WO2018224536A1 - Inhibiteurs de parp destinés à être utilisés pour le traitement du cancer - Google Patents

Inhibiteurs de parp destinés à être utilisés pour le traitement du cancer Download PDF

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WO2018224536A1
WO2018224536A1 PCT/EP2018/064873 EP2018064873W WO2018224536A1 WO 2018224536 A1 WO2018224536 A1 WO 2018224536A1 EP 2018064873 W EP2018064873 W EP 2018064873W WO 2018224536 A1 WO2018224536 A1 WO 2018224536A1
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cancer
sf3b1
inhibitor
parp inhibitor
individual
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PCT/EP2018/064873
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Rachael NATRAJAN
Christopher James LORD
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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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates a poly ADP ribose polymerase (PARP) inhibitor for use in a method of treating an individual with cancer which is mutated or deficient in the SF3B1 gene.
  • PARP poly ADP ribose polymerase
  • Regulated splicing of the cellular transcriptome is essential for normal growth and development. It involves removal of intronic DNA from pre-mRNA transcripts via the activity of a common set of small nuclear RNAs (snRNAs) and associated proteins which assemble together with into a complex known as the spliceosome. Aberrant expression of splicing patterns has been linked to oncogenic processes in cancer that arise from mutations in pre- mRNA splice sites or in the protein components of the splicing machinery.
  • snRNAs small nuclear RNAs
  • RNA splicing machinery such as SF3B1 in 15% of chronic lymphocytic leukaemias (CLL) , 10% of uveal melanomas, 4% of pancreatic cancers and 2% of breast cancers. These mutations have been shown to impact RNA splicing events in CLLs and uveal melanomas and breast cancers, and it is proposed that mis-spliced pre-mRNAs encode proteins that promote tumorigenesis and that these mutations result in neomorphic functions, and in some cases are associated with poor prognosis.
  • CLL chronic lymphocytic leukaemias
  • mis-spliced pre-mRNAs encode proteins that promote tumorigenesis and that these mutations result in neomorphic functions, and in some cases are associated with poor prognosis.
  • targeting represents a new paradigm in cancer therapy as it provides an important counterpart to targeting classical single gene drivers .
  • CLL chronic lymphocytic leukaemia
  • pancreatic cancer pancreatic cancer
  • uveal melanoma uveal melanoma
  • mucosal melanoma mucosal melanoma
  • breast cancer also occur at low
  • Hotspot mutations occur most frequently at amino acids R625, R626, H662, K666 and K700 ( Figure IB) . Mutations in these hotspot regions have been postulated as bona-fide drivers.
  • the present inventors investigated whether dysfunction in RNA splicing is implicated in SF3B1 mutant cancers and whether tumours harbouring these mutations could be therapeutically targeted.
  • Massively parallel RNA-sequencing of primary breast cancers identified consistent patterns of aberrant splicing in SF3B1 mutant tumours that validated in a re-analysis of RNA-sequencing data from The Cancer Genome Atlas (TCGA) .
  • TCGA Cancer Genome Atlas
  • the present inventors observed a core set of transcripts that are consistently aberrantly spliced in SF3B1 mutant tumours irrespective of tumour type, providing a surrogate or biomarker of mutation status.
  • the present inventors further investigated whether SF3B1 mutant cells could be exploited therapeutically by performing a 5-day high-throughput drug cell viability screen utilising K562 isogenic cell lines harbouring the SF3B1 K700E hotspot mutation that was confirmed by qRT-PCR to show the conserved signature of alternative splicing (Figure 3A-C) .
  • Further validation in long-term (14 day) clonogenic assays confirmed that SF3B1 K700E mutant cells are selectively sensitive to inhibition with a number of
  • references to SF3B1 denote Splicing Factor 3b Subunit 1 having the HGNC ID: 10768.
  • the HUGO Gene Symbol report for SF3B1 can be found at:
  • the present invention provides a poly ADP ribose polymerase (PARP) inhibitor for use in a method of treating an individual with cancer, which is mutated or deficient in the SF3B1 gene.
  • PARP poly ADP ribose polymerase
  • the present invention provides a poly ADP ribose polymerase (PARP) inhibitor for use in a method of treating an individual with cancer which is mutated or deficient in the SF3B1 gene, the method comprising:
  • PARP inhibitor to the individual with cancer which is mutated or deficient in the SF3B1 gene.
  • Examples of types of cancer in which there are known include mutations in the SF3B1 gene include myleodysplastic syndrome (MDS) , chronic lymphocytic leukaemia (CLL) , pancreatic cancer, uveal melanoma and breast cancer.
  • MDS myleodysplastic syndrome
  • CLL chronic lymphocytic leukaemia
  • pancreatic cancer pancreatic cancer
  • uveal melanoma uveal melanoma and breast cancer.
  • the present invention provides a method of selecting an individual having cancer for treatment with a poly ADP ribose polymerase (PARP) inhibitor, the method comprising:
  • the method may further comprises administering a therapeutically effective amount of the PARP inhibitor to the individual .
  • the present invention provides a method for treating an individual having cancer with a poly ADP ribose polymerase (PARP) inhibitor, the method comprising:
  • the step of testing the sample to determine whether the cancer is mutated or deficient in SF3B1 gene is performed on nucleic acid sequences obtained from an individual's cancerous or non-cancerous cells Suitable techniques are well known in the art and include the use of direct sequencing, hybridisation to a probe, restriction fragment length polymorphism (RFLP) analysis, single-stranded conformation polymorphism (SSCP) , 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
  • RFLP restriction fragment length polymorphism
  • SSCP single-stranded conformation polymorphism
  • PCR amplification of specific alleles amplification of DNA target by PCR followed
  • 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.
  • Figure 1 Recurrent SF3B1 mutations in cancer.
  • SF3B1 mutations are associated with signatures of differential splicing.
  • Figure 4 SF3B1 mutant cells show an impaired response to DNA damage. Representative immunofluorescence and quantification of ⁇ 2 ⁇ foci in A) K562 K700E and B) NALM6 H662Q isogenic cells +/- 4Gy irradiation, showing that SF3B1 mutant cells show impaired response to DNA damage, seen by the presence of ⁇ 2 ⁇ foci at 24 hours post radiation.
  • SF3B1 denote Splicing Factor 3b Subunit 1 having the HGNC ID: 10768.
  • Regulated splicing of the cellular transcriptome is essential for normal growth and development. It involves removal of intronic DNA from pre-mRNA transcripts via the activity of a common set of small nuclear RNAs (snRNAs) and associated proteins which assemble together with into a complex known as the spliceosome [ 1 ] ( Figure 1) . Aberrant expression of splicing patterns has been linked to oncogenic processes that arise from mutations in pre- mRNA splice sites or in the protein components of the splicing machinery themselves in multiple malignancies [2-4 ] .
  • snRNAs small nuclear RNAs
  • Figure 1 Aberrant expression of splicing patterns has been linked to oncogenic processes that arise from mutations in pre- mRNA splice sites or in the protein components of the splicing machinery themselves in multiple malignancies [2-4 ] .
  • SF3B1 hotspot mutations are also frequently found in solid cancers including, 10% of uveal melanomas mainly the R625 hotspot [11], 4% of pancreatic cancers, mainly the K700 hotspot [12] and 3% of breast cancers K700 hotspot [ 13-15 ] .
  • SF3B1 mutations have been associated with poor prognosis [ 16, 17] and impact RNA splicing events.
  • SF3B1 mutations are proposed to result in neomorphic functions [ 18 , 19] and that mis-spliced pre-mRNAs encode proteins that promote tumorigenesis [ 20 ] , however, evidence also suggests that SF3B1 hotspot mutations induce aberrant 3' splice site selection, leading to nonsense mediated decay (NMD) and subsequent down- regulation of about half of the aberrant mRNAs [21-24] .
  • NMD nonsense mediated decay
  • Spliceosomal gene mutations are known to drive hematopoietic stem-progenitor cell expansion in vivo[24, 25], however, it is unknown how these mutations contribute to tumorigenesis in solid cancers, given that inhibition of mutant SF3B1 does not inhibit proliferation [26] .
  • types of cancer in which there are known include mutations in the SF3B1 gene include
  • myleodysplastic syndrome MDS
  • AML acute myeloid leukaemia
  • CLL chronic lymphocytic leukaemia
  • pancreatic cancer uveal melanoma, breast cancer, mucosal melanoma, cutaneous melanoma, adenoid cystic carcinoma, acral melanoma, endometrial cancer, adenoid cystic carcinomas of the breast and salivary gland, bladder cancer, colorectal cancer, prostate cancer, lung cancer, medulloblastoma, ampullary carcinoma, hepatocellular carcinoma, Diffuse Large B-Cell Lymphoma, renal clear cell carcinoma, stomach adenocarcinoma, Cholangiocarcinoma, multiple myeloma, Esophagogastric Cancer, low grade glioma, Cervical cancer, colon adenocarcinoma, glioblastoma, mesothelioma, thymo
  • PARP inhibitors refer to compounds or substances that inhibit the expression levels or a biological activity of poly ADP ribose polymerase (PARP) .
  • PARP poly ADP ribose polymerase
  • PARP1 is a protein that is important for repairing single-strand breaks in DNA. If such nicks persist unrepaired until DNA is replicated (which must precede cell division) , then the
  • PARP inhibitors can cause multiple double strand breaks to form, and in tumours mutations these double strand breaks cannot be efficiently repaired, thereby leading to the death of the cells.
  • noncancerous cells do not replicate DNA as often as cancer cells, and generally have other homologous repair pathways working, the normal cells can survive PARP inhibition.
  • PARP inhibitors have an additional mode of action: localizing PARP proteins at sites of DNA damage, which has relevance to their anti-tumor activity. The trapped PARP protein-DNA complexes are highly toxic to cells because they block DNA replication. Small Molecule Inhibitors
  • PARP inhibitors examples include Olaparib (AZD2281), Rucaparib (AG014699) , Niraparib (MK4827), Talazoparib (BMN-673) , Veliparib (ABT-888), Iniparib (BSI 201), E7016, CEP 9722, BGB-290, E7449, AG-14361, INO-1001, A-966492, PJ34 HC1, UPF 1069, AZD2461,
  • references to "Olaparib” denote 1- (Cyclopropylcarbonyl) -4- [5- [ (3, 4-dihydro-4-oxo-l- phthalazinyl ) methyl ] -2-fluorobenzoyl ] piperazine , having the ChemSpider ID: 23343272.
  • the ChemSpider report for Olaparib, as well as its structure, can be found at:
  • Rucaparib (AG014699) denote 8-Fluoro-2- ⁇ 4- [ (methylamino ) methyl ] phenyl ⁇ -1 , 3 , 4 , 5-tetrahydro-6H- azepino [5, 4, 3-cd] indol-6-one having the ChemSpider ID: 8107584.
  • the ChemSpider report for Rucaparib, as well as its structure, can be found at: http://www.chemspider.com/Chemical- Structure .8107584.html .
  • references to "Niraparib” denote 2- ⁇ 4-[(3S)-3-Piperidinyl] phenyl ⁇ -2H-indazole-7-carboxamide having the ChemSpider ID: 24531930.
  • the ChemSpider report for ETP-46464, as well as the structure, can be found at
  • Niraparib may also be used in the form of Niraparib tosylate.
  • references to "Talazoparib” denote (8S, 9R) -5-Fluoro-8- (4-fluorophenyl) -9- (1-methyl-lH-l, 2, 4- triazol-5-yl)-2,7,8, 9-tetrahydro-3H-pyrido [ 4 , 3 , 2-de ] phthalazin-3- one having the ChemSpider ID: 28637772.
  • the ChemSpider report for Talazoparib, as well as the structure, can be found at:
  • references to "E7016” denote the PARP inhibitor with the IUPAC name 10- ( ( 4-Hydroxypiperidin-l- yl ) methyl ) chromeno [ 4 , 3 , 2-de ] phthalazin-3 ( 2H) -one .
  • references to "CEP 9722" denote 10- (Aminomethyl ) -4,5,6, 7-tetrahydro-lH-cyclopenta [a] pyrrolo [3,4- c] carbazole-1, 3 (2H) -dione having the ChemSpider ID: 8124051.
  • the ChemSpider report for CEP 9722, as well as the structure, can be found at: http://www.chemspider.com/Chemical- Structure.8124051.html .
  • references to BGB-290 denote the PARP inhibitor with the IUPAC name (lOaR) -2-Fluoro-5, 8, 9, 10, 10a, 11- hexahydro-10a-methyl-5, 6, 7a, 11- tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (7H) -one .
  • references to E7449 denotes the dual inhibitor of PARPl/2 and tankyrase 1/2 with the IUPAC name 8- ( 1 , 3-Dihydro-2H-isoindol-2-ylmethyl ) -1 , 2-dihydro-3H- pyridazino [ 3 , 4 , 5-de ] quinazolin-3-one .
  • the ChemSpider report for E7449, as well as the structure, can be found at
  • references to AG-14361 denotes the PARP inhibitor with the IUPAC name 2- ⁇ 4-
  • references to INO-1001 denotes the PARP inhibitor with the IUPAC name 3-Aminobenzamide .
  • references to A-966492 denotes the PARP inhibitor with the IUPAC name 2- ⁇ 2-Fluoro-4- [ (2S) -2- pyrrolidinyl ] phenyl ⁇ - ⁇ -benzimidazole-4-carboxamide .
  • references to PJ34 HC1 denotes the PARP inhibitor with the IUPAC name N 2 ,N 2 -Dimethyl-N- (6-oxo-5, 6-dihydro- 2-phenanthridinyl) glycinamide hydrochloride (1:1) .
  • references to UPF 1069 denotes the PARP inhibitor with the IUPAC name 5- (2-Oxo-2-phenylethoxy) - 1 (2H) -isoquinolinone .
  • the ChemSpider report for UPF 1069, as well as the structure, can be found at
  • references to AZD2461 denotes the PARP inhibitor with the IUPAC name 4- ⁇ 4-Fluoro-3- [ ( 4-methoxy-l- piperidinyl ) carbonyl ] benzyl ⁇ -1 ( 2H) -phthalazinone .
  • the ChemSpider report for AZD2461, as well as the structure, can be found at http : //www . chemspider . com/Chemical-
  • references to ME0328 denotes the PARP inhibitor with the IUPAC name 3- (4-Oxo-l, 4-dihydro-2- quinazolinyl) -N- [ (IS) -1-phenylethyl] propanamide .
  • references to BGP-15 2HC1 denotes the PARP inhibitor with the IUPAC name 3-Pyridinecarboximidamide , N- [2-hydroxy-3- (1-piperidinyl) propoxy] -, hydrochloride (1:2) .
  • references to NU1025 denotes the PARP inhibitor with the IUPAC name 8-Hydroxy-2-methyl-4 ( 1H) - quinazolinone .
  • references to NVP-TNKS656 denotes the Tankyrase and PARP inhibitor with the IUPAC name N- (Cyclopropylmethyl ) -2- [4- ( 4-methoxybenzoyl ) -1-piperidinyl ] -N- [ (4- oxo-1, 5,7, 8-tetrahydro-4H-pyrano [ 4 , 3-d] pyrimidin-2- yl) methyl] acetamide .
  • the ChemSpider report for NVP-TNKS 656 as well as the structure, can be found at
  • references to NMS-P118 denotes the PARP1 inhibitor with the IUPAC name 2- [1- (4, 4-
  • Another class of inhibitors useful for treatment of SF3B1 mutated or deficient cancer includes nucleic acid inhibitors which inhibit activity or function by down-regulating production of active PARP polypeptide. This can be monitored using
  • 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, 90:543-584, 1990 and Crooke, Ann. Rev. Pharmacol. Toxicol., 32:329-376, 1992.
  • 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
  • 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.
  • the complete sequence corresponding to the coding sequence in reverse orientation need not be used.
  • 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
  • RNA interference is a two-step process.
  • 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 target the corresponding mRNA sequence specifically for destruction (Zamore, Nature Structural Biology, 8, 9, 746-750, 2001.
  • RNAi may also be efficiently induced using chemically synthesized siRNA duplexes of the same structure with 3 '-overhang ends
  • 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 expression, e.g., see Kashani-Sabet & Scanlon, Cancer 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), developmentally regulated sequence-specific translational repression of mRNA by micro-RNAs (miRNAs), and targeted
  • Double- stranded RNA (dsRNA) -dependent post transcriptional silencing also known as RNA interference (RNAi)
  • RNAi Double- stranded RNA
  • 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 extensive with 90% silencing induced by a few molecules of siRNA.
  • RNA sequences are termed “short or small interfering RNAs” (siRNAs) or “microRNAs” (miRNAs) depending on their origin. Both types of sequence may be used to down- regulate gene expression by binding to complimentary RNAs and either triggering mRNA elimination (RNAi) or arresting mRNA translation into protein.
  • siRNA are derived by processing of long double stranded RNAs and when found in nature are typically of exogenous origin.
  • miRNA are examples of interfering RNAs
  • siRNA and miRNA can inhibit the
  • 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
  • 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
  • the molecule may have 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) .
  • 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.
  • 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) .
  • Another alternative is the expression of a short hairpin RNA molecule (shRNA) in the cell.
  • 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
  • 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 stabilise the hairpin structure.
  • 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 regulated using a tissue specific promoter.
  • the siRNA, longer dsRNA or miRNA is produced
  • 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
  • siRNA molecules containing them 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
  • 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
  • modified nucleotides may also include 2 ' substituted sugars such as 2'-0-methyl- ; 2-0- 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 .
  • 2 ' substituted sugars such as 2'-0-methyl- ; 2-0- 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 arab
  • 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,N4- ethanocytosine , 8-hydroxy-N6-methyladenine , 4-acetylcytosine, 5-
  • Antibodies may be employed in the present invention as an example of a class of inhibitor useful for treating SF3B1 gene mutated or deficient cancer, and more particularly as inhibitors of PARP . 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 SF3B1 gene mutated or deficient cancer that might be treatable according to the present
  • 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.
  • 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; (iv) the dAb fragment (Ward, E.S.
  • Fv, scFv or diabody molecules may be stabilised by the incorporation of disulphide bridges linking the VH and VL domains (Reiter et al, Nature Biotech, 14: 1239-1245, 1996) .
  • Minibodies comprising a scFv joined to a CH3 domain may also be made (Hu et al, Cancer Res., 56: 3055-3061, 1996) .
  • 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 fluorescein, rhodamine, phycoerythrin and Texas Red.
  • 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 SF3B1 gene deficient or mutated cancers with PARP inhibitors.
  • a SF3B1 gene deficient or mutated cancer may be identified as such by testing a sample of cancer cells from an individual, for example to determine whether the SF3B1 gene contains one or more mutations. Examples of cancers having SF3B1 deficiencies or mutations are set out in described above with reference to [3, 4, 9-20] . Thus, types of cancer in which there are known include mutations in the SF3B1 gene include
  • myleodysplastic syndrome MDS
  • AML acute myeloid leukaemia
  • CLL chronic lymphocytic leukaemia
  • pancreatic cancer uveal melanoma, breast cancer, mucosal melanoma, cutaneous melanoma, adenoid cystic carcinoma, acral melanoma, endometrial cancer, adenoid cystic carcinomas of the breast and salivary gland, bladder cancer, colorectal cancer, prostate cancer, lung cancer, medulloblastoma, ampullary carcinoma, hepatocellular carcinoma, Diffuse Large B-Cell Lymphoma, renal clear cell carcinoma, stomach adenocarcinoma, Cholangiocarcinoma, multiple myeloma, Esophagogastric Cancer, low grade glioma, Cervical cancer, colon adenocarcinoma, glioblastoma, mesothelioma, thymo
  • CLL chronic lymphocytic leukaemias
  • pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
  • the SF3Bl-deficient cancer is characterised by one or more SF3B1 gene mutation (s) or defects (s) occurring in somatic pre-cancerous or cancerous cells. While SF3B1 mutations are mostly believed to be somatic, there is some evidence SF3B1 mutations are associated with clonal hematopoiesis, e.g. as a result of ageing, and there may also be SF3B1 deficient cancers characterised by one or more SF3B1 gene mutation (s) occurring in the germ line of the individual patient.
  • a SF3B1 gene 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 SF3B1 gene to evaluate whether expression of the protein is absent or at a reduced level compared to normal .
  • the SF3B1-deficient cancer is characterised by the cancer cells having a defect in or the cancer cells exhibiting epigenetic inactivation of a SF3B1 gene, or loss of protein function.
  • a cancer may be identified as a SF3B1 deficient cancer by determining the activity of the SF3B1 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 SF3B1 gene or the sample may be of cancer cells, e.g. where the cells forming a tumour exhibit defects in SF3B1 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, preferably from the same tissue.
  • the activity of the SF3B1 gene may be determined by using techniques well known in the art such as Western blot analysis, immunoprecipitation, 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 SF3B1 gene or the sample may be of cancer cells, e.g. where the cells forming a tumour contain one or more SF3B1 gene mutations .
  • Activity may be determined relative to 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 SF3B1 gene expression may involve
  • determining the presence or amount of SF3B1 gene mRNA in a sample include determining the presence of SF3B1 gene mRNA (i) using a labelled probe that is capable of hybridising to the SF3B1 gene nucleic acid; and/or (ii) using PCR involving one or more primers based on a SF3B1 gene nucleic acid sequence to determine whether the SF3B1 gene transcript is present in a sample.
  • the probe may also be immobilised as a sequence included in a microarray. It is also possible to use quantitative PCR or nanostring nCounter technology to assess the downstream consequences of mutation, i.e. in the case of SF3B1 mutations alternative splicing of the 'core' set of transcripts we have identified to be alternatively spliced.
  • detecting SF3B1 gene mRNA is carried out by extracting RNA from a sample of the tumour and measuring
  • SF3B1 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 substrate to form the array.
  • a cancer may be identified as SF3B1
  • 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 SF3B1 deficient or mutated 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 SF3B1 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 o the nucleic acid sequence and may reduce or abolish the
  • the variant nucleic acid may encode a variant polypeptide which has reduced or abolished activity or may encode a wild-type
  • a variant nucleic acid may have one or more mutations or polymorphisms relative to the wild-type sequence.
  • the determination of whether a patient has a SF3B1 cancer can be carried out by analysis of SF3B1 protein expression, for example by examining whether levels of SF3B1 protein are supressed.
  • the presence or amount of SF3B1 protein may be determined using a binding agent capable of specifically binding to the SF3B1 protein, or fragments thereof.
  • a preferred type of SF3B1 protein binding agent is an antibody capable of
  • 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 SF3B1 protein.
  • the method for determining the presence of a SF3B1 protein may be carried out on tumour samples for example using immunohistochemical (IHC) analysis or in situ RNA-hybridisation .
  • 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 SF3B1 protein.
  • the present invention provides an assay comprising :
  • the present invention also includes methods of screening that employ PARP as a protein target for the screening of candidate compounds to find PARP inhibitors. Accordingly, methods of screening may be carried out for identifying candidate agents that are capable of inhibiting PARP, for subsequent use of development as agents for the treatment of SF3B1 gene mutated or deficient. 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 PARP can then be determined in the presence and absence of the one or more candidate compounds to determine whether a given candidate is a PARP 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.
  • an antibody e.g. an antibody
  • a peptide e.g. an antibody
  • a peptide e.g. an antibody
  • a peptide e.g. an antibody
  • a peptide e.g. molecular weight of less than 100 Da.
  • organic or inorganic compound e.g. molecular weight of less than 100 Da.
  • candidate agents that are compounds is preferred.
  • any type of candidate agent for any type of candidate agent,
  • 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.
  • 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. This has the advantage that the patient or disease profile of known therapeutic agents might be expanded or modified using the screening techniques disclosed herein, or for
  • the agent in question may be tested to determine whether it is not lethal to normal cells or otherwise is suited to therapeutic use. Following these studies, the agent may be manufactured and/or used in the preparation of a medicament, pharmaceutical composition or dosage form.
  • 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 t 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. spectroscopic techniques, X-ray diffraction data and NMR. Computational analysis, similarity mapping (which models the charge and/or volume of a pharmacophore, rather than the bonding between atoms) and other techniques can be used in this modelling process. In a variant of this approach, the three-dimensional structure of the ligand and its binding partner are modelled. This can be especially useful where the ligand and/or binding partner change conformation on binding, allowing the model to take account of this in the design of the mimetic.
  • the physical properties e.g. stereochemistry, bonding, size and/or charge
  • data from a range of sources e.g. spectroscopic techniques, X-ray diffraction data and NMR.
  • Computational analysis, similarity mapping
  • 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 be selected onto which chemical groups which mimic the pharmacophore can be grafted.
  • 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.
  • active agents herein for the treatment of SF3B1 deficient or mutated cancer may be administered alone, but it is generally preferable to provide them in pharmaceutical compositions that additionally comprise with one or more pharmaceutically
  • 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
  • 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
  • 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 effector, a drug, an antibody or an inhibitor.
  • Coupling partners can be covalently linked to compounds of the invention via an appropriate functional group on the compound such as a hydroxyl group, a carboxyl group or an amino group.
  • Other derivatives include formulating the compounds with
  • 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
  • the active agents disclosed herein for the treatment of SF3B1 deficient cancer according to the present invention are:
  • prophylactically effective amount or a “therapeutically effective amount” (as the case may be, although prophylaxis may be considered therapy) , this being sufficient to show benefit to the individual.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage etc., 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
  • composition may be administered alone or in combination with other treatments, either
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing the active compound into association with a carrier which may constitute one or more accessory ingredients. In general, 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 SF3B1 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 ingestion); 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,
  • Formulations suitable for oral administration e.g., by
  • ingestion 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; and aqueous and non- aqueous 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.
  • 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 non- aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other micro
  • Suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • 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 SF3B1 gene mutated or deficient cancer may be used in the methods described herein in combination with standard
  • radiotherapy also leads to DNA strand breaks, causing severe DNA damage and leading to cell death
  • PARP 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 radiotherapy.
  • additional agents that might be employed in combination with the use of PARP inhibitors as disclosed herein include one or more spliceosomal inhibitors, for example agents that target components of the spliceosome, such as SF3B1, e.g. using a SF3B1 inhibitor.
  • spliceosomal inhibitors for example agents that target components of the spliceosome, such as SF3B1, e.g. using a SF3B1 inhibitor.
  • small molecule inhibitors of SF3B1 are known in the art, see for example
  • chemotherapeutic agents include Amsacrine (Amsidine) , Bleomycin, Busulfan, Capecitabine (Xeloda) ,
  • Carboplatin Carmustine (BCNU) , Chlorambucil (Leukeran) ,
  • Liposomal daunorubicin Lomustine, Melphalan, Mercaptopurine , Mesna, Methotrexate, Mitomycin,
  • 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
  • transcripts in SF3B1 K700E mutant breast versus subtype matched wild-type tumours and have
  • SF3B1 mutant cancers are sensitive to PARP inhibitors
  • K562 and NALM6 SF3B1 mutant and wild-type isogenic cells were treated with 4gy of irradiation. 24 hours post radiation

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Abstract

La présente invention concerne l'utilisation d'inhibiteurs de poly(ADP-ribose) polymérase (PARP) dans le traitement d'un cancer qui est muté ou déficient dans le gène SF3B sur la base de résultats indiquant que des mutations dans SF3B1 peuvent être thérapeutiquement traitées dans des cancers au moyen d'inhibiteurs de PARP et présentent une réponse altérée à une lésion d'ADN.
PCT/EP2018/064873 2017-06-07 2018-06-06 Inhibiteurs de parp destinés à être utilisés pour le traitement du cancer WO2018224536A1 (fr)

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