WO2021099558A1 - Polythérapies - Google Patents

Polythérapies Download PDF

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WO2021099558A1
WO2021099558A1 PCT/EP2020/082867 EP2020082867W WO2021099558A1 WO 2021099558 A1 WO2021099558 A1 WO 2021099558A1 EP 2020082867 W EP2020082867 W EP 2020082867W WO 2021099558 A1 WO2021099558 A1 WO 2021099558A1
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receptor
inhibitor
compound
activity
kinase
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David Stanley BAILEY
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Bailey David Stanley
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to combination therapy for cancer and particularly to methods for identifying new anti-cancer combinations.
  • the invention also relates to the combination of an inhibitor of phosphoinositide 3-kinase (PI3K) signalling with an inhibitor of target gene activity or function, where the target gene is as identified by the methods of the invention.
  • PI3K phosphoinositide 3-kinase
  • the invention further relates to the combination of an inhibitor of phosphodiesterase (PDE) activity or function with an inhibitor of target gene activity or function, where the target gene is as identified by the methods of the invention
  • Glioblastoma multiforme is the most common and aggressive malignant glioma, with patients having a median survival of just over one year (Batash et al., 2017).
  • First line therapy remains empiric and consists of surgical resection followed by radiation with concurrent and adjuvant temozolomide, a DNA damaging agent (Stupp et al., 2005).
  • Clinical trials of inhibitors targeting the pathways frequently mutated in GBM have had disappointing results for a variety of reasons, including drug resistance and inclusion of molecularly heterogeneous patients (Cloughesy et al., 2014; Mendelsohn, 2013).
  • Current chemotherapies, together with surgery and radiotherapy, provide only minor patient benefit, and there is a considerable need for development of effective new therapies.
  • PI3K/Akt pathway which appears particularly important in glioblastoma proliferation but also plays a central role in the regulation of tumour cell survival, motility, angiogenesis and metabolism (Zhao et al., 2017). This has led to many attempts to target the PI3K/Akt pathway as a potential treatment option for glioblastoma (Cancer Genome Atlas Research Network,
  • phosphodiesterases have been implicated in GBM development and outcome (Cesarani et al 2017, Sengupta et al 2011), and chemical inhibitors of phosphodiesterases such as PDE10A inhibitor PF- 02545920 have been developed for the treatment of the brain disease schizophrenia, although this research has been discontinued.
  • the invention provides a method, preferably an in vitro method, of providing a combination therapy, said combination comprising a first and a second compound, the method comprising a. contacting test cells with the first compound, b. measuring the effects of the first compound on the transcriptome of the test cells, so as to create a transcriptomic profile for the first compound, c. selecting as a target gene for combination therapy a gene whose expression is perturbed in the transcriptomic profile, d. selecting as the second compound an inhibitor of the target gene for combination therapy, wherein the gene is implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • the combination therapy is preferably a cancer combination therapy, preferably where the cancer is glioblastoma multiforme.
  • the first compound may be an anti-proliferative agent.
  • the first compound is an inhibitor of PI3K signalling.
  • the first compound is an inhibitor of phosphodiesterase (PDE) activity or function, preferably PDE10A activity or function.
  • PDE phosphodiesterase
  • the invention provides a method of treating or preventing cancer in a subject, comprising administering to a subject in need thereof an effective amount of a compound, wherein the compound is an inhibitor of the activity or function of a target gene selected from: Janus Kinase 2 (JAK2), Salt Inducible Kinase 1 (SIK1), Ribosomal Protein S6 Kinase A5 (RPS6KA5), Serum/Glucocorticoid Regulated Kinase 1 (SGK1), BCL2 Associated Athanogene 1 (BAG1), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), Pancreatic Lipase Related Protein 3 (PNLIPRP3), or Yippee-Like 1 (YPEL1).
  • a target gene selected from: Janus Kinase 2 (JAK2), Salt Inducible Kinase 1 (SIK1), Ribosomal Protein S6 Kinase A5 (RPS6KA5), Serum/Glucocortico
  • the compound may be administered simultaneously or sequentially with an inhibitor of PI3K signalling.
  • the cancer may be resistant to the inhibitor of PI3K signalling when administered alone.
  • the invention provides an inhibitor of phosphoinositide 3-kinase (PI3K) signalling for use in a method of treating or preventing cancer in a subject, wherein the method comprises the step of administering the inhibitor of PI3K signalling simultaneously or sequentially with an inhibitor of the activity or function of a target gene selected from: Janus Kinase 2 (JAK2), Salt Inducible Kinase 1 (SIK1), Ribosomal Protein S6 Kinase A5 (RPS6KA5), Serum/Glucocorticoid Regulated Kinase 1 (SGK1), BCL2 Associated Athanogene 1 (BAG1), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), Pancreatic Lipase Related Protein 3 (PNLIPRP3), or
  • the invention provides the use of an inhibitor of phosphoinositide 3-kinase (PI3K) signalling in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the medicament is administered simultaneously or sequentially with an inhibitor of the activity or function of a target gene selected from: Janus Kinase 2 (JAK2), Salt Inducible Kinase 1 (SIK1), Ribosomal Protein S6 Kinase A5 (RPS6KA5), Serum/Glucocorticoid Regulated Kinase 1 (SGK1), BCL2 Associated Athanogene 1 (BAG1), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), Pancreatic Lipase Related Protein 3 (PNLIPRP3), or Yippee-Like 1 (YPEL1).
  • PI3K phosphoinositide 3-kinase
  • the invention provides the use of an inhibitor of phosphodiesterase (PDE) activity or function in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the medicament is administered simultaneously or sequentially with an inhibitor of the activity or function of a target gene selected from: Salt Inducible Kinase 1 (SIK1), Serum/Glucocorticoid Regulated Kinase 1 (SGK1), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), or Pancreatic Lipase Related Protein 3 (PNLIPRP3).
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function.
  • the cancer may be resistant to the inhibitor of PDE activity or function, preferably the inhibitor of PDE10A activity or function, when administered alone.
  • the invention further provides a kit comprising an inhibitor of PDE activity or function, or of an inhibitor of PI3K signalling, and an inhibitor of the activity or function of a target gene selected from: Salt Inducible Kinase 1 (SIK1), Serum/Glucocorticoid Regulated Kinase 1 (SGK1), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), or Pancreatic Lipase Related Protein 3 (PNLIPRP3).
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function.
  • the cancer may be resistant to the inhibitor of PDE activity or function, preferably the inhibitor of PDE10A activity or function, when administered alone.
  • the invention provides a compound for use in a method of treating or preventing cancer in a subject, wherein the compound is an inhibitor of the activity or function of a target is selected from: Janus Kinase 2 (JAK2), Nuclear Receptor subfamily 3 C2 (NR3C2), Histone deacetylase 5 (HDAC5), vitamin D receptor (VDR), DNA topoisomerase I mitochondrial (TOP1MT), Insulin like Growth Factor 1 Receptor (IGF1 R), Transient receptor potential cation channel subfamily V member 1 (TRPV1), Kinase Insert Domain Receptor (KDR), Glutamate Ionotropic Receptor Kainate Type Subunit 2 (GRIK2), Phosphodiesterase 4D (PDE4D), PIM3, Bradykinin Receptor B2 (BDKRB2), Ribosomal protein S6 kinase a2 (RPS6KA2), and UDP-glucose ceramide glucosyltransfera
  • JK2 Janus
  • the invention provides the use of a compound in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the compound is an inhibitor of the activity or function of a target is selected from: Janus Kinase 2 (JAK2), Nuclear Receptor subfamily 3 C2 (NR3C2), Histone deacetylase 5 (HDAC5), vitamin D receptor (VDR), DNA topoisomerase I mitochondrial (TOP1MT), Insulin like Growth Factor 1 Receptor (IGF1R), Transient receptor potential cation channel subfamily V member 1 (TRPV1), Kinase Insert Domain Receptor (KDR), Glutamate Ionotropic Receptor Kainate Type Subunit 2 (GRIK2), Phosphodiesterase 4D (PDE4D), PIM3, Bradykinin Receptor B2 (BDKRB2), Ribosomal protein S6 kinase a2 (RPS6KA2), and UDP-glucose ceramide glucosyltrans
  • JK2
  • IGF1R Insulin like Growth Factor 1 Receptor
  • TRPV1 Transient receptor potential cation channel subfamily V member 1
  • KDR Kinase Insert Domain Receptor
  • Glutamate Ionotropic Receptor Kainate Type Subunit 2 Glutamate Ionotropic Receptor Kainate Type Subunit 2
  • PDE4D Phosphodiesterase 4D
  • PIM3K Bradykinin Receptor B2
  • RPS6KA2 Ribosomal protein S6 kinase a2
  • UGCG UDP-glucose ceramide glucosyltransferase
  • the invention provides an inhibitor of phosphoinositide 3-kinase (PI3K) signalling for use in a method of treating or preventing cancer in a subject, wherein the method comprises the step of administering the inhibitor of PI3K signalling simultaneously or sequentially with an inhibitor of the activity or function of a target gene selected from: Janus Kinase 2 (JAK2), Nuclear Receptor subfamily 3 C2 (NR3C2), Histone deacetylase 5 (HDAC5), vitamin D receptor (VDR), DNA topoisomerase I mitochondrial (TOP1MT), Insulin like Growth Factor 1 Receptor (IGF1R), Transient receptor potential cation channel subfamily V member 1 (TRPV1), Kinase Insert Domain Receptor (KDR), Glutamate Ionotropic Receptor Kainate Type Subunit 2 (GRIK2), Phosphodiesterase 4D (PDE4D), PIM3, Bradykinin Receptor B2 (BDKRB2), Ribosomal a target gene selected from
  • the invention provides the use of an inhibitor of phosphoinositide 3-kinase (PI3K) signalling in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the medicament is administered simultaneously or sequentially with an inhibitor of the activity or function of a target gene selected from: Janus Kinase 2 (JAK2), Nuclear Receptor subfamily 3 C2 (NR3C2), Histone deacetylase 5 (HDAC5), vitamin D receptor (VDR), DNA topoisomerase I mitochondrial (TOP1 MT),
  • PI3K phosphoinositide 3-kinase
  • IGF1R Insulin like Growth Factor 1 Receptor
  • TRPV1 Transient receptor potential cation channel subfamily V member 1
  • KDR Kinase Insert Domain Receptor
  • Glutamate Ionotropic Receptor Kainate Type Subunit 2 Glutamate Ionotropic Receptor Kainate Type Subunit 2
  • PDE4D Phosphodiesterase 4D
  • PIM3 Bradykinin Receptor B2
  • RPS6KA2 Ribosomal protein S6 kinase a2
  • UGCG UDP-glucose ceramide glucosyltransferase
  • the cancer may be resistant to the inhibitor of PI3K signalling when administered alone.
  • the cancer may be resistant to the inhibitor of target gene activity or function when administered alone.
  • the cancer may be resistant to both inhibitors when each inhibitor is administered alone.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising an inhibitor of phosphoinositide 3-kinase (PI3K) signalling and an inhibitor of the activity or function of a target gene selected from: Janus Kinase 2 (JAK2), Nuclear Receptor subfamily 3 C2 (NR3C2), Histone deacetylase 5 (HDAC5), vitamin D receptor (VDR), DNA topoisomerase I mitochondrial (TOP1 MT), Insulin like Growth Factor 1 Receptor (IGF1R), Transient receptor potential cation channel subfamily V member 1 (TRPV1), Kinase Insert Domain Receptor (KDR), Glutamate Ionotropic Receptor Kainate Type Subunit 2 (GRIK2), Phosphodiesterase 4D (PDE4D), PIM3, Bradykinin Receptor B2 (BDKRB2), Ribosomal protein S6 kinase a2 (RPS6KA2), and UDP-glucose ceramide glucosy
  • the invention further provides a kit comprising an inhibitor of phosphoinositide 3-kinase (PI3K) signalling, and an inhibitor of the activity or function of a target gene selected from: Janus Kinase 2 (JAK2), Nuclear Receptor subfamily 3 C2 (NR3C2), Histone deacetylase 5 (HDAC5), vitamin D receptor (VDR), DNA topoisomerase I mitochondrial (TOP1 MT), Insulin like Growth Factor 1 Receptor (IGF1 R), Transient receptor potential cation channel subfamily V member 1 (TRPV1), Kinase Insert Domain Receptor (KDR), Glutamate Ionotropic Receptor Kainate Type Subunit 2 (GRIK2), Phosphodiesterase 4D (PDE4D), PIM3, Bradykinin Receptor B2 (BDKRB2), Ribosomal protein S6 kinase a2 (RPS6KA2), and UDP-glucose ceramide glucosyltransferase
  • the target is selected from: Janus Kinase 2 (JAK2), DNA topoisomerase I mitochondrial (TOP1 MT), or Insulin like Growth Factor 1 Receptor (IGF1 R).
  • JK2 Janus Kinase 2
  • TOP1 MT DNA topoisomerase I mitochondrial
  • IGF1 R Insulin like Growth Factor 1 Receptor
  • the invention provides a compound for use in a method of treating or preventing cancer in a subject, wherein the compound is an inhibitor of the activity or function of a target is selected from 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Sphingosine 1 -phosphate receptor 1 (S1 PR1), Interleukin 1 Beta (IL1 B), Adenosine A1 Receptor (ADORA1), Bradykinin Receptor B2 (BDKRB2), Somatostatin Receptor 2 (SSTR2), Hydroxysteroid 11-Beta Dehydrogenase 1 (HSD11 B1), Androgen Receptor (AR), Phosphodiesterase 7B (PDE7B), Endothelin Receptor Type A (EDNRA), b2 adrenoreceptor (ADRB2), vitamin D receptor (VDR), Phosphodiesterase 4D (PDE4D), Interleukin 6 (IL6)
  • HMGCR 3-
  • the invention provides use of a compound in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the compound is an inhibitor of the activity or function of a target is selected from: 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Sphingosine 1- phosphate receptor 1 (S1 PR1), Interleukin 1 Beta (IL1 B), Adenosine A1 Receptor (ADORA1), Bradykinin Receptor B2 (BDKRB2), Somatostatin Receptor 2 (SSTR2), Hydroxysteroid 11-Beta Dehydrogenase 1 (HSD11 B1), Androgen Receptor (AR), Phosphodiesterase 7B (PDE7B), Endothelin Receptor Type A (EDNRA), b2 adrenoreceptor (ADRB2), vitamin D receptor (VDR), Phosphodiesterase 4D (PDE4D), Interleukin 6
  • HMGCR 3-
  • the invention provides a method of treating or preventing cancer in a subject, comprising the step of administering a compound comprising an inhibitor of the activity or function of a target gene selected from: 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Sphingosine 1- phosphate receptor 1 (S1PR1), Interleukin 1 Beta (IL1 B), Adenosine A1 Receptor (ADORA1), Bradykinin Receptor B2 (BDKRB2), Somatostatin Receptor 2 (SSTR2), Hydroxysteroid 11-Beta Dehydrogenase 1 (HSD11 B1), Androgen Receptor (AR), Phosphodiesterase 7B (PDE7B), Endothelin Receptor Type A (EDNRA), b2 adrenoreceptor (ADRB2), vitamin D receptor (VDR), Phosphodiesterase 4D (PDE4D), Interleukin 6 (IL
  • HMGCR 3-
  • the invention provides an inhibitor of phosphodiesterase (PDE) activity or function for use in a method of treating or preventing cancer in a subject, wherein the method comprises the step of administering the inhibitor of PI3K signalling simultaneously or sequentially with an inhibitor of the activity or function of a target gene selected from: 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Sphingosine 1-phosphate receptor 1 (S1PR1), Interleukin 1 Beta (IL1B), Adenosine A1 Receptor (ADORA1), Bradykinin Receptor B2 (BDKRB2), Somatostatin Receptor 2 (SSTR2), Hydroxysteroid 11 -Beta Dehydrogenase 1 (HSD11B1), Androgen Receptor (AR), Phosphodiesterase 7B (PDE7B), Endothelin Receptor Type A (EDNRA), b2 adrenoreceptor (AD
  • HMGCR 3-H
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function.
  • the cancer may be resistant to the PDE inhibitor when administered alone.
  • the cancer may be resistant to the inhibitor of target gene activity or function when administered alone.
  • the cancer may be resistant to both inhibitors when each inhibitor is administered alone.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising an inhibitor of phosphodiesterase (PDE) activity or function and an inhibitor of the activity or function of a target gene selected from: 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Sphingosine 1 -phosphate receptor 1 (S1PR1), Interleukin 1 Beta (IL1B), Adenosine A1 Receptor (ADORA1), Bradykinin Receptor B2 (BDKRB2), Somatostatin Receptor 2 (SSTR2), Hydroxysteroid 11-Beta Dehydrogenase 1 (HSD11B1), Androgen Receptor (AR), Phosphodiesterase 7B (PDE7B), Endothelin Receptor Type A (EDNRA), b2 adrenoreceptor (ADRB2), vitamin D receptor (VDR), Phosphodiesterase 4D (PDE4D), Interleukin 6 (IL6),
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function.
  • the invention further provides a kit comprising an inhibitor of phosphodiesterase (PDE) activity or function and an inhibitor of the activity or function of a target gene selected from: 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Sphingosine 1-phosphate receptor 1 (S1PR1), Interleukin 1 Beta (IL1B),
  • HMGCR 3-Hydroxy-3-Methylglutaryl-CoA Reductase
  • S1PR1 Sphingosine 1-phosphate receptor 1
  • IL1B Interleukin 1 Beta
  • ADORA1 Adenosine A1 Receptor
  • BDKRB2 Bradykinin Receptor B2
  • Somatostatin Receptor 2 SSTR2
  • HSD11B1 Hydroxysteroid 11-Beta Dehydrogenase 1
  • AR Androgen Receptor
  • PDE7B Phosphodiesterase 7B
  • EDNRA Endothelin Receptor Type A
  • ADRB2 b2 adrenoreceptor
  • VDR vitamin D receptor
  • Phosphodiesterase 4D PDE4D
  • Interleukin 6 IL6
  • Vascular Endothelial Growth Factor A VAGFA
  • Thyroid Hormone Receptor alpha THRA
  • TOP1MT DNA topoisomerase I mitochondrial
  • TOP1MT Interleukin 1 Receptor Accessory Protein
  • IL1RAP Purine Nucleoside Phosphorylase
  • KCNG1 Glutamate Ionotropic Receptor
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function.
  • the target may be Sphingosine 1 -phosphate receptor 1 (S1PR1). In any of the fifteenth to nineteenth aspects, the target may be 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR).
  • S1PR1 Sphingosine 1 -phosphate receptor 1
  • HMGCR 3-Hydroxy-3-Methylglutaryl-CoA Reductase
  • an inhibitor of PI3K signalling interacts with and inhibits the activity or function of PI3K, preferably a PI3K isoform selected from PIK3CA/p110a, PIK3CB/p110p and/or PIK3CD/p1106.
  • the inhibitor of PI3K signalling may additionally interact with and inhibit the activity or function of one or more of Casein Kinase
  • CK2 and/or Myosin Light-chain Kinase (MLCK).
  • MLCK Myosin Light-chain Kinase
  • a preferred inhibitor of PI3K signalling is 2-Morpholin- 4-yl-8-phenylchromen-4-one (LY-294002).
  • the cancer may be resistant to the inhibitor of the target when administered alone.
  • the invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.
  • FIG. 3 Morphology of U87MG cells treated with Fucoxanthin or LY-294002.
  • Panels A, B U87MG cells without compound treatment (controls), visualised at 24h and 48h, respectively;
  • Panels C, D U87MG cells treated with Fucoxanthin, visualised at 24h and 48h respectively;
  • Panels E, F U87MG cells treated with LY-294002, visualised at 24h and 48h, respectively.
  • Treatments with LY-294002 and Fucoxanthin were performed at concentrations of 19.9 pM and 199.5 pM, respectively.
  • G is control
  • H Fucoxanthin
  • I LY-29400248h after treatment.
  • Apoptotic cells were detected by Annexin V- FITC/PI staining and death cells were detected by PI. Viable cells are shown in the lower left quarter (Q3- LL), early apoptotic cells are shown in the lower right quarter (Q4-LR), late apoptotic cells are shown in the upper right quarter (Q2-UR) and necrotic or mechanically damaged cells are shown in the upper left quarter (Q1-UL).
  • PCA Principal Components
  • Figure 5 Euclidean distance based heatmap and clustering of the samples. The samples were clustered based on treatment first and then by time. LY-29400224h (L24), LY-29400248h (L48) treatments, Fucoxanthin 24h (F24) and Fucoxanthin 48h (F48) treatments, Control 24h (C24), Control 48h (C48). Up- regulated genes are shown in red; down-regulated genes are shown in green. Only significantly differentially expressed genes are shown. The colors used are the same as those used in the PCA analysis.
  • FIG. 6 Venn Diagram showing the in-common and unique responses of the two treatments in gene expression space.
  • A Gene up-expression at 24 h and 48 h for LY294002 and Fucoxanthin treated U87MG cells.
  • B Gene down-expression at 24 h and 48 h for LY294002 and Fucoxanthin treated U87MG cells. Note that few up-regulated genes are shared by the two treatments, in contrast to much higher overlap in down-regulated genes.
  • Figure 7 Comparison of gene expression signature in response to LY-294002 and Fucoxanthin at 24h and 48h.
  • A Top 25 up-regulated genes in LY-294002 treatment at 24h (L24, left side) and at 48h (L48, right side) relative to no-treatment controls, and comparison to the expression signature seen in fucoxanthin at the same timepoints.
  • B Top 25 down-regulated genes in LY-294002 treatment at 24h (L24, left side) and at 48h (L48, right side) relative to no-treatment controls, and comparison to the expression signature seen in fucoxanthin at the same timepoints.
  • Figure 8. Comparison of gene expression signature in response to LY-294002 and Fucoxanthin at 24h and 48h.
  • FIG. 9 Volcano plot of the 4 treatments showing the top 25 down-regulated genes (left side, in green) and the top 25 up-regulated genes (right side, in red) accompanied by their level of expression, expressed as logarithm-based 2 fold changes (Log2FC, ⁇ -1 or > 1) and corrected p-value as logarithm- based 10 false discovery rate (LoglOFDR P-value, ⁇ 0.05).
  • D top 25 differentially expressed genes in U87MG responding to Fucoxanthin at 48h.
  • FIG. 10 PI3K/Akt signalling Pathway WikiPathway map representations.
  • A Down-regulated (left tables, in green) and up-regulated genes (left tables in red) in response to individual treatments;
  • B L24, PI3K/Akt signalling pathway affected by LY-294002 at 24h;
  • C L48, PI3K/Akt signalling Pathway affected by LY-294002 at 48h;
  • D F24, PI3K/Akt signalling Pathway affected by Fucoxanthin at 24h;
  • E F48, PI3K/Akt signalling Pathway affected by Fucoxanthin 48h.
  • FIG. 11 Retinoblastoma gene in cancer pathway, WikiPathway map representations.
  • A Down- regulated (left tables, in green) and up-regulated genes (left tables in red) in response to individual treatments;
  • B L24.
  • C L48.
  • D Retinoblastoma gene in cancer pathway affected by LY-29400248h
  • F24 Retinoblastoma gene in cancer pathway affected by Fucoxanthin 24h
  • E F48.
  • FIG. 12 Network representation of the CMap analysis. Yellow lines are perturbagens with significantly correlating gene signatures and blue lines perturbagens with anti-correlating signatures. Blue squares are compounds from IOTA ' S GBM Drug Bank. LY-294002 and Fucoxanthin have drug counterparts with similar gene signatures, including groups of antibiotics and anti-protozoal / antifungal agents as well as antipsychotics and antidepressants and compounds with described effects in GBM cell lines. They also share similar gene expression signatures with other PI3K inhibitors such as Quinostatin and Wortmannin, as indicated. Figure 13. Summary of differential drug induced gene expression. U87MG cells treated for 24h (L24,
  • FIG. 14 Differential drug induced gene expression in the PI3K pathway. Shown are members of the PI3K pathway which are among the top 25 upregulated genes in LY-294002 (left) and Fucoxanthin (right) treated cells, at 24h and 48h. Note that JAK2 is up-regulated 24 h and 48 h following LY-294002 treatment. JAK2 is also up-regulated 24 h but not 48 h after Fucoxanthin treatment.
  • FIG. 15 Combination of LY-294002 with JAK2 inhibitors (A) ruxolitinib and (B) AZD1480. Cells were exposed to LY294002 in concentrations ranging from 10 _6 M to 10 _3 M, alone or in combination with JAK inhibitor at 10, 25 or 50 pM. Cell survival after 72h is given as a percentage of 1.1% DMSO control.
  • Figure 16 Drug response of U87MG, T98G and A172 GBM cell lines to 24 hour treatment with primary inhibitors.
  • A LY-294002, a PI3K inhibitor.
  • B PF-02545920, a phosphodiesterase (PDE) inhibitor.
  • FIG. 17 Drug response of U87MG, T98G and A172 GBM cell lines to treatment with inhibitors of drug targets JAK2 and SIK1 , as elucidated by the target discovery method described herein.
  • A Treatment with AZD1480, an inhibitor of kinase target JAK2, observed after treating glioblastoma cells with the primary PI3K inhibitor LY-294002.
  • B Treatment with WH-4-023, a secondary drug treatment used to target the emerging drug target SIK1 observed after primary treatment with both the PDE10A inhibitor PF- 02545920 and the PI3K inhibitor LY-294002.
  • C Treatment with HG-9-91-01 , a drug treatment which targets the emerging drug target SIK1 observed after primary treatment with both the PDE10A inhibitor PF-02545920 and the PI3K inhibitor LY-294002.
  • FIG. 19 Drug response of U87, A172, and/or T98 GMB cells to PDE10A inhibitor PF-02545920 following 24 hours exposure.
  • Left hand column shows selected genes (in the top 200 upregulated) for which clinically approved drugs are known.
  • Right hand column shows selected genes (in the top 200 upregulated) for which inhibitors are known, and which represent lead compounds for the generation of clinical drugs.
  • Figure 20 Top upregulated genes in five treatment conditions, as outlined in Examples 11-12.
  • B Treatment with PF-02545920 for 24 hours in U87 cells (column 1), A172 cells (column 2) and T98 cells (column 3).
  • Figure 21 Schematic overviews of the methods according to the first and second aspects.
  • A Cancer drug discovery pipeline according to the methods of the first aspect herein, wherein primary drug treatments are used to generate transcriptomic profiles from which target genes may be identified as emerging drug targets.
  • B Cancer treatment clinical pipeline according to the methods of the second aspect herein, wherein patient cells having received a first drug treatment are sampled, their transcriptomic profiles obtained, and target genes identified as emerging resistance targets. Selected secondary drug treatments may then be administered, whether simultaneously or sequentially with the primary treatment, in order to cure the disease.
  • the invention relates to identifying target genes for inhibition in cancer treatment or prophylaxis.
  • the first and second aspects of the invention relate to identifying target genes, and providing therapeutic combinations against said targets, for cancer combination therapy.
  • a “combination therapy”, or a “therapeutic combination” relates to two or more compounds useful in treating or preventing a disease when delivered simultaneously or sequentially to a subject.
  • the combination therefore comprises at least a first and a second compound, which may be for sequential or simultaneous administration.
  • “Compounds”, in this context, comprise at least one therapeutic agent, for example a cytotoxic or anti-cancer agent.
  • Test cells refers to any suitable cells in vivo, ex vivo or in vitro.
  • Test cells may be pathological cells, i.e. cells having or displaying symptoms of a dysfunction or disease.
  • test cells may be cancer cells, such as glioblastoma cells, although cells of any of the cancers described herein will also be suitable.
  • Suitable cancer cell lines or glioblastoma cell lines may include primary human cancer cells, such as low-passage patient-derived glioma and glioblastoma cell lines, or established cell lines such as the well characterised cell lines A172, LN18, LN229, LNZ308, T98G, U118, U138, U251 , U343, U373 and U87, or selected glioma and glioblastoma cell lines from more extensive cell culture collections such as the well-known ATCC and ECACC cell collections, as well as cell collections dedicated to GBM such as the HGCC.
  • a particularly preferred GBM cell line is U87MG.
  • test cells may be cancer cells, preferably glioblastoma cells, which are derived from a patient for whom the cancer combination therapy is intended for.
  • the methods provide a personalised cancer combination therapy which is tailored to the patient’s cancer.
  • the test cells may be obtained from a patient, for example following tumour resection.
  • the test cells may be located in situ in the patient during the administration of the first compound.
  • test cells are contacted with the first compound at the 72h-EC50 concentration.
  • test cells are contacted with the first compound at the 72h-EC50 concentration, and measurement occurs no later than 48hrs after exposure to the first compound.
  • test cells are contacted with the first compound at the 72h-EC50 concentration, and measurement occurs no sooner than 24h and no later than 48hrs after exposure to the first compound.
  • Measurement may entail obtaining a sample of mRNA from the test cells and quantifying the levels of transcripts, for example through qPCR or microarray analysis. Measurement may involve comparing the quantified levels of transcripts to a reference. Suitable references include untreated cells, i.e. cells of the same cell line which are not exposed to the first compound. The method may involve measuring and quantifying the levels of transcripts in cells identical to the test cells in all aspects except their exposure to the first compound, so as to create a reference.
  • the method may employ a known or pre-generated standard reference.
  • Transcript levels may be “normalised” to the expression levels of a “housekeeping gene”.
  • Housekeeping genes are those that are always expressed because they are constantly required by the cell, hence, they are always present under any conditions. Examples include as ubiquitin, actin, GAPDH, or other housekeeping genes which will be known to the skilled person.
  • the transcriptomic profile is constructed for all transcripts, for example by using a universal probe or primer mix, and is a “whole” transcriptome profile.
  • the transcriptomic profile is constructed only for a subset of transcripts.
  • a transcriptomic profile may include one or more genes which are implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • a transcriptomic profile may be limited by pathway, for example to genes in the PI3K or retinoblastoma pathways.
  • a transcriptomic profile may be limited to genes for which inhibitory and/or approved drugs are known.
  • a transcriptomic profile may additionally include one or more housekeeping genes.
  • transcriptomic profile reports the changes in the transcriptome induced by a treatment.
  • the method measures the effects of the compound on the transcriptome of the test cells at a first and a second time-point.
  • the transcriptomic profile that is constructed includes time as a variable alongside expression, capturing not just whether but when expression is affected.
  • the first time point may be before the second time point, and may be separated by an incubation in the presence of the test compound.
  • Such time points may represent an “early” and a “late” drug response.
  • the time points may be separated by a period of 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 36, 48, 60, or 72 hours or more.
  • the first time point may be 24 hr after contacting the test cells with the compound and the second time point may be 48 hr after contacting the test cells with the compound, for a separation of 24 hr.
  • “Early” drug responses may include shock responses and immediate anti-toxin effects, whilst “late” drug responses will tend to include “escape” response, such as regulation of alternative pathways to compensate for the action of the first compound.
  • a gene whose expression is perturbed in both the “early” and “late” time-points is a candidate for selection as a target gene, as this may reveal a sustained reliance on the gene when challenged by the first compound, and its disruption may enhance the effect of the first compound.
  • a gene whose expression is perturbed only in the early time-point may be a target gene, as it may represent an immediate or “front-line” response to the first compound, and its disruption may enhance the effect of the first compound.
  • a gene whose expression is perturbed only in the late time-point may be a target gene, as it may represent a downstream response to the first compound, the disruption of which may restore sensitivity to and enhance the effect of the first compound.
  • a perturbed gene may be expressed at 1/2 times, 1/3 times, 1/4 times, 1/5 times, 1/6 times, 1/7 times, 1/8 times, 1/9 times, 1/10 times, 1/15 times, or 1/20 times or less of the level of its wild-type or reference expression.
  • a target gene gene is, by virtue of its implication in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation, expected to enhance cell sensitivity to the first compound if administered in combination with the first compound.
  • a cell When a cell is challenged with a compound, it attempts to “escape” the effects by (i) upregulating expression of genes which positively upregulate compensatory pathways, and (ii) downregulating expression of genes which negatively regulate compensatory pathways.
  • Compensatory pathways are those which substitute for the function conveyed by the gene targeted by the first compound. For example, if the first compound inhibits a pro-proliferative pathway, the cell will respond by upregulating genes which promote alternative proliferative genes and pathways, whilst downregulating anti-proliferative regulators. Similarly, if the first compound promotes a pro-apoptotic pathway, the cell will respond by upregulating anti-apoptotic genes and pathways, and downregulating pro-apoptotic genes and pathways.
  • a gene implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation may be a gene which is a known regulator of in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • the step of selecting a gene whose expression is perturbed as a target gene may comprise comparing the expression in the test cells to expression in normal cells - either to control cells or to a set of known standards - in order to determine relative changes in expression.
  • the gene regulates angiogenesis, mTOr signalling, or NFKB signalling.
  • Target genes may be genes implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation, which are up-regulated (i.e. for which relative expression increases) in the cell.
  • a positive regulator whose expression is upregulated following treatment may be a candidate target gene.
  • a target gene that is upregulated is expressed at 150%, 160%, 170%, 180%, 190% or 200% or more of its wild-type or reference expression. In some embodiments, a target gene that is upregulated is expressed at 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, or 20 times or more of the level of its wild-type or reference expression.
  • target genes may be genes implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation, which are down-regulated (i.e. for which relative expression decreases) in the cell.
  • a negative regulator whose expression is downregulated following treatment may be a candidate target gene.
  • a target gene that is downregulated is expressed at 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1% or less of its wild-type or reference expression.
  • the process for identifying target genes based on the transcriptomic profile may reveal a shortlist of several genes which are perturbed following drug challenge with the first compound and are implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • a target gene may be selected from the shortlist based on meeting one or more further criteria.
  • the step of selecting a gene as a target gene may therefore comprise selecting a gene (i) that is implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation, (ii) that has perturbed expression in following exposure to the first compound, and (iii) one or more additional criteria as defined below.
  • a gene which is a “positive regulator” is one which functions to promote, accelerate, increase or enhance a process.
  • a positive regulator of angiogenesis works to increase angiogenesis.
  • a gene which is a “negative regulator” is one which functions to inhibit, supress or prevent a process. Therefore, a negative regulator of angiogenesis would work to reduce angiogenesis.
  • the compounds may alter cell viability, for example the first or second compound may comprise compounds that are cytotoxic to mammalian cells. Suitable compounds may include for example active anti-cancer agents. In other embodiments, the compounds may alter phenotypic properties displayed by mammalian cells, causing cell cycle perturbation, apoptosis enhancement, or changes in antigen display.
  • the compounds may alter a phenotypic property of mammalian cells.
  • the compounds may reduce or inhibit the proliferation, viability, migration, invasion and/or angiogenesis of mammalian cells, such as cancer cells; increase or promote apoptosis and/or radio-sensitisation; and/or may alter a cell surface phenotype, such as EGFRvlll or other neoantigen, or a molecular characteristic associated with differentiation and apoptotic processes, antigen display and cell renewal.
  • the compounds may regulate, for example reduce or inhibit, angiogenesis, mTOr signalling, or NFKB signalling.
  • chemotherapeutic agents for example alkylating agents such as platinum complexes including cisplatin, mono(platinum), bis(platinum), tri-nuclear platinum complexes and carboplatin, thiotepa and cyclosphosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechloreth
  • alkylating agents such as platinum complexes including
  • paclitaxel TAXOL
  • docetaxel TXOTERE
  • platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; binblastine; vindesine; navelbine; novantrone; teniposide; daunomycin; aminopterin; ibandronate; CPT11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine (XELODA); Topoisomerase inhibitors such as doxorubicin HCI, daunorubicin citrate, mitoxantrone HCI, actinomycin D, etoposide, topotecan HCI,
  • a first or second compound may include one or more compounds shown to be active in preclinical models of GBM. Suitable compounds may include; 2-Amino-3H-phenoxazin-3-one, 2- Hydroxyoleic acid, 3-(3,4-dichlorophenyl)-1-(3,4-dimethylphenyl)-1-(5-methyl-4,5-dihydro-1 ,3-thiazol-2- yl)urea, 3-Deazaneplanocin, 4egi-1 , 5-Nonyloxytryptamine, 6-Hydroxyquinoline-4-carboxylic acid, 7-Ethyl- 10-hydroxycamptothecin, 7-Hydroxystaurosporine, 8-Bromo-cyclic AMP, 8-Hydroxy-2-methyl-1H- quinazolin-4-one, 9-ING-41 , A-966492, Abemaciclib, Abt-737, AC1MMYR2, Acalabrutinib,
  • Bufalin Buparlisib, Cabazitaxel, Caffeic acid phenethyl ester, Caffeine, Camptothecin, Capecitabine, Capmatinib, Captopril, Carboplatin, Cardamonin, Carmustine, carnosol, Carvacrol, Casticin, Cathepsin S Inhibitor, Caudatin, CBL-0137, CC-115, CC-223, Cediranib, Celastrol, Celecoxib, Ceritinib, Cerivastatin, Chaetocin, Chloroquine, Chlorpromazine, Cilengitide, Cisplatin, Cladribine, Clioquinol, Clofazimine, Clorgiline, Cordycepin, Crenolanib, Crizotinib, Cryptotanshinone, Cucurbitacin I, CUDC-101 , Curcumin, Cycloheximide, Cyclophosphamide, D609, Da
  • Digitoxigenin Digitoxin, Digoxigenin, Digoxin, Dihydroartemisinin, Dimethylaminomicheliolide, Dinaciclib, Disufenton sodium, Disufenton sodium, Docetaxel, Dorsomorphin, Dovitinib, Doxazosin, Doxorubicin, Eflornithine, Embelin, Enasidenib, Entrectinib, Enzastaurin, Epigallocathecin, Epigallocathecin Gallate, Epirubicin, Erdafitinib, Erlotinib, Etoposide, Everolimus, Evodiamine, Evofosfamide, Farnesylthiosalicylic acid, Fasudil, Fenofibrate, Fingolimod, Fingolimod, Flavopiridol, Flubendazole, Fluorouracil, Fluvoxamine, Foretinib, Forskolin, Fotemustine, Fucoxanthin
  • the methods of the first and second aspects may be extended to generate additional transcriptomic profiles in order to provide more extensive combination therapies.
  • the method is extended to identify further target genes by: d. selecting an inhibitor of the target gene for combination therapy as the second compound e. contacting test cells with the second compound, and optionally the first compound, f. measuring the effects of the second, or first and second, compound on the transcriptome of the test cells, so as to create a second transcriptomic profile, g. selecting as a further target gene for combination therapy a gene whose expression is perturbed in the second transcriptomic profile, wherein said gene is implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • the method may provide a series of target genes by: a. contacting test cells with a compound, b. measuring the effects of the compound on the transcriptome of the test cells, so as to create a transcriptomic profile for the first compound, c. selecting as a target gene for combination therapy a gene whose expression is perturbed in the transcriptomic profile, wherein the gene is implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radiosensitisation, d. repeating steps a to c one or more times, each time supplementing or substituting the compound in the previous step a with an inhibitor of the target gene identified in previous claim c, until the desired number of target genes has been provided.
  • this embodiment of the second aspect may be extended to provide a fourth compound by repeating the contacting and measuring steps with the third compound, optionally in combination with the first and/or second compound, to create a third transcriptomic profile; selecting a further target gene that is perturbed in the third transcriptomic profile; and selecting an inhibitor of this target as a fourth compound in the combination therapy. This may be repeated to provide a fifth, sixth, etc. compound for the combination.
  • step d) selecting an inhibitor of the target gene for combination therapy as a further compound, and e) optionally repeating steps a to d one or more times, each time supplementing or substituting the compound used in step a with the further compound identified in the previous step d, until the desired number of further compounds has been identified.
  • the method may be used to sequentially identify compounds for use in a treatment which is tailored to the individual and their cancer, which is dynamic, heterogeneous and adapts in response to treatment.
  • the methods of the first and second aspects are performed on more than one set of test cells.
  • steps a) and b) may be performed on two or more populations of test cells, so as to create a first transcriptomic profile for the first compound for the first population of test cells, and a second transcriptomic profile for the first compound for the second population of test cells.
  • Step c) may therefore comprise selecting as a target gene for combination therapy a gene whose expression is perturbed in the first and second transcriptomic profile, wherein said gene is implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • the test cells may be the same cells that are contacted with the first compound in step a), in order to model ongoing therapy.
  • the test cells may be of the same type as those in step a) but may have not previously been contacted with the first compound.
  • the invention also provides a therapeutic combination provided by the method of the second aspect.
  • the invention also provides a therapeutic combination provided by the method of the second aspect, for use in a method of treating or preventing cancer in a subject, wherein the method comprises the step of administering the first compound simultaneously or sequentially with the second compound.
  • the therapeutic combination comprises further compounds, for example a fourth, fifth, etc. compound, these may independently be administered simultaneously or sequentially with the first and/or second compound.
  • the invention also provides the use therapeutic combination provided by the method of the second aspect in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the medicament administers an effective amount of the first compound simultaneously or sequentially with an effective amount of the second compound to a subject in need thereof.
  • the therapeutic combination comprises further compounds, for example a fourth, fifth, etc. compound, these may independently be administered simultaneously or sequentially with the first and/or second compound.
  • the invention also provides a method of treating or preventing cancer with the therapeutic combination according to the second aspect, the method comprising administering simultaneously or sequentially to a subject in need thereof an effective amount of the first compound and an effective amount of second compound.
  • the therapeutic combination comprises further compounds, for example a fourth, fifth, etc. compound, these may independently be administered simultaneously or sequentially with the first and/or second compound.
  • the cells are resistant to the first and/or second compound if administered alone.
  • the cell may be sensitive to the first and second compound.
  • inhibitor relates to a compound or substance which reduces or suppresses the activity or function of a target.
  • the target of an inhibitor is a target gene.
  • a target may be one or more proteins or nucleic acids (such as mRNAs).
  • An inhibitor may have multiple targets, which may share structural homology (e.g. in the case of related proteins) or a shared function (e.g. in the case of a pathway inhibitor).
  • Inhibitors include a compound or substance which interacts with its target, for example a competitive or non-competitive/allosteric inhibitor.
  • a competitive inhibitor competes with a substrate for the active site, whist an allosteric inhibitor binds to a site other than the active site and prevents substrate binding for example by stabilising a conformation which abolishes or disrupts the active form of the target.
  • These interactions are typically reversible, however an inhibitor may be an irreversible inhibitor, for example an inhibitor which covalently links to a target, blocking or disrupting the active form.
  • an inhibitor may be a transcriptional inhibitor, which reduces or abolishes the expression of a target.
  • Inhibitors may alternatively be biologic compounds, for example peptides and more preferably an antibody or antigen binding fragment thereof.
  • Monoclonal antibodies, polyclonal antibodies, humanised antibodies, chimeric antibodies, and Fab and Fab2 fragments of antibodies are all suitable as inhibitors in the invention.
  • Inhibitors may also reduce or suppress the activity or function of a target indirectly, for example through suppressing or abolishing the transcription and/or translation of a gene encoding the target.
  • an inhibitor may be an antisense oligonucleotide (ASO) or interfering RNA, for example a small interfering RNA (siRNA), encoding the complement of at least part of the gene encoding the target and which, when expressed, reduces or prevents the expression of said target in a cell.
  • ASO antisense oligonucleotide
  • siRNA small interfering RNA
  • a “phosphatidylinositol 3-kinase (PI3K) pathway inhibitor”, an “inhibitor of phosphatidylinositol 3-kinase (PI3K) signalling” or an “inhibitor of the phosphatidylinositol 3-kinase (PI3K) signalling pathway” are used interchangeably and refer to a compound which inhibits, downregulates or abolishes signalling through the PI3K signalling pathway. It is therefore an inhibitor which targets one or more components in the PI3K pathway and, as a consequence, downregulates or abolishes PI3K signalling.
  • the inhibitor’s action may comprise or consist of direct interaction with and inhibition of PI3K activity or function.
  • the PI3K pathway is an intracellular signal transduction pathway that functions to stimulate cell to proliferation and growth, and simultaneously inhibit cell apoptosis.
  • the pathway involves many members, however key proteins involved include receptor tyrosine kinases (RTKs), phosphatidylinositol 3-kinases (PI3Ks), phosphatidylinositol-4,5-bisphosphate (PIP2), phosphatidylinositol-3,4,5-bisphosphate (PIP3) and AKT/protein kinase B.
  • RTKs are cell surface receptors for multiple growth factors, cytokines and hormones. Ligands binding to RTKs promote activation of PI3Ks.
  • PI3K family kinases are capable of phosphorylating the 3’-hydroxyl group of the inositol ring of phosphatidylinositol.
  • Phosphatidylinositol containing PIP2 and PIP3 are minor phospholipid components of cell membranes, and their activation through PI3K-mediated phosphorylation allows the recruitment of AKT to the plasma membrane, where it is in turn activated.
  • AKT/protein kinase B is a serine/threonine-specific protein kinase that enhances the survival of cells by preventing apoptosis through blocking pro-apoptotic proteins and processes, such as through negatively regulating Bcl-2 family members and p53.
  • AKT also promotes cell cycle advancement through its phosphorylation and inhibition of G1 state associated factors P21/Waf1/Cip1 and P27/Kip2. Additionally, AKT promotes cell growth through inhibition of TSC2 and indirect activation of the mTOR complex 1.
  • a review of the PI3K pathway can be found in Hemmings, B. A., & Restuccia, D. F., Cold Spring Harbor Perspectives in Biology, 4(9), a011189.
  • Inhibitors of PI3K signalling may interact with and inhibit the activity or function, ordownregulate the expression, of a PI3K and one or more target proteins involved in the PI3K pathway selected from RTK, PIP2, PIP3, and/or AKT.
  • the inhibitor may interact with and inhibit the activity or function, or downregulate the expression, of one or more target proteins involved in the PI3K pathway selected from RTK, PIP2, PIP3, and/or AKT, and may show no interaction or effect on PI3K itself.
  • An inhibitor of PI3K signalling may be a PI3K inhibitor.
  • a PI3K inhibitor may in particular directly interact with and inhibit the activity or function of, one or more PI3K isoform.
  • PI3Ks are members of a family of kinases capable of phosphorylating the hydroxyl group of the inositol ring of phosphatidylinositol. All PI3Ks consist of two domains: a catalytic domain P110 and a regulatory domain P85. They are divided into classes I to III. A review of the PI3K family can be found in Jean & Kiger, (2014), Classes of phosphoinositide 3-kinases at a glance, Journal of Cell Science, 727(Pt 5), 923-928.
  • PI3K inhibitor preferably interacts with and inhibits activity or function of one or more Class I PI3K isoform.
  • Class I PI3K isoforms function as heterodimers consisting of one of four catalytic p110 subunits (PIK3CA/p110a, PIK3CB/p110b, PIK3CD/p110d, or PIK3CG/p110y) and a regulatory subunit selected from PIK3R1/p85a (or its splice variants p55a and p50a), PIK3R2/p85p, PIK3R3/p55y, PIK3R5/p101 or PIK3R6/p84.
  • Some PI3K inhibitors interact with and inhibit activity or function of PIK3CA/p110a.
  • Some PI3K inhibitors interact with and inhibit activity or function of PIK3CB/p110b. Some PI3K inhibitors interact with and inhibit activity or function of PIK3CD/p110d. Some PI3K inhibitors interact with and inhibit activity or function of PIK3CG/p110y. Some PI3K inhibitors interact with and inhibit activity or function of one or more, two or more, three or more, or all PI3K isoforms selected from PIK3CA/p110a, PIK3CB/p110b, PIK3CG/p110y and/or PIK3CD/p110d. Preferably, the PI3K inhibitor interacts with and inhibits activity or function of PIK3CA/p110a, PIK3CB/p110b and PIK3CD/p110d.
  • a PI3K inhibitor may not interact with and may have no effect on the activity or function of one or more Class I PI3K isoform, e.g. one, two, three, or four selected from PIK3CA/p110a, PIK3CB/p110b, PIK3CG/p110y and/or PIK3CD/p110d.
  • the PI3K inhibitor optionally and additionally inhibits activity or function of Class III PI3K isoform PIK3C3/Vps34.
  • the PI3K inhibitor inhibits activity or function of PIK3CA/p110a, RIK3 ⁇ B/r110b and PIK3CD/p110d, but does not substantially inhibit activity or function of PIK3CG/p110y.
  • An inhibitor of PI3K signalling may, in addition or as an alternative to inhibition of Class I PI3K isoform as described above, interact with and inhibit activity or function of one or more Class II PI3K isoform.
  • the class II family has three members in humans - PIK3C2A/PI3KC2a, RIK3 ⁇ 2B/RI3K ⁇ 2b and PIK3C2G/PI3KC2y. There is no known obligatory regulatory subunit.
  • the inhibitor of PI3K signalling interacts with and inhibits one, preferably two, or all three, selected from P I K3C2A/P 13KC2a , RIK3 ⁇ 2B/RI3K ⁇ 2b and PIK3C2G/PI3KC2y. Additionally or alternatively, the inhibitor of PI3K signalling may interact with and inhibit activity or function of Class III PI3K isoform PIK3C3/Vps34. This is the only class III PI3K in humans, which exists as a dimer of catalytic PIK3C3/Vps34 and its regulatory subunit PIK3R4/Vps15.
  • Inhibitor of PI3K signalling may additionally or alternatively interact with and inhibit activity or function of a phosphatidylinositol 4-kinase alpha (PI4K) selected from phosphatidylinositol 4-kinase alpha (PI4KA), phosphatidylinositol 4-kinase beta (PI4KB), phosphatidylinositol 4-kinase 2-alpha (PI4K2A), and/or phosphatidylinositol 4-kinase 2-beta (PI4K2B).
  • PI4K phosphatidylinositol 4-kinase alpha
  • PI4KA phosphatidylinositol 4-kinase alpha
  • PI4KB phosphatidylinositol 4-kinase beta
  • PI4K2A phosphatidylinositol 4-kinase 2-alpha
  • the PI4K family catalyses phosphorylation of phosphatidylinositol at the D-4 position, and are part of the PI3K signalling pathway.
  • An inhibitor of PI3K signalling may be a non-selective pan-PI3K inhibitor.
  • a “non-selective pan-PI3K inhibitor” refers to a substance or compound which inhibits, either by inhibiting activity or function of or by reducing expression of, multiple targets within the PI3K signalling pathway. In this way, the inhibitor effectively downregulates signalling through the pathway.
  • a non-selective pan- PI3K inhibitor may target one, two, three, four, or more targets selected from a RTK, a PI3K, PIP2, PIP3, and/or AKT.
  • a non-selective pan-PI3K inhibitor may inhibit one or more additional targets outside of the PI3K signalling pathway, either by interacting with them and inhibiting their activity or function, or by reducing their expression.
  • the additional targets are selected from casein kinase 2 (CK2), Myosin Light-chain Kinase (MLCK, and/or mammalian target of rapamycin (mTOR).
  • CK2 casein kinase 2
  • MLCK Myosin Light-chain Kinase
  • mTOR mammalian target of rapamycin
  • a non-selective pan-PI3K inhibitor may target, for example may interact with and inhibit the activity or function of at least a PI3K class I, a PI3K class
  • Some PI3K inhibitors do not interact with and inhibit the activity or function of PI3K class I, II, III, and/or PI4K. In particular, they may not interact with and inhibit the activity or function of PI3K class III.
  • Exemplary non-selective pan-PI3K inhibitors are wortmannin, BEZ235 (Dactolisib), PI-103, Buparlisib (BKM120, NVP-BKM120), GDC-0941 (Pictilisib), PI828, and 2-Morpholin-4-yl-8-phenylchromen-4-one (LY-294002) (Gharbi et al., 2007).
  • LY-294002 is a relatively weak, pan-PI3K inhibitor showing inhibition in cell-free assays of the first 3 PI3K isoforms (Liu et al., 2017).
  • LY294002 It inhibits RI3Ka/d/b with IC50 of 0.5 pM/0.57 pM/0.97 pM, respectively. Similar to LY294002, BEZ235 and GDC-0941 also show pan-PI3K activity and are currently in clinical trials for glioblastoma. The structure of LY294002 is shown below:
  • the inhibitor of PI3K signalling is BEZ235 (Dactolisib) or a salt, conjugate, prodrug, or derivative thereof.
  • the inhibitor of PI3K signalling is GDC-0941 (Pictilisib), or a salt, conjugate, prodrug, or derivative thereof.
  • the inhibitor of PI3K signalling is wortmannin, or a salt, conjugate, prodrug, or derivative thereof.
  • the inhibitor of PI3K signalling is LY-294002, or a salt, conjugate, prodrug, or derivative thereof.
  • the inhibitor of PI3K signalling has similar chemical and biological properties to LY-294002.
  • the inhibitor of PI3K signalling may show pan-PI3K selectivity similar to LY294002, and may have a comparable selectivity and/or affinity to LY-294002, may have the same or similar binding mode in x-ray crystallography, or may compete with LY-294002 for substrate binding sites.
  • such an inhibitor has a lower dose-limiting toxicity than LY-294002.
  • a PI3K inhibitor is a PI3K inhibitor other than fucoxanthin.
  • an “inhibitor of phosphodiesterase (PDE) activity or function” is a compound that reduces or inhibits the activity or function of one or more protein with phosphodiesterase activity.
  • An inhibitor of phosphodiesterase (PDE) activity or function may be selective for PDE1 , PDE2, PDE3, PDE4, PDE5, PDE7, or PDE10. Alternatively, the inhibitor may be a non-specific PDE inhibitor.
  • an inhibitor of phosphodiesterase (PDE) activity or function is an inhibitor of PDE10A activity or function.
  • An exemplary inhibitor of PDE10A activity or function is activity or function is 2-[4-(1-Methyl-4-pyridin-4-yl- 1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-02545920), or an inhibitor of PDE which has similar chemical and biological properties to PF-02545920.
  • PF-02545920 is an orphan drug developed for the treatment of the brain disease schizophrenia, but which has been discontinued.
  • the inhibitor of PDE activity or function is PF-02545920, or a salt, conjugate, prodrug, or derivative thereof.
  • a “target gene” is a gene which has been identified by the methods of the first and second aspects as implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation in the cancer, and therefore is selected as a target for an inhibitory drug.
  • cancer cells upregulate the expression of one or more genes implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radiosensitisation, in order to overcome and “escape” the inhibitory effect of the drug challenge. By inhibiting the target gene, the cancer cells are denied this escape.
  • a target gene is preferably a kinase.
  • a target gene may be selected from Janus Kinase 2 (JAK2), Salt Inducible Kinase 1 (SIK1), Ribosomal Protein S6 Kinase A5 (RPS6KA5), Serum/Glucocorticoid Regulated Kinase 1 (SGK1), BCL2 Associated Athanogene 1 (BAG1), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), Pancreatic Lipase Related Protein 3 (PNLIPRP3), and Yippee-Like 1 (YPEL1).
  • JK2 Janus Kinase 2
  • SIK1 Salt Inducible Kinase 1
  • RPS6KA5 Ribosomal Protein S6 Kinase A5
  • SGK1 Serum/Glucocorticoid Regulated Kinase 1
  • BAG1 BCL2 Associated Athanogene 1
  • BAG1 BCL2 Associated A
  • targets were identified according to the methods of first aspect, using an inhibitor of PI3K signalling and/or PDE activity or function.
  • An inhibitor of any of these target genes will find utility in the treatment or prevention of cancers as described herein, however inhibitors of these target genes are particularly contemplated when administered simultaneously or sequentially with an inhibitor of PI3K signalling, or with an inhibitor of PDE activity or function, as defined herein.
  • an inhibitor of PI3K signalling may be administered simultaneously or sequentially with an inhibitor of a target gene selected from: Janus Kinase 2 (JAK2), BCL2 Associated Athanogene 1 (BAG1), Pancreatic Lipase Related Protein 3 (PNLIPRP3), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), and Yippee-Like 1 (YPEL1).
  • a target gene selected from: Janus Kinase 2 (JAK2), BCL2 Associated Athanogene 1 (BAG1), Pancreatic Lipase Related Protein 3 (PNLIPRP3), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), and Yippee-Like 1 (YPEL1).
  • JAK2 Janus Kinase 2
  • BAG1 BCL2 Associated Athanogene 1
  • PNLIPRP3 Pancreatic Lipase Related Protein 3
  • NR4A3 Nuclear Receptor Subfamily 4 Group A Member 3
  • YPEL1 Yi
  • the invention relates to the combination of an inhibitor of PI3K signalling and an inhibitor of a target gene activity or function. These inhibitors may be administered simultaneously or sequentially.
  • This combination finds use in the treating of cancer, and in the manufacture of medicaments for use in treating or preventing cancer.
  • the inhibitor of PI3K signalling is as defined herein.
  • Suitable target genes are selected from the genes implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation that shows increased expression in U87 cells at 24hr and/or 48hr following treatment with an inhibitor of PI3K signalling. These are shown in Table 3.
  • Suitable inhibitors for use in the tenth to thirteenth aspects in combination with an inhibitor of PI3K signalling may include those which inhibit a target gene as identified by the method according to the first aspect of the invention as those for which the expression is perturbed following exposure to the inhibitor of PI3K signalling, and which is implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • the inhibitors may inhibit the activity or function of a target gene listed in Figure 18.
  • Suitable inhibitors for use in the tenth to thirteenth aspects include those which inhibit the activity or function of a target gene selected from: NR3C2, HDAC5, TOP1 MT, IGF1 R, TRPV1 , GRIK2, JAK2, PDE4D, PIM3, RPS6KA2, UGCG, VDR, KDR, and BDKRB2.
  • the target gene may be selected from VDR, IGF1 R, TOP1 MT, JAK2, KDR, and BDKRB2.
  • the target gene may be selected from Janus Kinase
  • the target gene is selected from Janus Kinase 2 (JAK2), DNA topoisomerase I mitochondrial (TOP1 MT), or Insulin like Growth Factor 1 Receptor (IGF1 R).
  • the target gene is selected from Janus Kinase 2 (JAK2), Nuclear Receptor subfamily
  • the target gene is JAK2.
  • JAK2 Histone deacetylase 5
  • VDR vitamin D receptor
  • VDR DNA topoisomerase I mitochondrial
  • IGF1 R Insulin like Growth Factor 1 Receptor
  • TRPV1 Transient receptor potential cation channel subfamily V member 1
  • KDR Kinase Insert Domain Receptor
  • the target gene is JAK2.
  • a suitable inhibitor for use as in the tenth to thirteenth aspects in combination with an inhibitor of PI3K signalling may inhibit the activity or function of a target gene selected from:
  • the target gene may be selected from PLK3, ADAMTS5, IGFBP1 , ACKR3, PDK4, KCNJ2, SIK1 , MMP1 , RPS6KA2, MMP3, CLCN7, SGK1 , MMP10, GPR84, PKD2, AMDHD2, TRPM7, PIM1 , DKK1 , MMP15, MCOLN1 , ITPR1 , PIM3, UPP1 , LSS, H1 F0, TAS2R31 , PTGES, KDM3A, DYRK3, PLD1 , RPS6KA5, TNIK, MAP3K8, NR4A2, TESK2, EZH1 , PFKFB2, SIK2, TNKS, KDM7A, DYRK1 B, FASN, NEK9, and MAP2.
  • the target gene may be selected from PLK3, ADAMTS5, IGFBP1 , ACKR3, PDK4, KCNJ2, SIK1 , MMP
  • the target gene is selected from PLD1 , ADAMTS5, RPS6KA5, SIK1 , MMP1 , CLCN7, SGK1 , KCNJ2, MMP15, PTGES, H1 F0, PDK4, LSS, MMP3, or PIM1 .
  • the inhibitor of the activity or function of a target gene administered simultaneously or sequentially with an inhibitor of PI3K signalling has a target gene selected from: JAK2, SIK1 , RPS6KA5, SGK1 , BAG1 , NR4A3, PNLIPRP3, and YPEL1.
  • the target gene is JAK2.
  • a method of treating or preventing cancer comprising administering to a subject an effective amount of an inhibitor of PI3K signalling as defined herein simultaneously or sequentially with an inhibitor of the activity or function of a target gene as shown in columns 1 and/or 2 of Figure 20A herein.
  • an inhibitor of PI3K signalling as described herein for use in treating or preventing cancer wherein the inhibitor of PI3K signalling is administered to a subject simultaneously or sequentially with the inhibitor of the activity or function of a target gene as shown in columns 1 and/or 2 of Figure 20A herein.
  • the inhibitor of the target gene for use in treating or preventing cancer wherein the inhibitor of the activity or function of the target gene is administered to a subject simultaneously or sequentially with an inhibitor of PI3K signalling as defined herein.
  • the invention relates to the combination of an inhibitor of PDE activity or function and an inhibitor of a target gene activity or function. These inhibitors may be administered simultaneously or sequentially.
  • This combination finds use in the treating of cancer, and in the manufacture of medicaments for use in treating or preventing cancer.
  • the inhibitor of PDE activity or function is as described herein.
  • a preferred inhibitor of PDE activity or function is an inhibitor of PDE10A activity or function.
  • Suitable target genes are selected from the genes implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radiosensitisation that shows increased expression in U87, A172 and/or T98 cells at 24hr following treatment with an inhibitor of PDE activity or function. These are shown in Table 3.
  • Suitable target genes for use in the fourteenth to eighteenth aspects in combination with an inhibitor of PDE activity or function may be identified by the method according to the first aspect of the invention as those for which the expression is perturbed following exposure to the inhibitor of PDE activity or function, and which is implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • the inhibitors may inhibit the activity or function of a target gene listed in Figure 19.
  • Suitable inhibitors for use in the fourteenth to eighteenth aspects include those which inhibit the activity or function of a target gene selected from: EDNRA, VDR, S1 PR1 , TOP1 MT, KCNG1 , SSTR2, HMGCR, AR, PDE7B, THRA, GRIK2, SCN9A, DRD2, PTH1 R, IL1 B, ADORA1 , BDKRB2, HSD11 B1 , ADRB2, PDE4D, IL6, VEGFA, IL1 RAP, PNP, CYP11A1 , HCAR2, IL4R, and PTGER2.
  • the target gene may be selected from EDNRA, VDR, S1 PR1 , TOP1 MT, and KCNG1 .
  • the target gene may be selected from SSTR2, HMGCR, AR, PDE7B, THRA, GRIK2, SCN9A, DRD2 and PTH1 R.
  • the target gene may be selected from IL1 B, ADORA1 , BDKRB2, S1 PR1 , HSD11 B1 , ADRB2, PDE4D, IL6, VEGFA, IL1 RAP, PNP, CYP11A1 , HCAR2, IL4R, and PTGER2.
  • a suitable inhibitor for use as outlined in the fourteenth to eighteenth aspects in combination with an inhibitor of PDE activity or function may inhibit the activity or function of a target gene selected from: SIK1 , ADAMTS5, GPR84, C5AR1 , PDK4, ACKR3, IL1A, CTH, C3AR1 , HSD17B14, SLC33A1 , RPS6KA2, CLCN7, PFKFB2, TK2, NR4A2, OGT, CHKA, FHIT, SGK1 , SLC11A2, FPR1 , CLCN6, TD02, AKR1 C2, MMP15, PH0SPH01 , PLK2, LIPG, AKR1 C3, HMOX1 , GPR183, CAMK2A, CYP1 B1 , AKR1 C1 , KDR, ST3GAL1 , PTGES, LSS, FABP3, HMGCS1 , P2RX7, MVK,
  • the target gene may be selected from SIK1 , ADAMTS5, GPR84, C5AR1 , PDK4, ACKR3, IL1 A, CTH, C3AR1 , HSD17B14, SLC33A1 , RPS6KA2, CLCN7, PFKFB2, TK2, NR4A2, OGT, CHKA, FHIT, SGK1 , SLC11 A2, FPR1 , CLCN6, TD02, AKR1 C2, MMP15, PH0SPH01 , PLK2, LIPG, AKR1 C3, HMOX1 , GPR183, CAMK2A, CYP1 B1 , AKR1 C1 , KDR, ST3GAL1 , and PTGES.
  • the target gene may be selected from LSS, FABP3, HMGCS1 , LIPG, P2RX7, HMOX1 , MVK, ELOVL6, CYP51 A1 , ABHD6, PIK3C2B, OPRL1 , ENTPD1 , HSD17B7, XIAP, DNMT3B, SLC11A2, SIK1 , KDM3A, DDIT3, CA12, CBS, ADAMTS1 , EPHA8, LRRK2, MANBA, ASIC1 , GPR183, EIF2AK3, MAP3K8, PLA2G10, CHKA, PADI3, MPG, CTSK, CLCN6, and QPCTL.
  • the target gene may be selected from SQLE, STAT5B, NR4A2, NNMT, DUSP1 , SIK1 , RPS6KA2, SLC02A1 , GRK5, SGK1 , PLA2G4A, HSD17B2, KDM7A, IGFBP4, DRD2, H1 F0, SLC16A7,
  • the target gene may be selected from HMGCS1 , CTH, HSD17B7, FRK, GPR3, MAP3K5, CYP51A1 , DYRK3, NIM1 K, P2RX7, PIM3, TGM2, LPAR2, AKT3, HSD3B1 , AURKB, TNNI3K, and QPCTL.
  • the target gene is selected from: SIK1 , NR4A2, SGK1 , HMGCS1 , LIPG, P2RX7, HMOX1 , CTH, CYP51A1 , RPS6KA2, HSD17B7, SLC11A2, CHKA, CLCN6, GPR183, or QPCTL.
  • an inhibitor of PDE activity or function is used with an inhibitor of SIK1 activity or function.
  • These genes all have known inhibitors.
  • a preferred inhibitor of PDE activity or function for use in these embodiments is an inhibitor of PDE10A activity or function.
  • the inhibitor of the activity or function of a target gene administered simultaneously or sequentially with an inhibitor of PDE activity or function has a target gene selected from: SIK1 , SGK1 , NR4A3, and PNLIPRP3.
  • an inhibitor of PDE activity or function is used with an inhibitor of SIK1 activity or function.
  • the target gene is not Cell Adhesion Molecule 2 (CADM2), Growth/differentiation factor 15 (GDF15), Baculoviral IAP Repeat Containing 3 (BIRC3), or Slit Guidance Ligand 3 (SLIT3).
  • CEM2 Cell Adhesion Molecule 2
  • GDF15 Growth/differentiation factor 15
  • BIRC3 Baculoviral IAP Repeat Containing 3
  • Slit Guidance Ligand 3 Slit Guidance Ligand 3
  • the inhibitor of target gene function or activity is an inhibitor of JAK2 activity or function
  • the inhibitor of JAK2 activity or function may be a Type I protein kinase inhibitor.
  • the inhibitor of JAK2 activity or function may be an ATP-competitive inhibitor of JAK2.
  • JAK1 and JAK2 downregulates the JAK-signal transducer and activator of transcription (STAT) pathway, inhibiting proliferation, inducing apoptosis, and reducing numerous cytokine plasma levels.
  • STAT JAK-signal transducer and activator of transcription
  • the inhibitor of JAK2 activity or function has similar chemical and biological properties to ruxolitinib.
  • the inhibitor of JAK2 activity or function may have JAK2-selective inhibitory properties similar to ruxolitnib, a comparable selectivity and/or affinities for JAK2 as ruxolitinib, the same or similar binding mode in x-ray crystallography and/or may compete with ruxolitinib for binding sites on JAK2.
  • the inhibitor of JAK2 activity or function may be 5-Chloro-N2-[(1S)-1-(5-fluoro- 2-pyrimidinyl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)-2,4-pyrimidine-2, 4-diamine (AZD1480), or a salt, conjugate, prodrug, or derivative thereof.
  • AZD1480 4-diamine
  • the structure of AZD1480 is shown below:
  • the inhibitor of JAK2 activity or function has similar chemical and biological properties to AZD1480.
  • the inhibitor of JAK2 activity or function may have a comparable selectivity and/or affinities for JAK2 as AZD1480, may have the same or similar binding mode in x-ray crystallography and/or may compete with AZD1480 for binding sites on JAK2.
  • such an inhibitor has an improved dose-limiting toxicity relative to AZD1480.
  • JAK2 inhibitors without either JAK1 or JAK3 inhibitory activities may be preferable, since chronic dosing required for many treatments carries the potential risk of immunosuppressive side effects related to inhibition of JAK1 , JAK3, or TYK2, suggesting that identification of a JAK2 selective inhibitor may offer increased safety.
  • the inhibitor of JAK2 activity or function is not Ruxolitinib.
  • the inhibitor of a target gene is an inhibitor of SIK1 activity or function.
  • Inhibitors of SIK1 activity or function find particular utility when administered simultaneously or sequentially with an inhibitor of PDE activity or function, particularly the PDE10A inhibitor PF-02545920.
  • Preferred inhibitors of SIK1 activity or function may prevent or reduce activating phosphorylation of SIK1.
  • the inhibitor may be a Type I protein kinase inhibitor.
  • An inhibitor of SIK1 activity or function may be an ATP-competitive inhibitor
  • a preferred inhibitor of SIK1 activity or function is WH-4-023 (2,6-Dimethylphenyl-N-(2,4- dimethoxyphenyl)-N-[2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]carbamate) (CAS Number 837422-57-8), or a compound with comparable activity to WH-4-023.
  • the structure of WH-4-023 is shown below:
  • the inhibitor of SIK1 activity or function is WH-4-023, or a salt, conjugate, prodrug, or derivative thereof.
  • the inhibitor of SIK1 activity or function is HG-9-91-01 , or a salt, conjugate, prodrug, or derivative thereof.
  • the inhibitor of target gene activity or function is an inhibitor of HMGCR activity or function.
  • Preferred inhibitors of HMGCR activity or function include statins.
  • Statins are clinically approved drugs, and are recommended for cardiovascular diseases such as hypertension and heart attacks
  • a statin may be selected from atovastatin, cerivastatin, fluvastatin, lovastating, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, or a salt or derivative thereof.
  • a preferred statin is Atorvastatin or a salt or derivative thereof.
  • the inhibitors of target genes, and combinations of inhibitor of target genes with an inhibitor of PI3K signalling or an inhibitor of PDE activity or function finds use in the treatment or prevention of cancer.
  • Cancer cells exposed to PI3K or PDE inhibitors need to escape from the inhibitory effect and activate alternative growth through target genes, for example through JAK2 or SIK1.
  • Challenge with PI3K signalling inhibitors results in up-regulation of the target gene (e.g. JAK2 or SIK1), reflecting a pro- proliferative role within the glioblastoma cells as they react to the growth inhibition caused by down- regulation of the PI3K or PDE pathway.
  • a method of treating or preventing cancer comprising administering to a subject an effective amount of an inhibitor of PDE10A activity or function as defined herein simultaneously or sequentially with an inhibitor of the activity or function of a target gene as shown in columns 1 , 2, and/or 3 of Figure 20B herein.
  • an inhibitor of PDE10A activity or function as described herein for use in treating or preventing cancer wherein the inhibitor of PDE10A activity or function is administered to a subject simultaneously or sequentially with the inhibitor of the activity or function of a target gene as shown in columns 1 , 2, and/or 3 of Figure 20B herein.
  • the inhibitor of the target gene for use in treating or preventing cancer wherein the inhibitor of the activity or function of the target gene is administered to a subject simultaneously or sequentially with an inhibitor of PDE10A activity or function as defined herein.
  • first and second compounds are in particular contemplated, and find use in the treatment of cancer, and in the manufacture of medicaments for the treatment of cancer as described herein:
  • the first compound is an inhibitor of PI3K signalling
  • the second compound is preferably an inhibitor of JAK2 activity or function
  • the first compound may be an inhibitor of JAK2 activity or function and the second compound may be an inhibitor of PI3K signalling.
  • the inhibitor of PI3K signalling is LY-294002 or a salt or derivative thereof.
  • the inhibitor of JAK2 activity or function may be Ruxolitinib, AZD1480, or a salt or derivative thereof.
  • the first compound is an inhibitor of PDE activity or function
  • the second compound is preferably an inhibitor of JAK2 activity or function
  • the first compound may be an inhibitor of JAK2 activity or function and the second compound may be an inhibitor of PDE activity or function.
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function, e.g. PF- 02545920.
  • the inhibitor of PI3K signalling is LY-294002 or a salt or derivative thereof.
  • the inhibitor of JAK2 activity or function may be Ruxolitinib, AZD1480, or a salt or derivative thereof.
  • the first compound is an inhibitor of PDE activity or function
  • the second compound is preferably an inhibitor of SIK1 activity or function
  • the first compound may be an inhibitor of SIK1 activity or function and the second compound may be an inhibitor of PDE activity or function.
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function, e.g. PF- 02545920 or a salt or derivative thereof.
  • the inhibitor of SIK1 activity or function may be HG-9-91-01 , or WH-4-023, or a salt or derivative thereof.
  • the first compound is an inhibitor of PDE activity or function
  • the second compound is preferably an inhibitor of PNLIPRP3 activity or function
  • the first compound may be an inhibitor of PNLIPRP3 activity or function
  • the second compound may be an inhibitor of PDE activity or function.
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function, e.g. PF-02545920 or a salt or derivative thereof.
  • the first compound is an inhibitor of PDE activity or function
  • the second compound is preferably an inhibitor of NR4A3 activity or function
  • the first compound may be an inhibitor of NR4A3 activity or function
  • the second compound may be an inhibitor of PDE activity or function.
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function, e.g. PF-02545920 or a salt or derivative thereof.
  • the first compound is an inhibitor of PDE activity or function
  • the second compound is preferably an inhibitor of S1PR1 activity or function
  • the first compound may be an inhibitor of S1 PR1 activity or function
  • the second compound may be an inhibitor of PDE activity or function.
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function, e.g. PF-02545920.
  • the first compound is an inhibitor of PDE activity or function
  • the second compound is preferably an inhibitor of HMGCR activity or function
  • the first compound may be an inhibitor of HMGCR activity or function
  • the second compound may be an inhibitor of PDE activity or function.
  • the inhibitor of PDE activity or function is preferably an inhibitor of PDE10A activity or function, e.g. PF-02545920.
  • treatment or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • Treatment includes preventing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition prior to the induction of the disease; suppressing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition after the inductive event but prior to the clinical appearance or reappearance of the disease; inhibiting the disease, that is, arresting the development of clinical symptoms by administration of a protective composition after their initial appearance; preventing re-occurring of the disease and/or relieving the disease, that is, causing the regression of clinical symptoms by administration of a protective composition after their initial appearance.
  • prevention of cancer refers to preventing the progression of a tumour. Tumours may be classified by grade (“The 2016 World Health Organisation Classification of Tumours of the Central Nervous System: a summary". Acta Neuropathologica. 131 (6): 803-820). A cancer may be prevented from progression from low-grade (WHO grade I or II) to high-grade (WHO grade III or IV). “Prevention of cancer” may include preventing a benign or pre-cancerous tumour from progressing to a malignant or cancerous state. “Prevention of cancer” may include preventing a cancer or tumour from arising from healthy tissue.
  • prevention of cancer may also include preventing a cancer from spreading, for example from metastasising.
  • the terms “metastasis,” “metastatic,” and “metastatic cancer” can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part, such as from the lung to the brain.
  • metastatic cancer refers to a disease in which a subject has or had a primary tumour and has one or more secondary tumours.
  • non-metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumour but not one or more secondary tumours.
  • metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumour and with one or more secondary tumours at a second location or multiple locations, e.g., in the brain.
  • prevention of cancer may also include preventing the recurrence of a cancer which is in partial or complete remission.
  • cancer in remission refers to a decrease in or disappearance of signs and symptoms of cancer.
  • Partial remission refers to a cancer which has a decrease in some, but not all signs and symptoms have decreased or disappeared.
  • a cancer in partial remission may exhibit decreases in tumour sise, cancer cell count, metastasis rate, etc.
  • the active compounds may be administered to a subject or patient simultaneously or sequentially, by any suitable route or administration.
  • Patient refers to a living organism suffering from or prone to a disease or condition that can be treated by using the methods provided herein.
  • the term does not necessarily indicate that the subject has been diagnosed with a particular disease, but typically refers to an individual under medical supervision.
  • a subject or patient is human.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, ortransdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • compositions described herein are administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy.
  • additional therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy.
  • the compounds of the invention can be administered alone or can be coadministered to the patient.
  • Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).
  • compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • “Simultaneous” administration refers to administration of the agents together, for example as a pharmaceutical composition containing the agents (i.e. a combined preparation), or immediately after each other and optionally via the same route of administration, e.g. to the same artery, vein or other blood vessel.
  • the inhibitor of PI3K signalling or of PDE activity or function and the inhibitor of the target gene activity or function may be administered simultaneously in a combined preparation.
  • the two or more of the agents may be administered via different routes of administration.
  • Simultaneous administration may refer to administration at the same time, or within e.g.
  • “Sequential” administration refers to administration of one or more of the agents followed after a given time interval by separate administration of another of the agents. It is not required that the two agents are administered by the same route, although this is the case in some embodiments.
  • the time interval may be any time interval, including hours, days, weeks, months, or years.
  • Sequential administration may refer to administrations separated by a time interval of one of at least 10 min, 30 min, 1 hr, 6 hrs, 8 hrs, 12 hrs, 24 hrs, 36 hrs, 48 hrs, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 6 weeks, 2 months, 3 months, 4 months, 5 months or 6 months.
  • the inhibitors may be administered simultaneously or sequentially with one or more further compounds.
  • an inhibitor of PI3K signalling and an inhibitor of target gene activity or function are administered simultaneously or sequentially, either or both may be administered simultaneously or sequential with one or more further compounds.
  • an inhibitor of PDE activity or function and an inhibitor of target gene activity or function are administered simultaneously or sequentially, either or both may be administered simultaneously or sequential with one or more further compounds.
  • the further compound is an inhibitor of Insulin Like Growth Factor 1 Receptor (IGF1 R) activity or function and/or an inhibitor of Serine/threonine-protein kinase 1 (SGK1) activity or function.
  • IGF1 R Insulin Like Growth Factor 1 Receptor
  • SGK1 Serine/threonine-protein kinase 1
  • Suitable compounds may include; 2-Amino-3H-phenoxazin-3-one, 2-Hydroxyoleic acid, 3-(3,4- dichlorophenyl)-1-(3,4-dimethylphenyl)-1-(5-methyl-4,5-dihydro-1 ,3-thiazol-2-yl)urea, 3-Deazaneplanocin, 4egi-1 , 5-Nonyloxytryptamine, 6-Hydroxyquinoline-4-carboxylic acid, 7-Ethyl-10-hydroxycamptothecin, 7- Hydroxystaurosporine, 8-Bromo-cyclic AMP, 8-Hydroxy-2-methyl-1H-quinazolin-4-one, 9-ING-41 , A- 966492, Abemaciclib, Abt-737, AC1MMYR2, Acalabrutinib, Acetazolamide, Ad
  • the inhibitors described herein may be delivered across the blood-brain barrier into the brain, for example through intracranial administration.
  • blood-brain barrier refers to a highly selective semipermeable membrane barrier that separates the circulating blood from the brain and extracellular fluid in the central nervous system. The barrier provides tight regulation of the movement of ions, molecules and cells between the blood and the brain, see e.g. Daneman and Prat, Cold Spring Harb Perspect Biol. 2015;7(1):a020412. Many therapeutic molecules are generally excluded from transport from blood to brain due to their negligible permeability over the brain capillary endothelial wall.
  • Inhibitors may be capable of crossing the blood-brain barrier into the brain, for example by virtue of a targeting domain and/or encapsulation in a liposomal or similar carrier, and are delivered for example by intravenous injection or through the gastrointestinal or oral route.
  • an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient.
  • This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme or protein relative to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist.
  • an effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Efficacy can also be expressed as "-fold" increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott,
  • the compounds described herein may be formulated as pharmaceutical compositions or medicaments for clinical use and may comprise a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
  • the composition may be formulated for topical, parenteral, systemic, intracavitary, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoural, subcutaneous, intradermal, intrathecal, oral, ortransdermal routes of administration which may include injection or infusion.
  • Suitable formulations may comprise the antigen-binding molecule in a sterile or isotonic medium.
  • Medicaments and pharmaceutical compositions may be formulated in fluid, including gel, form. Fluid formulations may be formulated for administration by injection or infusion (e.g. via catheter) to a selected region of the human or animal body.
  • the invention provides a pharmaceutical composition comprising an inhibitor of PI3K signalling and an inhibitor of a target gene activity or function.
  • the inhibitor of PI3K signalling and an inhibitor of target gene or function may be as described herein.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an inhibitor of PDE activity or function, preferably PDE10A activity or function, and an inhibitor of a target gene activity or function.
  • the inhibitor of PDE activity or function and an inhibitor of target gene or function may be as described herein.
  • the pharmaceutical composition may comprise one or more pharmaceutically acceptable binders, diluents, or excipients.
  • the pharmaceutical compositions may be formulated for delivery across the blood-brain barrier, for example via intracranial injection.
  • the pharmaceutical composition may be for the treatment or prevention of a cancer, preferably glioblastoma multiforme.
  • the invention provides a kit comprising (i) an inhibitor of PI3K signalling or an inhibitor of PDE activity or function, preferably PDE10A activity or function, and (ii) an inhibitor of target gene activity or function.
  • the inhibitors may be as described herein.
  • the inhibitors (i) and (ii) may be formulated as pharmaceutical compositions which may comprise one or more pharmaceutically acceptable binders, diluents, or excipients.
  • the pharmaceutical compositions may be formulated for delivery across the blood- brain barrier, for example via intracranial injection.
  • a kit may contain multiple doses of the inhibitors, each of which may be packaged together or separately.
  • Inhibitors may be supplied as aqueous formulations, liquids, powders, pastes, gels, vials, tablets, pills, capsules, or any other formulation described herein.
  • the method may comprise sequentially administering the compounds in combination, for example by (i) administering the first compound, followed by (ii) the second compound simultaneously with the first compound, followed by (iii) the third compound simultaneously with the second and/or first compound, followed by (iv) a further compound simultaneously with any combination of the previous compounds. Steps (i) to (iv) may be separated by any length of time.
  • the first and second compounds may be any contemplated herein, the first compound is may in some embodiments be an inhibitor of PI3K signalling, and the second compound is preferably an inhibitor of JAK2 activity or function, or the first compound may be an inhibitor of JAK2 activity or function and the second compound may be an inhibitor of PI3K signalling.
  • the cancer is sequentially challenged with new drugs during ongoing therapy.
  • a compound may be administered at an initial effective dose, before reverting to a lower dose for subsequent stages - i.e. the first compound may be administered at a higher dose in step (i) than (ii)-iv), the second at a higher dose in step (ii) than steps (iii)-(iv), the third compound in a higher dose in step (iii) than in step (iv), etc.
  • the cancer is challenged with an initial effective dose of a compound, and ongoing therapy at a lower dose to avoid dose limiting toxicity or side effects.
  • a therapeutic combination provided by the method according to the second aspect for use in the treatment or prevention of cancer, preferably for the treatment of GBM.
  • the combination may be for sequential or simultaneous administration.
  • the invention also provides a method, preferably an in vitro method, of identifying target genes for combination therapy, comprising the steps of: a. contacting test cells with a first treatment, b. measuring the effects of the first treatment on the transcriptome of the test cells, so as to create a transcriptomic profile for the first treatment, c. selecting as a target gene for combination therapy a gene whose expression is perturbed in the transcriptomic profile, wherein the gene is implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • the invention also provides a method, preferably an in vitro method, of providing a therapeutic combination, the method comprising a. contacting test cells with a first treatment, b. measuring the effects of the first treatment on the transcriptome of the test cells, so as to create a transcriptomic profile for the first treatment, c. selecting as a target gene for combination therapy a gene whose expression is perturbed in the transcriptomic profile, d. selecting as the second treatment at least an inhibitor of the target gene for combination therapy, so as to provide a combination therapy comprising the first and second treatment, wherein the gene is implicated in the regulation of one or more of cell proliferation, viability, migration, invasion and angiogenesis, apoptosis or radio-sensitisation.
  • a “treatment” may comprise or consist of a therapeutic compound as defined above.
  • a treatment may comprise a suite of therapeutic compounds.
  • a treatment may comprise or consist of additional therapies, such as radiotherapy.
  • a “first treatment” may comprise or consist of any therapeutic compounds and/or therapies.
  • a “second treatment” comprises or consists of an inhibitor of the target gene, and may comprise additional compounds or therapies, so long as it includes an inhibitor of the target gene.
  • the second treatment may include one or more therapeutic compound and/or therapy which constituted the first treatment.
  • a cancer may be any unwanted cell proliferation (or any disease manifesting itself by unwanted cell proliferation), neoplasm or tumour or increased risk of or predisposition to the unwanted cell proliferation, neoplasm or tumour.
  • the cancer may be benign or malignant and may be primary or secondary (metastatic).
  • a neoplasm or tumour may be any abnormal growth or proliferation of cells and may be located in any tissue. Examples of tissues include the adrenal gland, adrenal medulla, anus, appendix, bladder, blood, bone, bone marrow, brain, breast, cecum, central nervous system (including or excluding the brain) cerebellum, cervix, colon, duodenum, endometrium, epithelial cells (e.g.
  • lymph node including abdominal lymph node, axillary lymph node, cervical lymph node, inguinal lymph node, mediastinal lymph node, pelvic lymph node, periaortic lymph node
  • lymphoblast maxilla, mediastinum, mesentery, myometrium, nasopharynx, omentume, oral cavity, ovary, pancreas, parotid gland, peripheral nervous system peritoneum, pleura, prostate, salivary gland, sigmoid colon, skin, small intestine, soft tissues, spleen, stomach, testis, thymus, thyroid gland, tongue, tonsil, trachea, uterus, vulva, white blood cells
  • the cancerto be treated or prevented is a cancer of the brain or central nervous system (CNS).
  • Brain cancers include primary brain tumours (tumours which start in the brain) and secondary brain tumours (i.e. cancerous tumours which have metastasised to the brain from another location in the body, also known as brain metastasis tumours).
  • the brain cancer is a primary brain tumour.
  • Primary brain tumours may originate in astrocytes, oligodendrocytes, ependyma, neurons or meninges.
  • Brain cancers may be subdivided into glioma (tumours of the glial cells), meningioma (tumours of the meninges), pituitary adenoma (tumours of the pituitary gland) and nerve sheath tumours.
  • the cancerto be treated or prevented is a glioma.
  • a glioma may be selected from an ependymoma, an astrocytoma, an oligodendroglioma, or a brain stem glioma.
  • Gliomas may be categorised according to their grade, as determined according to WHO Classification of Tumours of the Central Nervous System (“The 2016 World Health Organisation Classification of Tumours of the Central Nervous System: a summary". Acta Neuropathologica. 131 (6): 803-820).
  • the cancer to be treated or prevented may be a low-grade (WHO grade II or lower) glioma or, more preferably, a high-grade (WHO grade lll-IV) glioma.
  • the cancer to be treated or prevented is glioblastoma multiforme (GBM).
  • GBM is a primary cancer of the astrocytes, and is the most common primary malignant brain tumour in adults (Ostrom et al., 2017).
  • the GBM has one or more mutations in a signalling pathway selected from: RB, TP53, and receptor tyrosine kinase (RTK)/mitogen activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K).
  • RTK receptor tyrosine kinase
  • MAPK mitogen activated protein kinase
  • PI3K phosphoinositide 3-kinase
  • GBM can be stratified into 4 molecular subtypes based on gene expression according to Verhaak et al., 2010.
  • the cancer to be treated or prevented may be a GBM of the Classical subtype.
  • Classical GBM is characterised by extra copies of the EGFR, higher than normal expression of EGFR, retention of wild- type p53, loss of heterozygosity in chromosome 10, and chromosome 7 amplification.
  • the cancer to be treated or prevented may be a GBM of the Mesenchymal subtype.
  • Mesenchymal GBM can be characterised by high rates of mutations or other alterations in NF1 , the gene encoding Neurofibromin 1 and fewer alterations in the EGFR gene and less expression of EGFR than classical GBM.
  • a biomarker selected from Cell Adhesion Molecule 2 (CADM2), Growth/differentiation factor 15 (GDF15), Baculoviral IAP Repeat Containing 3 (BIRC3), and Slit Guidance Ligand 3 (SLIT3) in the diagnosis of a cancer, especially GBM.
  • CADM2 Cell Adhesion Molecule 2
  • GDF15 Growth/differentiation factor 15
  • BIRC3 Baculoviral IAP Repeat Containing 3
  • SLIT3 Slit Guidance Ligand 3
  • the first compound may be an inhibitor of PDE activity or function, preferably of PDE10A activity or function, as described herein.
  • first compound is an inhibitor of PI3K signalling and the biomarker is Cell Adhesion Molecule 2 (CADM2).
  • CADM2 Cell Adhesion Molecule 2
  • New target genes as identified by the first aspect may be treated using mRNA vaccines.
  • traditional vaccines comprise attenuated or cell-free antigenic protein fragments of a target protein against which immunity is to be acquired
  • an mRNA vaccine comprises an RNA sequence encoding a portion of the target gene which, upon administration and introduction into a cell, is translated into protein. This protein in turn induces an immune response against the target gene.
  • the immune response generating antigen is therefore expressed and synthesised in situ in the patient’s cells, allowing an immune response to be generated without the need to create and purify a protein vaccine, as all that needs to be changed is the underlying mRNA sequence.
  • an inhibitor of gene activity or function as used herein may be an mRNA vaccine and, in some aspects, the present disclosure provides an mRNA vaccine for use in a method of treating cancer.
  • An mRNA vaccine may comprise an RNA sequence comprising a portion of a target gene as defined herein.
  • the target gene may be selected from: 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Adenosine A1 Receptor (ADORA1), UDP-glucose ceramide glucosyltransferase (UGCG), Androgen Receptor (AR), BCL2 Associated Athanogene 1 (BAG1), Bradykinin Receptor B2 (BDKRB2), Cytochrome P450 Family 11 A1 (CYP11A1), DNA topoisomerase I mitochondrial (TOP1MT), Dopamine Receptor D2 (DRD2), Endothelin Receptor Type A (EDNRA), Glutamate Ionotropic Receptor Kainate Type Subunit 2 (GRIK2), Histone deacetylase 5 (HDAC5), Hydroxycarboxylic Acid Receptor 2 (HCAR2), Hydroxy
  • the target gene is selected from: Janus Kinase 2 (JAK2), Salt Inducible Kinase 1 (SIK1), Ribosomal Protein S6 Kinase A5 (RPS6KA5), Serum/Glucocorticoid Regulated Kinase 1 (SGK1), BCL2 Associated Athanogene 1 (BAG1), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), Pancreatic Lipase Related Protein 3 (PNLIPRP3), or Yippee-Like 1 (YPEL1); more preferably from: Salt Inducible Kinase 1 (SIK1), Serum/Glucocorticoid Regulated Kinase 1 (SGK1), Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), or Pancreatic Lipase Related Protein 3 (PNLIPRP3); and in either of these embodiments the mRNA vaccine may be administered simultaneously or sequentially with an inhibitor of PI3K activity or function.
  • the mRNA vaccine may further comprise a sequence encoding a protein which induces a stronger immune response.
  • the mRNA vaccine may include a sequence encoding an antigenic tag in phase with the portion of the target gene, such that the translated product of the mRNA sequence is a portion of the target gene fused to the antigenic tag.
  • Suitable tags may be bacterial in nature, for example a Toll-like receptor (TLR) agonist protein, or may comprise one or more cytokines.
  • the mRNA vaccine may be formulated with or administered alongside an adjuvant, for example an aluminium salt, squalene, MF59, or QS21 .
  • the term "about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, the term “about” means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In some embodiments, about means the specified value.
  • Fucoxanthin and LY-294002 were selected as reagents for investigation.
  • Fucoxanthin is a member of the xanthophyll class of carotenoids, and is present at high concentrations in the brown alga Saccharina latissimi (Galasso et al., 2017) where it plays an accessory role in light harvesting and radiation protection.
  • Fucoxanthin has been suggested to act in cancer by suppressing invasion and inducing apoptosis through PI3K/Akt pathway inhibition (Liu et al., 2016; Satomi, 2017) and JAK/STAT pathway inhibition (Kanno et al., 2013; Szymanska et al., 2015).
  • Fucoxanthin has a particularly interesting and unique molecular structure (Figure 1C), exhibiting antioxidant properties due to a long conjugated backbone characteristic of all carotenoids, and possessing unusual terminal allenic bond and conjugated carbonyl groups (Dembitsky and Maoka, 2007; Sangeetha et al., 2009).
  • Figure 1C a particularly interesting and unique molecular structure
  • Fucoxanthin has been shown to inhibit migration and invasion of metastatic melanoma and osteosarcoma cells in vitro and in vivo (Liu et al., 2016).
  • Fucoxanthin is metabolically unstable, upon metabolism producing Fucoxanthinol (Zhang et al., 2015), a factor to take into account when evaluating its transcriptomic effects.
  • LY-294002 is one of the PI3K/Akt inhibitors annotated as active in GBM annotated in the GBM Drug Bank, a public domain resource developed by IOTA Pharmaceuticals based on compounds known to influence the growth and development of glioblastoma (Svensson et al., 2018) http://www.gbmdrugbank.com/db.php).
  • the human glioblastoma cell line U87MG expressing the wild-type p53 gene (U87MG, p53wt, female, obtained from European Collection of Authenticated Cell Cultures) was maintained in DMEM/F12 media (Gibco, ThermoFisher, UK) supplemented with 10% foetal bovine serum (FBS) (Sigma, UK) and 5% antibiotic/antimycotic solution (Sigma, UK). Cells were maintained at 37°C in a humidified atmosphere of 95% air and 5% CO2 LY-294002 and Fucoxanthin were purchased from Sigma, UK and dissolved in dimethyl sulfoxide (DMSO) to obtain 0.1 M and 0.05 M stock solutions, respectively.
  • DMEM/F12 media Gibco, ThermoFisher, UK
  • FBS foetal bovine serum
  • antibiotic/antimycotic solution (Sigma, UK).
  • Cells were maintained at 37°C in a humidified atmosphere of 95% air and 5% CO2
  • cells were seeded into T25 flasks at a density of 5x10 5 cells/flask and allowed to adhere and grow for 24h.
  • the culture medium was removed, and fresh medium containing compound for test was added to each flask at the EC50 concentration for inhibiting proliferation at 72h, previously determined as 199.5 pM for LY-294002 and 19.9 pM for Fucoxanthin.
  • Control cells were treated with medium containing 1% DMSO alone. All experiments were performed in triplicate. Cells were visualised during culture using the EVOS Cell Imaging System (Thermo Fisher Scientific, UK).
  • the culture medium was removed from the plates, and the fresh medium containing tested compounds at different dilutions was added to the plates.
  • Control cells were treated with vehicle solution containing 1% DMSO. Blank controls without cells were also prepared.
  • 72h after treatment 5 pL of CCK-8 was added to every well containing 100 pL of tested compounds, controls or blank.
  • the plates were read using a Mithras LB940 multimode microplate reader (Berthold Technologies), and the absorbance values were determined at 490 nm. The percentage of surviving cells was calculated for each well using the formula: where At is absorbance of the medium with tested compound, A c is absorbance of control medium, and Ab is absorbance of blank medium.
  • the cells were trypsinised, centrifuged, resuspended in 500 pL of binding buffer followed by the addition of 5 pL Annexin V-FITC and 5 pL propidium iodide (PI) according to the manufacturer's instruction.
  • the samples were incubated at room temperature for 5 min in the dark and then analysed using a BD AccuriTM C6 Flow Cytometer. A total of 10,000 events were counted for each sample. Fluorescence was measured at an excitation wavelength of 480 nm with detection for PI at 530 nm and Annexin V at 585 nm.
  • RNA samples were further prepared by ATLAS Biolabs (Berlin, Germany) using their Affymetrix WT Expression Profiling Standard Service. The analysis was conducted on a Clariom S Human array with a fixed number of probes per transcript as probe sets consisting of a subset of 10 probes per gene (yielding >20,000 annotated genes, as documented by the NetAffx Analysis Center).
  • RNA sample was determined using the Agilent 2100 Bioanalyzer and Nanodrop.
  • Agilent 2100 Bioanalyzer and Nanodrop For library preparation (cDNA synthesis, amplification and labeling) GeneChip ® WT PLUS reagents were used.
  • 96-array plates were processed on an Applied Biosystems GeneChip 3000 instrument system followed by hybridisation, dyeing, washing, and scanning using the GeneChipTM Hybridisation, Wash, and Stain Kit from Affymetrix. Hybridisation controls, quality control parameters and primary data analysis was performed using Expression Console v1.4 (also from Affymetrix).
  • the average signal intensities for each probe set were analysed and an expression matrix was created by applying the RMA (Robust Multi-array Average) algorithm as a multi-chip model (Irizarry et al., 2003).
  • RMA Robot Multi-array Average
  • a threshold of 0.8 area under the receiver operating curve was applied to compare the exon and intron probe sets of housekeeping genes, to ensure a good separation within the data.
  • Microarray gene expression profiling and visualisation results were performed using the Affymetrix Transcriptome Analysis Console (TAC) software (ThermoFisher) which uses the limma package (Ritchie et al., 2015).
  • TAC Affymetrix Transcriptome Analysis Console
  • DEGs differentially expressed genes
  • a gene log 2 Fold Change (FC) level has to reach the threshold of ⁇ -1 or > 1 based on Tukey's bi-weight average between treatment and time matching controls (Kohl and Deigner, 2010). Tukey’s bi-weight averaging makes the average less sensitive to outliers (Tukey, 1973).
  • DEGs differentially expressed genes
  • WikiPathways map representations were used in which the signal intensities of DEGs involved in one particular enriched pathway can be shown as down-regulated or up- regulated in response to specific treatments (Kutmon et al., 2016). For pathway analysis, Fisher exact tests were used.
  • the Connectivity Map approach is based on the most significant differentially expressed genes characteristic of compound molecular response. Significantly differentially expressed genes were analysed using Connectivity Map 2. Differentially expressed genes IDs were mapped to Affymetrix HGU133-plus2 probe set IDs, which were then input into Connectivity Map. The down- and up-regulated genes responding to Fucoxanthin and LY-294002 treatment were used as the query signatures for comparing transcriptomic profiles to other compounds in CMap. The connectivity score was calculated based on Kolmogorov-Smirnov statistics (Smalley et al., 2010). This approach is described in detail in Alexander-Dann et al., 2018; Iwata and Yamanishi, 2019; and Oerton and Bender, 2017. Significant findings were cross-referenced to the Glioblastoma Drug Bank (Svensson et al., 2018).
  • the EC50 value for growth inhibition for Fucoxanthin was approximately 19.9 pM after 72h of treatment.
  • the EC50 value for growth inhibition for LY-294002 was 199.5 pM for LY-294002 ( Figure 2B) after 72h of treatment.
  • EXAMPLE 2 Morphological effects of Fucoxanthin and LY-294002 on U87MG cells
  • the target cell population, U87MG glioblastoma cells was treated with each compound at its 72h antiproliferative EC50, determined in an initial drug response study (Figure 2) in order to see “early” gene expression changes in response to drug challenge within 24h, a time point where no growth inhibition was evident ( Figure 2A), with “late” gene expression changes accompanying treatments at subsequent time points.
  • the “late” time point was 48h, prior to any overt toxicities emerging as the cells reached the EC50s of the compounds at 72h.
  • both PCA and hierarchical clustering indicate very high reproducibility within the data sets ( Figure 4). Also, according to both PCA and cluster analysis, a clear difference can be observed between the transcriptomic profiles exhibited by Fucoxanthin and LY-294002. LY-294002 produced more defined differences when compared to Fucoxanthin, indicating a more specific mechanism of action for LY- 294002.
  • Affymetrix Clariom S microarrays contain probe sets for both non-coding and coding genes.
  • FDR false discovery rate
  • EXAMPLE 5 Analysis of the TOD 25 aeries from LY-294002 and Fucoxanthin treatments
  • the top 25 expressed genes in response to LY-294002 at 24h and 48h were compared with those seen in Fucoxanthin treatments at the same time points ( Figure 7).
  • the top 25 expressed genes in response to Fucoxanthin at 24h and 48h were compared with those seen in LY-294002 treatments at the same time points ( Figure 8). Clear differences were seen between the gene expression profiles amongst the top 25 expressed genes in each treatment.
  • EXAMPLE 6 Pathways differentially modulated bv Fucoxanthin and LY-294002 treatments Following analysis of individual gene expression changes, we used WikiPathway analysis to obtain an overview of the main changes in signalling pathways characterising the response to the two compounds (Table 2).
  • Fucoxanthin has a transcriptomic effect on PI3K/Akt pathway, increasing the expression of 10 of its component genes after 24h, 5 of which are remain up-regulated after 48h treatment, while decreasing the expression of 24 genes after 24h, with 19 of these genes remaining downregulated after 48h treatment (p ⁇ 0.05 Benjamin Hochberg corrected Fisher exact test).
  • LY-294002 had no significant transcriptomic effect at the pathway level on the PI3K/Akt pathway (p>0.05 Benjamin Hochberg corrected Fisher exact test), even though it acts directly on this pathway by inhibition of PI3K. Only 4 genes at 24h and 8 genes at 48h were up-regulated from this large pathway while 17 and 19 genes, respectively, were down-regulated after 24h and 48h treatment (see Figure 10 for the wiring diagrams of the genes involved in PI3K/Akt pathway). In contrast, Fucoxanthin has a clear effect at 24h on the expression of components of the PI3K/Akt pathway, although this is not reflected by their continuing expression at 48h.
  • JAK2 modulates the PI3K/mTOR pathway (Rane and Reddy, 2000). Up-regulation of JAK2 could reflect a pro-proliferative role within the glioblastoma cells as they react to the growth inhibition caused by down-regulation of the PI3K pathway.
  • pro-proliferative genes Bcl-2, Serum/Glucocorticoid Regulated Kinase 1 (SGK1), Insulin like Growth Factor 1 Receptor (IGF1R) show similar induction patterns.
  • Serum/Glucocorticoid Regulated Kinase 1 (SGK1) up- regulation is of particular interest since this kinase has recently been shown to be a key survival kinase for glioblastoma stem cells (Kulkarni et al., 2018). This can be seen in detail in Figure 14.
  • SGK1 Serum/Glucocorticoid Regulated Kinase 1
  • Fucoxanthin has a marked transcriptomic effect on the Retinoblastoma pathway, downregulating all the genes in the pathway at 24h with a considerable number remaining down-regulated after 48h treatment.
  • LY-294002 similarly down-regulates this pathway, with 35 genes showing down-regulation at 24h, 19 of which remain down-regulated at the 48h treatment time ( Figure 11).
  • TP53 is the only gene up-regulated in both the PI3K/Akt and Retinoblastoma pathways, and this only in response to Fucoxanthin at 48h treatment. Many other signalling pathways were affected by both treatments, listed in Table 2. Amongst those of particular interest were the apoptosis and necrosis pathways, cell cycle and the EGFR pathways, elements of which characterise the U87MG growth response (Ghosh et al., 2005)
  • target-based drug discovery techniques e.g. fragment- based and structure-based drug discovery approaches
  • PI3K No proteins except isoforms of PI3K were identified using PIDGIN that also occurred within the set of up- or down-regulated genes seen using transcriptomics, and PI3K was only identified as a putative target for LY-294002, not Fucoxanthin or Fucoxanthinol. Additional proteins showing putative LY-294002 binding included Topoisomerase 1 and the GABA receptor P subunit. A further protein, the kinase PIM1 , was identified as a weak hit (seen in the transcriptomics data at 48h of LY-294002 treatment).
  • Connectivity Map is a method used routinely to compare the effects of drugs on gene expression space (Lamb et al., 2006). Besides providing clues to enable the determination of drug mode of action at a molecular level, the method also enables an objective comparison of drug properties (Alexander-Dann et al., 2018). Here, we used CMap to compare the gene expression “signatures” of LY-294002 and Fucoxanthin seen in our studies with U87MG cells, to drug-like compounds in CMap with similar gene expression signatures from other cells and tissues.
  • the gene expression signatures from U87MG cells treated with LY-294002 show very similar gene expression profiles to other PI3K drugs already deposited in CMap, including the PI3K pharmacological tools Quinostatin (which inhibits the lipid-kinase activity of the catalytic subunits of class la PI3Ks), and Wortmannin (a potent, selective and irreversible inhibitor of PI3K).
  • Quinostatin which inhibits the lipid-kinase activity of the catalytic subunits of class la PI3Ks
  • Wortmannin a potent, selective and irreversible inhibitor of PI3K
  • Fucoxanthin exhibits higher similarity to more compounds in the CMap archive with similar gene expression signatures (384 compounds, Figure 12), than does LY-294002 (182 compounds, Figure 12), possibly representing more interactions with cellular components.
  • An additional aspect of the method is the possibility of immediately determining the preferred subtype selectivity of the drugs required to treat drug-resistant cancers, in the case of GBM JAK2 selectivity over JAK1 or JAK3.
  • LY-294002 For LY-294002, within 24h of treatment at the 72h EC50, a clear gene expression pattern is seen in response to the drug. The pattern observed for U87MG cells parallels that seen when other established cancer cell lines are treated with LY-294002. Moreover, many of these “early” changes are recapitulated at the “late” 48h time point, indicative of a sustained drug response to LY-294002: over 44% of highly induced genes are shared at 24h and 48h of treatment. Even more distinctively, 61% of the down- regulated genes at 24h remain down-regulated at 48h. For Fucoxanthin, treatments at the 72h EC50 for24h and 48h show less correspondence, with only 28% of the highly induced genes seen at 24h remaining at 48h.
  • IGF1R Insulin like Growth Factor 1 Receptor
  • BCL2L11 and Serum/Glucocorticoid Regulated Kinase 1 can be seen, all of which can be involved in growth promotion and cell proliferation (Basnet et al., 2018; Peng et al., 2016).
  • the features of cell proliferation and growth promotion are shared by the majority of genes up-regulated by LY-294002, including IGF-1 R (Gariboldi et al., 2010; Zhou et al., 2016), IL-6 (Jin et al., 2012) (Qiu et al., 2013; West et al., 2018) , BAG-1 (Roth et al., 2000), IRS2 (Knobbe and Reifenberger, 2003) ( Figure 13).
  • a primary drug treatment is the “first compound” treatment used to generate the Gene Expression Index.
  • Treatments were performed with LY-294002, a PI3K inhibitor, and PF-02545920, a phosphodiesterase (PDE) inhibitor. All drug treatments were carried out on the three glioblastoma cell lines U87MG, T98G and A172. Results of this experiment can be seen in Figure 16.
  • PF02545920 inhibits the proliferation of glioblastoma cells indicates that it can be repositioned for glioblastoma and potentially other cancers.
  • Gene Expression Index we have developed for this drug using 3 different glioblastoma cells (A172, T98G and U87MG) highlights the induction of several new genes that may encode induced drug targets, drugs for which could be used in combination with PF-02545920.
  • U87 cells were treated with the PI3K inhibitor LY-294002 for 24 hours and 48 hours, giving two Gene Expression Indices from the two time points. All the expressed genes (in this case 18,316 genes) were ranked from highest (most induced, Rank 1) to lowest (most repressed, Rank 18,316). Further examples of GEIs produced by drug treatments were also generated with another drug, PF-02545920, as a primary treatment. Cells from U87MG, T98G and A172 cell lines were treated with PF-02545920 for 24 hours. Expression Indices were created for each cell type.
  • the most induced genes represent those genes that the inhibited cells express most, in response to inhibition by primary treatments.
  • the “Top 300” of the highly expressed genes from the two treatments (LY-294002 and PF-02545920) treatment are shown below in Table 3.
  • the “Top 48” are shown in Figure 20.
  • Topic 300 genes that the glioblastoma cells express to survive the treatment, which we call “survival genes”, amongst which are many novel drug targets.
  • Drug targets for which there already exist drugs or exploratory compounds can be identified amongst the Top 300 induced genes.
  • a tag indicates genes that code for protein targets which already have clinical candidate drugs available for them.
  • a “*” tag indicates genes which code for targets with medicinal chemistry ligands.
  • a “ ⁇ ” tag indicates targets which are relatively unknown, and the “ ⁇ ” tag indicates genes which remain to be characterized as either biological or chemical targets. The remaining genes have a biological rationale as targets (i.e.
  • EXAMPLE 14 Experimental validation of emerging drug targets Examining the Gene Expression Index induced by a primary drug treatment allows us to identify a selection of novel, drug-induced targets.
  • Drug targets identified from the Top 300 Genes lists in Example 13 were experimentally validated in three glioblastoma cell lines - U87MG, T98G and A172.
  • JAK2 and SIK1 Two such targets, JAK2 and SIK1 , have been investigated.
  • LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway. Mol. Med. Report. 5, 575-579.
  • Apatinib exerts antitumour effects on ovarian cancer cells. Gynecol. Oncol. 153, 165-174.
  • Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002. J. Biol. Chem. 280, 13728-13734.
  • Interferon regulatory factor 7 regulates glioma stem cells via interleukin-6 and Notch signalling. Brain 135, 1055-1069.
  • VHL tumour suppressor protein regulates tumourigenicity of U87-derived glioma stem-like cells by inhibiting the JAK/STAT signalling pathway. Int. J. Oncol. 42, 881-886.
  • Fucoxanthin Activates Apoptosis via Inhibition of PI3K/Akt/mTOR Pathway and Suppresses Invasion and Migration by Restriction of p38-MMP-2/9 Pathway in Human Glioblastoma Cells. Neurochem. Res. 41, 2728-2751.
  • CHAF1A Over-expression of CHAF1A promotes cell proliferation and apoptosis resistance in glioblastoma cells via AKT/F0X03a/Bim pathway. Biochem. Biophys. Res. Commun. 469, 1111-1116.
  • a next generation connectivity map L1000 platform and the first 1 ,000,000 profiles. Cell 171, 1437-1452.e17.

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Abstract

L'invention concerne un procédé d'identification de cibles pharmacopotentielles pour une polythérapie anticancéreuse, dans lequel procédé, les cellules d'essai sont mises en contact avec un composé, et une cible pharmacopotentielle est sélectionnée parmi les gènes dont la transcription est affectée. L'invention concerne également un procédé de fourniture d'une combinaison thérapeutique anticancéreuse, ainsi qu'une combinaison thérapeutique telle qu'identifiée par ce procédé, et ses procédés d'utilisation dans le traitement ou la prévention du cancer. Des exemples de cibles thérapeutiques sont fournis par ce procédé par l'intermédiaire des utilisations d'un inhibiteur de la signalisation de la phosphoinositide 3-kinase (RISK) et/ou d'un inhibiteur de l'activité ou de la fonction de la phosphodiestérase (PDE).
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