicular membranes (Birts et ai., 2010).
  • CTBPs early studies indicate the role of CTBPs in regulation of cellular transformation: E1A loses its C-terminai through Interaction with CTBP domain, which makes E1A it less effective in promoting ceil transformation, when collaborating with the mutant RAS.
  • CTBP1 degradation depends on APC in these ceils and APC mutation leads to increased CTBP1 resulting in the initiation of the formation of adenomas (Nadau!d et a!., 2006)
  • CTBPs have also been implicated in the cellular response to chemotherapy.
  • CTBP1 increases sensitivity to 5-FU in breast cancer. It is believed that the role of CTBP1 in chemotherapy could be due to the affect of the protein in signaling pathways that affect ceil survival and cell proliferation, such as genetic suppression of proapoptotic genes and the maintenance of mitotic fidelity (Bergman et a!., 2009).
  • This gene is also expressed in gastric cancer lines SNU1 , SNU18, Kato ill, MKN45, AGS and N87 (Fig. 1 ). in carrying out the silencing of this gene in the ceil line AGS using different concentrations of siRNA, it was observed that this gene expression decreases between 87 - 70% at 48 hrs post-transfection (Fig. 2). Subsequently, it was assessed whether the silencing of this gene affects the sensitivity to the treatment of three drugs commonly used in chemotherapy: 5-FU, Cisplatin and Epirubicin.
  • silencing of CTBP1 with siRNA increases approximately 8 times the sensitivity to 5-FU, 4 to 5 times the sensitivity to Cisplatin and 12-17 times the sensitivity to Epirubicin in relation to untreated cells (VVT) and the ones transfected with the control siRNA.
  • VVT untreated cells
  • CTBP1 is a new therapeutic target of interest for the treatment of gastric cancer, because it can enhance the effect of chemotherapeutic agents often used in the clinic.
  • the combination referred to herein relates to either a physical mixture of silenced CTBP-1 with the known anti-cancer compound or to separate administration of each component of the combination.

Abstract

This invention encompasses a novel composition comprising silenced CTBP- combined with a compound selected from among 5-FU, Cisplatin and Epirubicin. The invention further relates to a method of treating gastric cancer with a combination ofsi RNA silenced CTBP-1 and a compound selected from among 5-FU, Cisplatin and Epirubicin.

Description

USE OF CTBP1 siRNA FOR THE TREATMENT OF GASTRIC CANCER
FIELD OF THE INVENTION
This invention encompasses a novel composition comprising silenced CTBP-1 combined with a compound selected from among 5-FU, Cisplatin and Epirubicin. The invention further relates to a method of treating gastric cancer with a combination of siRNA silenced CTBP-1 and a compound selected from among 5-FU, Cisplatin and Epirubicin.
BACKGROUND OF THE INVENTION
Worldwide, gastric cancer is considered the fourth most common cancer and second most deadly cancer (Brenner et a!., 2009). The survival of resected gastric cancer is estimated between 10-30% (Dicken et aL, 2005). Using adjuvant therapy, either chemotherapy or radiotherapy to improve the survival in advanced lesions after surgery, in spite of multiple schemes, only 30% of patients presented a clinical response, the main complications being recurrence and systemic involvement (Cataiano et aL, 2005).
The most common chemotherapy protocol for gastric cancer is based on the use of three drugs in conjunction 5-Fiuorouracii (5-FU), Cisplatin and Epirubicin.
5-FU is known as an anti-metabolite that acts as an inhibitor of thymidyiate synthase; Epirubicin as an inhibitor of topoisomerase H; Cisplatin is a DNA intercalating compound that leads damage to DNA in cancer cells. However, the limited benefit and high toxicity of this scheme makes necessary the continued search for new molecular therapeutic approaches designed to reverse or overcome resistance to drugs such as the use of siRNA.
The gene CTBP1 encodes for a phosphoprotein that acts in the nucleus as a transcriptional repressor and In the cytoplasm in the maintenance of vesicular membranes (Birts et a!., 2010). Early studies indicate the role of CTBPs in regulation of cellular transformation; E1A loses its C-terminai through interaction with CTBP domain, which makes E1A it less effective in promoting cell transformation, when collaborating with the mutant RAS. Recently, control of the deregulation of the abundance of CTBP1 has been identified as a key step in the initiation of formation of colon tumors: CTBP1 degradation depends on APC in these cells and APC mutation leads to increased CTBP1 resulting in the initiation of the formation of adenomas (Nadauld et aL, 2006). Apart from their roles in the initiation and progression of tumorigenesis, CTBPs have also been implicated in the cellular response to chemotherapy.
SUMMARY OF THE INVENTION
The combination of existing chemotherapy with the introduction of intra-tumorai siRNA CTBP1 provides a promising therapeutic strategy for patients with gastric cancer resistant to chemotherapeutic agents.
In one embodiment of the present invention, a method of treating gastric cancer is provided comprising the steps of:
(1 ) silencing gene CTBP-1 with siRNA ;
(2) preparing a combination of the silenced CTBP-1 gene with an anti-cancer compound selected from the group consisting of 5-FU, Cisplatin and Epirubicin or mixtures thereof;
(3) administering a therapeutic dosage of the combination to a patient with gastric cancer.
In another embodiment of the present invention, a composition for treating gastric cancer is provided comprising CTBP-1 gene silenced with siRNA combined with an anticancer compound selected from the group consisting of 5-FU, Cisplatin and Epirubicin or mixtures thereof. Preferably the anti-cancer compound is 5-FU wherein the activity of the 5-FU against expressed cancer cell lines is enhanced by a factor of approximately 6; when the anticancer compound is Cisplatin the activity of Cisplatin against expressed cancer cell lines is enhanced by a factor of 4-5; and, when the anticancer compound is Epirubicin the activity of Epirubicin against expressed cancer cell lines is enhanced by a factor of 12-17.
Small interfering RNA (si RNA) are small pieces of double-stranded RNA, usually about 21 nucleotides long, with nucleotide overhangs at each end that can be used to interfere with the translation of protein by binding to and promoting the degradation of messenger RNA at specific sequences. Therefore they may prevent the production of specific proteins based on the nucleotide sequence of their corresponding mRNA. The process is called RNA interference and may also be referred to as siRNA silencing.
BF EF DESCRIPTION OF THE FIGURES Figure 1 illustrates CTBP1 expression in gastric cancer ceil lines.
Figure 2 illustrates a validation by PGR in real silencing time of CTBP1 at different siRNA concentrations, 48hrs post-transfection with siRNA.
Figure 3 shows the CTBP1 silencing increases sensitivity to 5-FU, Cisplatin and Epirubicin in two gastric cancer cell lines. The figures show the mean ± standard deviation of the result of three separate experiments.
DETAILED DESCRIPTION OF THE INVENTION
Materials and methods:
Cell lines and drugs
KN45 cell lines were grown in RPM1-1640 media and AGS cell lines in F12K, both media were supplemented with 10% characterized fetal bovine serum (FBS) (Hyclone, Logan, UT, USA) and 100 U/mi of Penicillin/Streptomycin (GibcoBRL Gaitbersburgh, MD, USA), Cells were grown in an incubator (NUAIRE, Plymouth, USA) at 37 °C with an atmosphere of 5% C02 and 90% humidity. The drugs 5-FU, Cispiatin and Epirubicin were donated for this research by the Kampar Oncology Laboratory (Santiago, Chile),
Transfection with siRNA
in 8-weli plates, 200,000 celis were cultured in their respective culture medium with 10% FBS for 24 h at 37 °C and 5% C02 pressure. Then cells were washed once with PBSIX and 900 μΙ of their respective medium without serum and without antibiotic were added.
The cells were transfected with a pool of 4 siRNAFiexitubeslRNACTBPI and siRNA control AHStars Negative Control (QIAGEN, Valencia, CA, USA) at a concentration of 5 nM with 2.5 μΙ of Lipofectamine 2000 (inviirogen, Carlsbad, CA, USA). After 7h of incubation, the transfection medium was removed and replaced by the respective culture medium supplemented with 10% FBS (Hyclone., Logan, UT, USA) and 100 U/mL of Penicillin plus 100 g/mL of Streptomycin (GibcoBRL, Gaithersburgh. MD, USA).
Analysis of ceil proliferation
24 hours after transfection, ceils were seeded in 96 well plates at a concentration of 10,000 ceils per well. After 24 hours, cells were faced with serial dilutions of each chemotherapeutic agent. The cell proliferation assay was performed after waiting 72 hours of incubation with each drug and it was performed using MTS-based ceil proliferation assay (CeilTitre Aqueous One Cell Proliferation assay; Promega). Each experiment was performed in triplicate. The IC50 values were calculated using GraphPad 5.0 software. The results of the response to the drugs were expressed as mean ± SD.
The gene CTBP1 encodes for a phosphoprotein that acts in the nucleus as a transcriptional repressor and in the cytoplasm in the maintenance of vesicular membranes (Birts et ai., 2010). Early studies indicate the role of CTBPs in regulation of cellular transformation: E1A loses its C-terminai through Interaction with CTBP domain, which makes E1A it less effective in promoting ceil transformation, when collaborating with the mutant RAS. Recently, control of the deregulation of the abundance of CTBP1 has been identified as a key step in the initiation of formation of colon tumors: CTBP1 degradation depends on APC in these ceils and APC mutation leads to increased CTBP1 resulting in the initiation of the formation of adenomas (Nadau!d et a!., 2006) Apart from their roles in the initiation and progression of tumorigenesis, CTBPs have also been implicated in the cellular response to chemotherapy.
Previous studies have shown that reducing CTBP1 increases sensitivity to 5-FU in breast cancer (Birts et a!., 2010). It is believed that the role of CTBP1 in chemotherapy could be due to the affect of the protein in signaling pathways that affect ceil survival and cell proliferation, such as genetic suppression of proapoptotic genes and the maintenance of mitotic fidelity (Bergman et a!., 2009).
Additionally, it has been demonstrated that this gene could promote drugs resistance by increased expression of the MDR1 gene (multi-drug resistance 1 ) (Jin et a!.. 2007).
From previous experiments conducted by the present inventors using PGR Pathway array methodology of the Wnt signaling pathway, it was discovered that deregulation of the Wnt pathway is mainly given by the activation of two ways: in the non- canonica!/JNKpathway and the calcium-mediated signaling pathway. Standing out in the canonical pathway Wnt gene over-expression CTBP1 known as an antagonist of this pathway. The level of expression of this gene in tumor tissues was 70.8 times higher than the controls of normal tissue adjacent to tumor.
This gene is also expressed in gastric cancer lines SNU1 , SNU18, Kato ill, MKN45, AGS and N87 (Fig. 1 ). in carrying out the silencing of this gene in the ceil line AGS using different concentrations of siRNA, it was observed that this gene expression decreases between 87 - 70% at 48 hrs post-transfection (Fig. 2). Subsequently, it was assessed whether the silencing of this gene affects the sensitivity to the treatment of three drugs commonly used in chemotherapy: 5-FU, Cisplatin and Epirubicin. As shown in Figure 3, in cell lines AGS and MKN45, silencing of CTBP1 with siRNA increases approximately 8 times the sensitivity to 5-FU, 4 to 5 times the sensitivity to Cisplatin and 12-17 times the sensitivity to Epirubicin in relation to untreated cells (VVT) and the ones transfected with the control siRNA. With these results we demonstrate that treatment with siRNA enhances the activity of 5-FU, Cisplatin and Epirubicin in the dose-response curves for these drugs.
With these results it is postulated that inhibition of CTBP1 is a new therapeutic target of interest for the treatment of gastric cancer, because it can enhance the effect of chemotherapeutic agents often used in the clinic.
The combination referred to herein relates to either a physical mixture of silenced CTBP-1 with the known anti-cancer compound or to separate administration of each component of the combination.
References
Bergman, L. M., Birts, C, N„, Dariey, M., Gabrieili, EL and Biaydes, J. P. (2009). Promote cell survival CtBPs Through the maintenance of mitotic fidelity. Mo! Cell Biol 29, 4539-4551 .
Birts, C. N., Harding, R„, Soosaipiilai, G., Haider, T., Azim-Araghi, A., Dariey, ., Cutress, R. I., Bateman, A. C, and Biaydes, J. P. (2010). Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance. Cell Biol 103, 1-19.
Brenner, H., Rothenbacher, D., and Arndt, V. (2009). Epidemiology of stomach cancer. Methods Mo! Biol 472, 467-477. Cataiano, V., LaBianca, R., Beretta, G. D., Gatta, G., Braud, F., and Van Cutsem, E, (2005). Gastric cancer. Crit Rev Hematol Oncol 54, 209-241. Dicken, B. J., Bigam, D. L, Cass, C, Mackey, J. R., Joy, A. A., and Hamilton, S. . (2005). Gastric adenocarcinoma: review and future Considerations for directions. Ann Surg 241 , 27-39.
Jin, W., Scotto, K. W., Hait, W. N.. and Yang, J. M. (2007). Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells. Biochem Pharmacol 74, 851-859.
Nadauld, L. D., Phelps, R., Moore, B. C, Eisinger, A., Sandoval, I. T., Chidester, S., Peterson, P. W., Manos, E. J., Sklow, B., Burt, R. W., and Jones, D. A. (2006). Control of adenomatous polyposis coli C-terminai binding protein- 1 Stability Regulates expression of intestinal retinal dehydrogenases. J Biol Chem 281 .

Claims

1 .- A method of treating gastric cancer comprising the steps of:
(1 ) silencing gene CTBP-1 with siRNA;
(2) preparing a combination of the silenced CTBP-1 gene with an anti-cancer compound selected from the group consisting of 5-FU, Cisplatin, Epirubicin and mixtures thereof;
(3) administering a therapeutic dosage of the combination to a patient with gastric cancer either separately or physically mixed.
2.- A composition for treating gastric cancer comprising CTBP-1 gene silenced with siRNA combined with an anti-cancer compound selected from the group consisting of 5-FU, Cisplatin and Epirubicin or mixtures thereof.
3. - A composition according to claim 2 wherein the anti-cancer compound is 5-FU and wherein the activity of 5-FU against expressed cancer cell lines is enhanced by a factor of approximately 6.
4. - A composition according to claim 2 wherein the anticancer compound is Cisplatin, wherein the activity of Cisplatin against expressed cancer cell lines is enhanced by a factor of 4-5.
5. - A composition according to claim 2 wherein the anticancer compound is Epirubicin, wherein the activity of Epirubicin against expressed cancer cell lines is enhanced by a factor of 12-17.
PCT/IB2013/055125 2012-06-25 2013-06-21 USE OF CTBP1 siRNA FOR THE TREATMENT OF GASTRIC CANCER WO2014001988A2 (en)

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Publication number Priority date Publication date Assignee Title
US9227956B2 (en) 2013-04-17 2016-01-05 Pfizer Inc. Substituted amide compounds

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