WO2018228990A1 - Inhibiteurs de kinases dépendantes des cyclines 4/6 destinés à être utilisés dans des méthodes de traitement du cancer - Google Patents

Inhibiteurs de kinases dépendantes des cyclines 4/6 destinés à être utilisés dans des méthodes de traitement du cancer Download PDF

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WO2018228990A1
WO2018228990A1 PCT/EP2018/065349 EP2018065349W WO2018228990A1 WO 2018228990 A1 WO2018228990 A1 WO 2018228990A1 EP 2018065349 W EP2018065349 W EP 2018065349W WO 2018228990 A1 WO2018228990 A1 WO 2018228990A1
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cancer
crebbp
inhibitor
individual
cdk4
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Rachael NATRAJAN
Barrie PECK
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The Institute Of Cancer Research: Royal Cancer Hospital
Breast Cancer Now
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates cyclin dependent kinase 4/ 6 inhibitors for use in methods of treating an individual with a cancer
  • CDK4/ 6 inhibitors are a proven therapeutic strategy for oestrogen receptor positive (ER+) breast cancers (BC) .
  • ER+ oestrogen receptor positive
  • BC breast cancers
  • the molecular determinants of sensitivity and resistance to CDK4/6 inhibition are unclear .
  • the present invention rises from work to identify further patient populations who would benefit from treatment with CDK4/6 inhibitors, such as Palbociclib.
  • CDK4/6 inhibitors such as Palbociclib.
  • Recent next generation sequencing studies have comprehensively mapped the genetic landscape of breast cancers and revealed that only a small number of genes are
  • the present invention utilized a functional genomics approach silencing the 200 most frequently mutated genes in breast cancer in 3 dimensional (3D) spheroid cultures to more accurately recapitulate in vivo-like conditions of solid tumours, using the MCF10A progression series cell line panel as a model of disease progression.
  • 3D 3 dimensional
  • a second targeted validation screen showed that silencing of a cohort of these genes, including the histone acetyltransferase CREBBP, promoted growth in 3D but had limited effect under traditional 2D culture conditions in both the MCF10 progression series and a larger panel of triple negative cell line models.
  • abemaciclib in short term spheroid assays was assessed. This resulted in a clear enhancement of sensitivity in CREBBP- null cells compared to wild-type. The observed increased sensitivity was further enhanced in combination with paclitaxel, suggesting a Gl/S- G2/M blockade may provide benefit in this model. Sensitivity to palbociclib was not observed in 2D culture, suggesting that hypoxic and nutrient gradients influence the spheroid response .
  • CREBBP is a bona fide tumour suppressor in up to a third of triple negative breast cancers
  • CREBBP-altered tumours display up-regulation of F0XM1, which alters cancer cell metabolism under nutrient stress conditions.
  • CREBBP-altered tumours are selectively sensitive to inhibitors that target F0XM1 activity, suggesting that this maybe a viable therapeutic approach for CREBBP altered cancers.
  • CREBBP- altered tumours display FOXM1 up-regulation and were selectively sensitive to CDK4/6 inhibition, therefore suggesting that either CREBBP -deficiency and/or FOXM1 up-regulation could be biomarkers for response to CDK4/6 inhibition.
  • references to CREBBP denote CREB binding protein having the HGNC ID: 2348.
  • F0XM1 Forkhead Box Ml protein having the HGNC ID: 3818.
  • the present invention provides a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for use in a method of treating an individual having a cancer characterised by CREB- binding protein (CREBBP) deficiency and/or up-regulation of FOXM1 expression .
  • CDK4/6 cyclin dependent kinase 4/6
  • the present invention provides a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for use in a method of treating an individual with a cancer characterised by CREB-binding protein (CREBBP) deficiency and/or up-regulation of FOXM1
  • CDK4/6 cyclin dependent kinase 4/6
  • CREBBP CREB-binding protein
  • the present invention provides the use of a cyclin dependent kinase 4/ 6 (CDK4/ 6) inhibitor in the manufacture of a medicament for the treatment of an individual with a cancer characterised by CREB-binding protein (CREBBP) deficiency and/or up- regulation of FOXM1 expression.
  • CDK4/ 6 cyclin dependent kinase 4/ 6
  • the present invention provides a kit comprising a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and instructions for using the CDK4/6 inhibitor for treating an individual with a cancer characterised by CREB-binding protein (CREBBP) deficiency and/or up-regulation of FOXM1 expression.
  • CDK4/6 cyclin dependent kinase 4/6
  • CREBBP CREB-binding protein
  • the present invention provides a method of selecting an individual having cancer for treatment with a CDK4/6 inhibitor, the method comprising:
  • the method further comprises administering a therapeutically effective amount of the CDK4/ 6 inhibitor to the individual .
  • the present invention provides a method of treating an individual having cancer, the method comprising:
  • the step of testing the sample to determine whether the cancer is mutated or deficient in CREBBP gene is performed on nucleic acid sequences obtained from an individual' cancerous or non-cancerous cells. Suitable techniques are well known in the art and include the use of direct sequencing,
  • RFLP restriction fragment length polymorphism
  • SSCP single-stranded conformation polymorphism
  • PCR amplification of specific alleles amplification of DNA target by PCR followed by a mini-sequencing assay, allelic discrimination during PCR
  • Genetic Bit Analysis pyrosequencing, oligonucleotide ligation assay, analysis of melting curves, testing for a loss of heterozygosity (LOH, next generation sequencing (NGS) techniques, single molecule sequencing techniques and nanostrmg nCounter technology .
  • LH loss of heterozygosity
  • NGS next generation sequencing
  • the test is performed on RNA sequences obtained from an individual's cancerous or non-cancerous cells. In yet further embodiments, the test is performed on proteins obtained from an individual's cancerous or non-cancerous cells.
  • FIG. 1 Functional genomics screen identifies a novel tumour suppressor gene CREBBP whose silencing impacts growth in a 3D- specific manner.
  • A Heat-map displaying z-scores of the biological effect of gene ablation in the MCF10 progression series of spheroids (MCFlOa, (MCFlO)NeoT, (MCFIO)ATI, (MCF10 ) DCI S . com, (MCFIO)CAIA, (MCFIO)CAID and (MCFIO)CAIH) (light grey is increasing z-score, dark grey is decreasing z-score) .
  • B Correlation of screen of top 50 hits from ATI ( TP53 wild-type (WT) ) and CA1H ( TP53 mutant) cells rescreened in 2D and spheroids, showing spheroid specific hits.
  • C Representative DCIS.com spheroids +/- siRNA mediated silencing of CREBBP showing increased size and proliferation (Ki67) immunohistochemsitry (IHC) .
  • D Representative DCIS.com spheroids +/- siRNA mediated silencing of CREBBP showing increased size and proliferation (Ki67) immunohistochemsitry (IHC) .
  • FIG. 2 CREBBP expression is altered in triple negative breast cancers resulting in increased dependency on the pro-proliferative factor FOXMl .
  • A Distribution of CREBBP-deficiency (mutations and copy number loss of CREBBP) in TNBC from The Cancer Genome Atlas (TCGA) and METABRIC. 32% of TNBC's from TCGA and 25% TNBC s in METABRIC show CREBBP-deficiency .
  • B CREBBP mRNA expression in TNBC patients from TCGA, showing significant lower levels of CREBBP in deficient cells.
  • C Kaplan Meier curve showing significant
  • Figure 3 CREBBP deficient cells are sensitive to CDK4/6 inhibition.
  • TCGA Recurrent CREBBP alterations in Uterine corpus endometrial cancers (TCGA) show reciprocal alterations in FOXM1 , Cyclin Bl and Cyclin El protein expression (reverse phase protein array, RPPA) . The percentage (%) of total alterations per dataset is displayed. Mutations are highlighted in mid grey
  • TCGA show reciprocal alterations in FOXM1 , Cyclin Bl and Cyclin El protein expression (RPPA) .
  • the percentage (%) of total alterations per dataset is displayed. Mutations are highlighted in mid grey
  • FIG. 5 CREBBP is altered in other tumour types. CREBBP protein expression was assessed in multiple solid tumours including
  • Barplot represents the proportion of cases with no (absent) , low, medium and high expression using the
  • CDK4/6 inhibitors refer to compounds or substances that inhibit the expression levels or a biological activity of cyclin dependent kinase (CDK) 4 and 6. Some inhibitors are known and further examples may be found by the application of screening technologies to these targets.
  • CDK4/6 inhibitors examples include Palbociclib, Abermaciclib (LY2835219 ) , Ribociclib (LEE011), Trilaciclib (G1T28), Voruciclib (P1446A-05), NSC 625987, PD 0332991 isethionate or Ryuvidine .
  • references to Palbociclib denote 6-Acetyl- 8-cyclopentyl-5-methyl-2- ⁇ [5- ( 1-piperazinyl ) -2- pyridinyl ] amino ⁇ pyrido [ 2 , 3-d] pyrimidin-7 ( 8H) -one, having the
  • the ChemSpider report for Palbociclib, as well as its structure, can be found at:
  • references to Trilaciclib denote 2 ' - ⁇ [5- ( 4 -Methyl -1-piperazinyl ) -2-pyridinyl ] amino ⁇ -7 ' , 8 ' -dihydro- 6 ' H-spiro [cyclohexane-1, 9 ' -pyrazino [1 ' , 2 ' : 1, 5] pyrrolo [2,3- d] pyrimidin] -6 ' -one having the ChemSpider ID: 58825997.
  • references to NSC 625987 denote 1,4- Dimethoxy-9 ( ⁇ ) -acridinethione having the ChemSpider ID: 2274471.
  • the ChemSpider report for NSC 625987, as well as its structure, can be found at: http://www.chemspider.com/Chemical-
  • references to PD 0332991 isethionate or Palbociclib isethionate denote 6-acetyl-8-cyclopentyl-5-methyl-2- [ [5- (1-piperazinyl) -2-pyridinyl] amino ] pyrido [ 2 , 3-d] pyrimidin-7 (8H) - one isethionate salt having the ChemSpider ID: 9653501.
  • references to Ryuvidine denote 2-Methyl-5- [ (4-methylphenyl) amino] -1, 3-benzothiazole-4, 7-dione having the ChemSpider ID: 422633.
  • Another class of inhibitors useful for treatment of CREBBP mutated or deficient cancer/FOXMl up-regulated cancer includes nucleic acid inhibitors which inhibit activity or function by down-regulating production of active CREBBP polypeptide. This can be monitored using conventional methods well known in the art, for example by screening using real time PCR as described in the examples.
  • CREBBP or F0XM1 may be inhibited using anti-sense or RNAi technology.
  • anti-sense or RNAi technology The use of these approaches to down-regulate gene expression is now well-established in the art.
  • Anti-sense oligonucleotides may be designed to hybridise to the complementary sequence of nucleic acid, pre-mRNA or mature mRNA, interfering with the production of the base excision repair pathway component so that its expression is reduced or completely or substantially completely prevented.
  • anti-sense techniques may be used to target control sequences of a gene, e.g. in the 5' flanking sequence, whereby the anti-sense oligonucleotides can interfere with expression control sequences.
  • the construction of anti-sense sequences and their use is described for example in Peyman & Ulman, Chemical Reviews,
  • Oligonucleotides may be generated in vitro or ex vivo for
  • administration or anti-sense RNA may be generated in vivo within cells in which down-regulation is desired.
  • double-stranded DNA may be placed under the control of a promoter in a "reverse orientation" such that transcription of the anti-sense strand of the DNA yields RNA which is complementary to normal mRNA transcribed from the sense strand of the target gene.
  • the complementary anti- sense RNA sequence is thought then to bind with mRNA to form a duplex, inhibiting translation of the endogenous mRNA from the target gene into protein. Whether or not this is the actual mode of action is still uncertain. However, it is established fact that the technique works.
  • the complete sequence corresponding to the coding sequence in reverse orientation need not be used. For example fragments of sufficient length may be used. It is a routine matter for the person skilled in the art to screen fragments of various sizes and from various parts of the coding or flanking sequences of a gene to optimise the level of anti-sense inhibition. It may be advantageous to include the initiating methionine ATG codon, and perhaps one or more nucleotides upstream of the initiating codon. A suitable fragment may have about 14-23 nucleotides, e.g., about 15, 16 or 17 nucleotides .
  • RNAi RNA interference
  • Drosophila, plants, and mammals are known in the art (Fire, Trends Genet., 15: 358-363, 19999; Sharp, RNA interference, Genes Dev. 15: 485-490 2001; Hammond et al . , Nature Rev. Genet. 2: 110-1119, 2001; Tuschl, Chem. Biochem. 2: 239-245, 2001; Hamilton et al . , Science 286: 950-952, 1999; Hammond, et al . , Nature 404: 293-296, 2000; Zamore et al . , Cell, 101: 25-33, 2000; Bernstein, Nature, 409: 363- 366, 2001; Elbashir et al, Genes Dev., 15: 188-200, 2001;
  • RNA interference is a two-step process. First, dsRNA is cleaved within the cell to yield short interfering RNAs (siRNAs) of about 21-23nt length with 5' terminal phosphate and 3' short overhangs ( ⁇ 2nt) .
  • siRNAs short interfering RNAs
  • the siRNAs target the corresponding mRNA sequence
  • RNAi may also be efficiently induced using chemically synthesized siRNA duplexes of the same structure with 3 '-overhang ends (Zamore et al, Cell, 101: 25-33, 2000) . Synthetic siRNA duplexes have been shown to specifically suppress expression of endogenous and
  • heterologous genes in a wide range of mammalian cell lines (Elbashir et al, Nature, 411: 494-498, 2001) .
  • nucleic acid is used which on
  • transcription produces a ribozyme, able to cut nucleic acid at a specific site and therefore also useful in influencing gene
  • Small RNA molecules may be employed to regulate gene expression. These include targeted degradation of mRNAs by small interfering RNAs (siRNAs), post transcriptional gene silencing (PTGs),
  • miRNAs micro-RNAs
  • targeted transcriptional gene silencing mRNAs
  • Double-stranded RNA (dsRNA) -dependent post transcriptional silencing also known as RNA interference (RNAi)
  • RNAi RNA interference
  • a 20-nt siRNA is generally long enough to induce gene-specific silencing, but short enough to evade host response. The decrease in expression of targeted gene products can be
  • siRNAs interfering RNAs
  • miRNAs miRNAs
  • RNAi triggering mRNA elimination
  • siRNA are derived by processing of long double stranded RNAs and when found in nature are typically of exogenous origin.
  • miRNA Micro-interfering RNAs
  • siRNA are endogenously encoded small non-coding RNAs, derived by processing of short hairpins.
  • siRNA and miRNA can inhibit the translation of mRNAs bearing partially complimentary target sequences without RNA cleavage and degrade mRNAs bearing fully complementary sequences .
  • the siRNA ligands are typically double stranded and, in order to optimise the effectiveness of RNA mediated down-regulation of the function of a target gene, it is preferred that the length of the siRNA molecule is chosen to ensure correct recognition of the siRNA by the RISC complex that mediates the recognition by the siRNA of the mRNA target and so that the siRNA is short enough to reduce a host response.
  • miRNA ligands are typically single stranded and have regions that are partially complementary enabling the ligands to form a hairpin.
  • miRNAs are RNA genes which are transcribed from DNA, but are not translated into protein. A DNA sequence that codes for a miRNA gene is longer than the miRNA. This DNA sequence includes the miRNA sequence and an approximate reverse complement.
  • the miRNA sequence and its reverse-complement base pair to form a partially double stranded RNA segment.
  • the design of microRNA sequences is discussed in John et al, PLoS Biology, 11(2), 1862- 1879, 2004.
  • the RNA ligands intended to mimic the effects of siRNA or miRNA have between 10 and 40 ribonucleotides (or synthetic analogues thereof), more preferably between 17 and 30 ribonucleotides, more preferably between 19 and 25 ribonucleotides and most preferably between 21 and 23 ribonucleotides.
  • the molecule may have symmetric 3' overhangs, e.g. of one or two ( ribo ) nucleotides , typically a UU of dTdT 3' overhang.
  • symmetric 3' overhangs e.g. of one or two ( ribo ) nucleotides , typically a UU of dTdT 3' overhang.
  • siRNA and miRNA sequences can be synthetically produced and added exogenously to cause gene downregulation or produced using expression systems (e.g. vectors) .
  • expression systems e.g. vectors
  • the siRNA is synthesized synthetically.
  • Longer double stranded RNAs may be processed in the cell to produce siRNAs (e.g. see Myers, Nature Biotechnology, 21: 324-328, 2003) .
  • the longer dsRNA molecule may have symmetric 3' or 5 ' overhangs, e.g. of one or two (ribo) nucleotides , or may have blunt ends.
  • the longer dsRNA molecules may be 25 nucleotides or longer.
  • the longer dsRNA molecules are between 25 and 30 nucleotides long. More preferably, the longer dsRNA molecules are between 25 and 27 nucleotides long. Most preferably, the longer dsRNA molecules are 27 nucleotides in length.
  • dsRNAs 30 nucleotides or more in length may be expressed using the vector pDECAP (Shinagawa et al . , Genes and Dev., 17: 1340-5, 2003) .
  • shRNAs are more stable than synthetic siRNAs.
  • a shRNA consists of short inverted repeats separated by a small loop sequence. One inverted repeat is complimentary to the gene target.
  • the shRNA is processed by DICER into a siRNA which degrades the target gene mRNA and suppresses expression.
  • the shRNA is produced endogenously (within a cell) by transcription from a vector.
  • shRNAs may be produced within a cell by transfecting the cell with a vector encoding the shRNA sequence under control of a RNA polymerase III promoter such as the human HI or 7SK promoter or a RNA polymerase II promoter.
  • the shRNA may be synthesised exogenously (in vitro) by transcription from a vector.
  • the shRNA may then be introduced directly into the cell.
  • the shRNA sequence is between 40 and 100 bases in length, more preferably between 40 and 70 bases in length.
  • the stem of the hairpin is preferably between 19 and 30 base pairs in length.
  • the stem may contain G-U pairings to
  • the siRNA, longer dsRNA or miRNA is produced endogenously (within a cell) by transcription from a vector.
  • the vector may be introduced into the cell in any of the ways known in the art.
  • expression of the RNA sequence can be any of the ways known in the art.
  • tissue specific promoter regulated using a tissue specific promoter.
  • the siRNA, longer dsRNA or miRNA is produced exogenously (in vitro) by transcription from a vector.
  • siRNA molecules may be synthesized using standard solid or solution phase synthesis techniques, which are known in the art.
  • Linkages between nucleotides may be phosphodiester bonds or alternatives, e.g., linking groups of the formula P(0)S, (thioate) ; P(S)S, (dithioate) ; P(0)NR'2; P(0)R'; P(0)OR6; CO; or CONR'2 wherein R is H (or a salt) or alkyl (1-12C) and R6 is alkyl (1-9C) is joined to adjacent nucleotides through-O-or-S- .
  • Modified nucleotide bases can be used in addition to the naturally occurring bases, and may confer advantageous properties on siRNA molecules containing them.
  • modified bases may increase the stability of the siRNA molecule, thereby reducing the amount required for silencing.
  • the provision of modified bases may also provide siRNA molecules, which are more, or less, stable than unmodified siRNA.
  • modified nucleotide base' encompasses nucleotides with a covalently modified base and/or sugar.
  • modified nucleotides include nucleotides having sugars, which are covalently attached to low molecular weight organic groups other than a hydroxyl group at the 3 'position and other than a phosphate group at the 5 'position.
  • modified nucleotides may also include
  • 2 ' substituted sugars such as 2'-0-methyl- ; 2-O-alkyl ; 2-0-allyl ; 2'-S-alkyl; 2'-S-allyl; 2'-fluoro- ; 2 ' -halo or 2; azido-ribose , carbocyclic sugar analogues a-anomeric sugars; epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars and sedoheptulose .
  • Modified nucleotides include alkylated purines and pyrimidines, acylated purines and pyrimidines, and other heterocycles . These classes of pyrimidines and purines are known in the art and include pseudoisocytosine , N4 , 4-ethanocytosine , 8- hydroxy-N6-methyladenine , 4-acetylcytosine, 5- (carboxyhydroxylmethyl) uracil, 5 fluorouracil , 5-bromouracil , 5-carboxymethylaminomethyl-2- thiouracil, 5-carboxymethylaminomethyl uracil, dihydrouracil , inosine, N6-isopentyl-adenine, 1- methyladenine , 1- methylpseudouracil , 1-methylguanine , 2 , 2-dimethylguanine,
  • Antibodies may be employed in the present invention as an example of a class of inhibitor useful for treating CREBBP gene mutated or deficient cancer, and more particularly as inhibitors of FOXMl. They may also be used in the methods disclosed herein for assessing an individual having cancer or predicting the response of an individual having cancer, in particular for determining whether the individual has the CREBBP gene mutated or deficient cancer or cancer
  • the term "antibody” includes an immunoglobulin whether natural or partly or wholly synthetically produced.
  • the term also covers any polypeptide or protein comprising an antibody binding domain.
  • Antibody fragments which comprise an antigen binding domain are such as Fab, scFv, Fv, dAb, Fd; and diabodies. It is possible to take monoclonal and other antibodies and use techniques of recombinant DNA technology to produce other antibodies or chimeric molecules, which retain the specificity of the original antibody. Such techniques may involve introducing DNA encoding the immunoglobulin variable region, or the complementarity determining regions (CDRs), of an antibody to the constant regions, or constant regions plus framework regions, of a different immunoglobulin. See, for instance, EP 0 184 187 A, GB 2,188,638 A or EP 0 239 400 A.
  • Antibodies can be modified in a number of ways and the term
  • antibody molecule should be construed as covering any specific binding member or substance having an antibody antigen-binding domain with the required specificity. Thus, this term covers antibody fragments and derivatives, including any polypeptide comprising an immunoglobulin binding domain, whether natural or wholly or partially synthetic. Chimeric molecules comprising an immunoglobulin binding domain, or equivalent, fused to another polypeptide are therefore included. Cloning and expression of chimeric antibodies are described in EP 0 120 694 A and EP 0 125 023 A. It has been shown that fragments of a whole antibody can perform the function of binding antigens.
  • binding fragments are (i) the Fab fragment consisting of VL, VH, CL and CHI domains; (ii) the Fd fragment consisting of the VH and CHI domains; (iii) the Fv fragment consisting of the VL and VH domains of a single antibody;
  • F(ab')2 fragments a bivalent fragment comprising two linked Fab fragments
  • scFv single chain Fv molecules
  • Fv, scFv or diabody molecules may be stabilised by the incorporation of disulphide bridges linking the VH and VL domains
  • Minibodies comprising a scFv joined to a CH3 domain may also be made (Hu et al, Cancer Res., 56: 3055-3061, 1996) .
  • Preferred antibodies used in accordance with the present invention are isolated, in the sense of being free from contaminants such as antibodies able to bind other polypeptides and/or free of serum components. Monoclonal antibodies are preferred for some purposes, though polyclonal antibodies are within the scope of the present invention .
  • the reactivities of antibodies on a sample may be determined by any appropriate means. Tagging with individual reporter molecules is one possibility.
  • the reporter molecules may directly or indirectly generate detectable, and preferably measurable, signals.
  • the linkage of reporter molecules may be directly or indirectly, covalently, e.g. via a peptide bond or non-covalently . Linkage via a peptide bond may be as a result of recombinant expression of a gene fusion encoding antibody and reporter molecule.
  • One favoured mode is by covalent linkage of each antibody with an individual fluorochrome, phosphor or laser exciting dye with spectrally isolated absorption or emission characteristics. Suitable fluorochromes include
  • Suitable chromogenic dyes include diaminobenzidine .
  • Other reporters include macromolecular colloidal particles or particulate material such as latex beads that are coloured, magnetic or paramagnetic, and biologically or chemically active agents that can directly or indirectly cause detectable signals to be visually observed, electronically detected or otherwise recorded.
  • These molecules may be enzymes which catalyse reactions that develop or change colours or cause changes in electrical properties, for example. They may be molecularly excitable, such that electronic transitions between energy states result in characteristic spectral absorptions or emissions. They may include chemical entities used in conjunction with biosensors. Biotin/avidin or biotin/streptavidin and alkaline phosphatase detection systems may be employed.
  • Antibodies according to the present invention may be used in screening for the presence of a polypeptide, for example in a test sample containing cells or cell lysate as discussed, and may be used in purifying and/or isolating a polypeptide according to the present invention, for instance following production of the polypeptide by expression from encoding nucleic acid. Antibodies may modulate the activity of the polypeptide to which they bind and so, if that polypeptide has a deleterious effect in an individual, may be useful in a therapeutic context (which may include prophylaxis) .
  • the present invention provides methods and medical uses for the treatment of CREBBP deficient or mutated cancers and/or FOXM1 up- regulated cancers with CDK4/6 inhibitors.
  • a CREBBP deficient or mutated cancer/FOXMl up-regulated cancer may be identified as such by testing a sample of cancer cells from an individual, for example to determine whether the CREBBP gene contains one or more mutations.
  • cancers with CREBBP mutations include breast cancer, lung cancer, follicular lymphoma, diffuse large B cell lymphoma, cutaneous squamous cell carcinoma, bladder cancer, uterine
  • the cancer may be characterised by an up-regulation of FOXMl expression.
  • Types of cancer that may be treated include cancer triple negative breast cancer (TNBC) , i.e. breast cancer that is oestrogen receptor- negative, progesterone receptor-negative and HER2 receptor-negative , or basal breast cancer, for example where the cancer lacks ER, PR and HER2 positivity, e.g. as assessed by routine
  • cancers treatable according to the present invention may also be CREBBP deficient.
  • Other types of cancer that may be CREBBP deficient include oesphogeal cancer, bladder cancer or lung cancer ( Figure 4A) .
  • the cancers treatable according to the present invention may also be CREBBP deficient.
  • the CREBBP-deficient cancer is characterised by one or more CREBBP gene mutation (s) or defects (s) occurring in somatic pre-cancerous or cancerous cells.
  • s CREBBP gene mutation
  • defects s
  • the CREBBP deficient cancer is characterised by one or more CREBBP gene mutation (s) occurring in the germ line of the individual patient.
  • s CREBBP gene mutation
  • a CREBBP deficient or mutated cancer may be identified as such by testing a sample of cancer cells from an individual to determine the expression of the CREBBP gene to evaluate whether expression of the protein is absent or at a reduced level compared to normal. The same approaches may be employed to determine whether the cancer is characterised by up-regulation of FOXMl expression.
  • the CREBBP-deficient cancer is characterised by the cancer cells having a defect in or the cancer cells exhibiting epigenetic inactivation of a CREBBP gene, or loss of protein function.
  • a cancer may be identified as a CREBBP deficient cancer and/or characterised by up-regulation of FOXMl expression by determining the activity of the CREBBP and/or FOXMl polypeptides in a sample of cells from an individual.
  • the sample may be of normal cells from the individual where the individual has a mutation in the CREBBP gene or the sample may be of cancer cells, e.g. where the cells forming a tumour exhibit defects in CREBBP activity.
  • Activity may be determined relative to a control, for example in the case of defects in cancer cells, a relative to non-cancerous cells,
  • the activity of the CREBBP or FOXMl genes may be determined by using techniques well known in the art such as Western blot analysis, immunohistology, chromosomal abnormalities, enzymatic or DNA binding assays, and plasmid-based assays .
  • the sample may be of normal cells from the individual where the individual has a mutation in the CREBBP gene or the sample may be cancer cells, e.g. where the cells forming a tumour contain one o more CREBBP gene mutations .
  • Activity may be determined relative a control, for example in the case of defects in cancer cells, relative to non-cancerous cells, preferably from the same tissue.
  • the determination of CREBBP gene expression may involve determining the presence or amount of CREBBP gene mRNA in a sample. Methods for doing this are well known to the skilled person. By way of example, they include determining the presence of CREBBP gene mRNA (i) using a labelled probe that is capable of hybridising to the CREBBP gene nucleic acid; and/or (ii) using PCR involving one or more primers based on a CREBBP gene nucleic acid sequence to determine whether the CREBBP gene transcript is present in a sample.
  • the probe may also be immobilised as a sequence included in a microarray. The same approaches may be employed to determine whether the cancer is characterised by up-regulation of FOXMl expression.
  • detecting CREBBP gene mRNA is carried out by extracting RNA from a sample of the tumour and measuring expression of one or more CREBBP gene specifically using quantitative real time RT-PCR.
  • the expression of CREBBP gene could be assessed using RNA extracted from a tumour sample using microarray analysis, which measures the levels of mRNA for a group of genes using a plurality of probes immobilised on a
  • nanostring nCounter technology which is useful for formalin fixed degraded material.
  • a cancer may be identified as CREBBP by determining the presence in a cell sample from an individual's tumour of one or more chromosomal abnormalities, for example deletions in part or loss of entire chromosomes, corresponding to gene loss.
  • Chromosomal abnormalities may be visualised through any karyotyping technique known in the art, including but not limited to Giemesa staining, quinacrine staining, Hoechst 33258 staining, DAPI ( 4 ' - 6-diamidino-2-phenylindole ) staining, daunomycin staining, and fluorescence in situ hybridization.
  • a cancer may be identified as a CREBBP
  • deficient cancer by determining the presence in a cell sample from the individual of one or more variations, for example, polymorphisms or mutations, in a nucleic acid encoding a CREBBP polypeptide.
  • Sequence variations such as mutations and polymorphisms may include a deletion, insertion or substitution of one or more nucleotides, relative to the wild-type nucleotide sequence.
  • the one or more variations may be in a coding or non-coding region of the nucleic acid sequence and may reduce or abolish the expression or function of the CREBBP gene.
  • the variant nucleic acid may encode a variant polypeptide which has reduced or abolished activity or may encode a wild-type polypeptide which has little or no expression within the cell, for example through the altered activity of a regulatory element.
  • a variant nucleic acid may have one or more mutations or polymorphisms relative to the wild-type sequence.
  • the present invention the present invention the
  • determination of whether a patient has a CREBBP cancer can be carried out by analysis of CREBBP protein expression, for example by examining whether levels of CREBBP protein are supressed.
  • the presence or amount of CREBBP protein may be determined using a binding agent capable of specifically binding to the CREBBP protein, or fragments thereof.
  • a preferred type of CREBBP protein binding agent is an antibody capable of specifically binding the CREBBP protein or fragment thereof.
  • the antibody may be labelled to enable it to be detected or capable of detection following reaction with one or more further species, for example using a secondary antibody that is labelled or capable of producing a detectable result, e.g. in an ELISA type assay.
  • a labelled binding agent may be employed in a western blot to detect CREBBP protein.
  • the same approaches may be employed to determine whether the cancer is characterised by up-regulation of FOXMl expression by measuring the amount of FOXMl protein in a sample ( Figure 2F) .
  • the method for determining the presence of a CREBBP protein may be carried out on tumour samples, for example using immunohistochemical (IHC) analysis.
  • IHC analysis can be carried out using paraffin fixed samples or frozen tissue samples, and generally involves staining the samples to highlight the presence and location of the CREBBP protein.
  • the present invention provides an assay comprising :
  • this many also entail measuring or quantifying measuring both CREBBP and F0XM1 expression or quantifying to determine whether the cancer is also characterised by up-regulation of FOXM1 expression and a deficiency in CREBBP expression.
  • the present invention also includes methods of screening candidate compounds to find CDK4/6 inhibitors. Accordingly, methods of screening may be carried out for identifying candidate agents that are capable of inhibiting CDK4/6, for subsequent use of development as agents for the treatment of a cancer characterised by a CREBBP gene mutation or deficiency or up-regulation of F0XM1 expression. Conveniently, this may be done in an assay buffer to help the components of the assay interact, and in a multiple well format to test a plurality of candidate agents. The activity of CDK4/6 can then be determined in the presence and absence of the one or more candidate compounds to determine whether a given candidate is a CDK4/6 inhibitor.
  • the candidate agent may be a known inhibitor of one of the protein targets disclosed herein, an antibody, a peptide, a nucleic acid molecule or an organic or inorganic compound, e.g. molecular weight of less than 100 Da.
  • candidate agents that are compounds is preferred.
  • combinatorial library technology provides an efficient way of testing a potentially vast number of different substances for ability to modulate activity of a target protein.
  • Such libraries and their use are known in the art.
  • the present invention also specifically envisages screening candidate agents known for the treatment of other conditions, and especially other forms of cancer.
  • the agent in question may be tested to determine whether it is not lethal to normal cells or otherwise is suited therapeutic use. Following these studies, the agent may be tested to determine whether it is not lethal to normal cells or otherwise is suited therapeutic use. Following these studies, the agent may be
  • peptides are unsuitable active agents for oral compositions as they tend to be quickly degraded by proteases in the alimentary canal.
  • Mimetic design, synthesis and testing is generally used to avoid randomly screening large number of molecules for a target property.
  • the pharmacophore Once the pharmacophore has been found, its structure is modelled to according its physical properties, e.g. stereochemistry, bonding, size and/or charge, using data from a range of sources, e.g.
  • a template molecule is then selected onto which chemical groups which mimic the pharmacophore can be grafted.
  • the template molecule and the chemical groups grafted on to it can conveniently be selected so that the mimetic is easy to synthesise, is likely to be pharmacologically acceptable, and does not degrade in vivo, while retaining the biological activity of the lead compound.
  • the mimetics found by this approach can then be screened to see whether they have the target property, or to what extent they exhibit it. Further optimisation or modification can then be carried out to arrive at one or more final mimetics for in vivo or clinical testing.
  • the active agents herein for the treatment of CREBBP deficient/FOXMl up-regulated cancer may be administered alone, but it is generally preferable to provide them in pharmaceutical compositions that additionally comprise with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
  • pharmaceutical compositions that additionally comprise with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
  • pharmaceutical compositions are provided in Remington's Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins.
  • derivatives of the therapeutic agents includes salts, coordination complexes, esters such as in vivo hydrolysable esters, free acids or bases, hydrates, prodrugs or lipids, coupling partners.
  • Salts of the compounds of the invention are preferably
  • salts are known to those skilled in the art.
  • Compounds having acidic groups such as phosphates or sulfates, can form salts with alkaline or alkaline earth metals such as Na, K, Mg and Ca, and with organic amines such as triethylamine and Tris ( 2-hydroxyethyl ) amine .
  • Salts can be formed between compounds with basic groups, e.g., amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid.
  • Compounds having both acidic and basic groups can form internal salts.
  • Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques well known in the art.
  • Derivatives include prodrugs of the compounds which are convertible in vivo or in vitro into one of the parent compounds. Typically, at least one of the biological activities of compound will be reduced in the prodrug form of the compound, and can be activated by conversion of the prodrug to release the compound or a metabolite of it .
  • Coupled derivatives include coupling partners of the compounds in which the compounds is linked to a coupling partner, e.g. by being chemically coupled to the compound or physically associated with it.
  • coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an
  • Coupling partners can be covalently linked to compounds of the invention via an
  • pharmaceutically acceptable includes compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • the active agents disclosed herein for the treatment of CREBBP deficient cancer according to the present invention are preferably for administration to an individual in a "prophylactically effective amount” or a “therapeutically effective amount” (as the case may be, although prophylaxis may be considered therapy) , this being
  • the actual amount administered, and rate and time-course of administration, wi 11 depend on the nature and severity of what is being treated.
  • Prescription of treatment is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 20th Edition, 2000, Lippincott, Williams & Wilkins.
  • a composition may be administered alone or in combination with other treatments, either simultaneously or sequentially, dependent upon the condition to be treated.
  • formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of
  • Such methods include the step of bringing the active compound into association with a carrier which may constitute one or more accessory ingredients.
  • a carrier which may constitute one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • agents disclosed herein for the treatment of CREBBP deficient cancer may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired action, including but not limited to, oral (e.g. by
  • topical including e.g. transdermal, intranasal, ocular, buccal, and sublingual
  • pulmonary e.g. by inhalation or
  • insufflation therapy using, e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal,
  • intracapsular subcapsular, intraorbital, intraperitoneal,
  • intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal by implant of a depot, for example, subcutaneously or intramuscularly .
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants , buffers, preservatives, stabilisers,
  • bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient
  • aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's
  • concentration of the active compound in the solution is from about 1 ng/ml to about 10 mg/ml, for example from about 10 ng/ml to about 1 mg/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.
  • Compositions comprising agents disclosed herein for the treatment of CREBBP gene mutated or deficient cancer/FOXMl up-regulated cancer may be used in the methods described herein in combination with standard chemotherapeutic regimes or in conjunction with
  • radiotherapy As radiotherapy also leads to DNA strand breaks, causing severe DNA damage and leading to cell death, the combination of radiotherapy with CDK4/ 6 inhibitors offers the potential to lead to formation of double strand breaks from the single-strand breaks generated by the radiotherapy in tumor tissue. This combination could therefore lead to either more powerful therapy with the same radiation dose or similarly powerful therapy with a lower radiation dose, potentially avoiding some of the side effects with
  • chemotherapeutic agents include administration of a taxane, such as Paclitaxel, Docetaxel, Abraxane and Taxostere, eribulin, vinoebulin or a MCTl/4 inhibitor or a metabolic inhibitor or a monocarboxylase transporters
  • inhibitors such as AZD3965.
  • chemotherapeutic agents include Amsacrine
  • Ifosfamide (Mitoxana) , Irinotecan (CPT-11, Campto) , Leucovorin (folinic acid), Liposomal doxorubicin (Caelyx, Myocet) , Liposomal daunorubicin (DaunoXome®) Lomustine, Melphalan, Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin
  • Teniposide (Vuraon) , Thiotepa, Tioguanine (6-TG) (Lanvis), Topotecan (Hycamtin) , Treosulfan, Vinblastine (Velbe) , Vincristine (Oncovin) , Vindesine (Eldisine) or Vinorelbine (Navelbine) .
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • a suitable dose of the active compound is in the range of about 100 mg to about 250 mg per kilogram body weight of the subject per day.
  • the active compound is a salt, an ester, prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound, and so the actual weight to be used is increased proportionately.
  • CREBBP is a novel tumour suppressor gene
  • CREBBP regulates global gene transcription by altering the acetylation state of histones and non-histones and has been associated with the progression of several tumour types (Iyer, Ozdag et al . 2004, Dietze, Bowie et al . 2005, Mullighan, Zhang et al . 2011, Pasqualucci, Dominguez-Sola et al . 2011) .
  • TNBC's harbour genomic alterations in CREBBP (copy number (CN) loss and mutations) and associated with poor survival ( Figure 2A-C) .
  • TNBC's harbouring CREBBP genomic alterations have increased abundance of FOXMl and its downstream transcriptional targets (CCNB1, CCNE1, XRCC1 and BRCA2) ( Figure 2D) .
  • CREBBP-null cells are selectively dependent on FOXMl activation as they showed selective sensitivity to FOXMl transcriptional binding inhibitors ( Figure 2E) .
  • primary breast cancers with high FOXMl protein showed loss or low levels of CREBBP protein expression ( Figure 2F) .
  • CREBBP-deficient cells are sensitive to CDK4/6 inhibition
  • CREBBP-null isogenic cells show up-regulation of FOXMl and selective sensitivity to a number of CDK4/ 6 inhibitors including palbociclib and abemaciclib (Figure 3A) .
  • FOXMl is a downstream target of CDK4 and CDK6 (Anders, Ke et al . 2011) .
  • the observed increased sensitivity was further enhanced in combination with paclitaxel ( Figure 3B) , suggesting a G1/S-G2/M blockade may provide benefit in this model.
  • Sensitivity to palbociclib was not observed in 2D culture, suggesting that hypoxic and nutrient gradients influence the spheroid response.
  • CREBBP-deficient cells show metabolic re-wiring
  • CDK4/ 6 is known to activate FOXMl and supresses reactive oxygen species protecting cells from senescence.
  • metabolic plasticity influenced sensitivity of CREBBP-deficient cells to palbociclib in spheroid models.
  • our analysis showed that CREBBP-deficient spheroids derive approximately 50% of their energetic demands from acetate, compared to below 5% for CREBBP- ⁇ spheroids (Figure 4E) .
  • Figure 4E Rescue of the phenotype by addition of acetate highlighted dependency on the FOXMl axis.
  • acetate-based positron-emission tomography PET
  • X1 C- acetate imaging has been shown to be more sensitive and accurate than glucose-based PET for prostate cancer.
  • acetate- based tracers e.g. nc-acetate
  • the CREBBP/FOXMl axis is altered in multiple solid tumours
  • CREBBP-deficiency is associated with a poorer overall survival in uterine carcinomas ( Figure 4B) .
  • Analysis of data from TCGA identified that CREBBP deficient cancers show up-regulation of FOXM1 and its down-stream targets akin to triple-negative breast cancer ( Figure 4C) . This suggests CREBBP deficiency leads to FOXM1 up-regulation in multiple cancer types, all of which may benefit from CDK4/6 inhibitor treatment.
  • Figure 5A shows barplot representations of the proportion of cases with no (absent) , low, medium and high expression using the Allred scoring system, which Figure 5B provides representative immunohistochemistry images.

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Abstract

L'invention concerne l'utilisation d'inhibiteurs de kinases dépendantes des cyclines 4/6 dans des méthodes de traitement d'un individu atteint d'un cancer caractérisé par une déficience en protéine de liaison à CREB et/ou une régulation positive de l'expression de FOXM1, ainsi que des méthodes correspondantes de sélection et de traitement de patients pour un traitement.
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