[go: up one dir, main page]

WO2025151077A1 - Procédé de prédiction et de résistance cible à une chimiothérapie dans un cancer - Google Patents

Procédé de prédiction et de résistance cible à une chimiothérapie dans un cancer

Info

Publication number
WO2025151077A1
WO2025151077A1 PCT/SG2025/050013 SG2025050013W WO2025151077A1 WO 2025151077 A1 WO2025151077 A1 WO 2025151077A1 SG 2025050013 W SG2025050013 W SG 2025050013W WO 2025151077 A1 WO2025151077 A1 WO 2025151077A1
Authority
WO
WIPO (PCT)
Prior art keywords
subject
macir
cancer
therapy
expression
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/SG2025/050013
Other languages
English (en)
Inventor
Anand Devaprasath JEYASEKHARAN
Michal Marek HOPPE
Zi Yan Charmaine ONG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
National University of Singapore
Original Assignee
National University of Singapore
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by National University of Singapore filed Critical National University of Singapore
Publication of WO2025151077A1 publication Critical patent/WO2025151077A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57426—Specifically defined cancers leukemia
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • 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 invention relates generally to oncology biomarkers.
  • the invention relates to a method for determining resistance to a cancer therapy by detecting levels of macrophage immunometabolism regulator (MACIR).
  • MACIR macrophage immunometabolism regulator
  • DLBCL Diffuse large B cell lymphoma
  • R-CHOP a combination of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone
  • Salvage treatments for these relapsed/refractory cases are effective only in a fraction of cases. It would be beneficial to be able to identify poor responders early, so that they can be treated with adjunctive therapies in addition to R-CHOP or with alternative therapies.
  • a method of treating a subject suffering from a cancer comprising: a) determining the likelihood of resistance of the subject to a cancer therapy by detecting an increased level of macrophage immunometabolism regulator (MACIR) expression as compared to a reference in a sample obtained from the subject, wherein an increased level of MACIR expression indicates that the subject has an increased likelihood of resistance to the cancer therapy; and b) treating the subject found to have an increased likelihood of resistance to the cancer therapy.
  • MACIR macrophage immunometabolism regulator
  • MACIR macrophage immunometabolism regulator
  • NGS Next-generation sequencing
  • high-throughput sequencing may also be performed for DNA or RNA detection. These sequencing techniques allow for the identification of nucleic acids present in low or high abundance in a sample, or which are otherwise not detected by more conventional hybridisation methods or a quantitative PGR method. NGS typically incorporates the addition of nucleotides followed by washing steps.
  • methods herein comprise detecting a polypeptide expression product of MAC1R. In one embodiment, methods herein comprise detecting the level of MACIR protein.
  • the level of MACIR may be detected using antibody-based techniques such as enzyme- linked immunosorbent assay (ELISA), Luminex® assay or Western blotting.
  • An antibody or antigen-binding fragment thereof that binds to MACIR may be used.
  • the antibody may be further conjugated to a detectable label (such as a fluorescent, luminescent or enzyme label) to allow detection.
  • the antibody may be detected using a secondary antibody that is conjugated to a label (such as a fluorescent, luminescent or enzyme label).
  • SPR surface plasmon resonance
  • Non-immunological methods may also be used to detect a polypeptide product of MACIR.
  • labelled aptamers e.g., a radiolabeled, chromophore-labeled, fluorophore-labeled, or enzyme-labeled aptamer
  • An aptamer refers to a nucleic acid that has a specific binding affinity for a target molecule.
  • a suitable aptamer can be identified using any known method, including but not limited to the SELEX process, and prepared or synthesised in accordance with any known method, including chemical synthesis methods and enzymatic synthesis methods.
  • binding agents for detecting a polypeptide may include, e.g., small molecules, lectins, ligand-binding receptors, affybodies, ankyrins, alternative antibody scaffolds (e.g., diabodics), imprinted polymers, avimers, peptidomimetics, peptoids, peptide nucleic acids, threose nucleic acids, synthetic receptors, and modifications and fragments of these.
  • kits for use in the methods herein to detect MACIR expression.
  • the kits may comprise nucleic acids, such as oligonucleotide probes or primers, for detecting an RNA expression product (e.g., an mRNA) of the MACIR gene.
  • the kits may comprise antibodies or antigen-binding fragments thereof for detecting a polypeptide expression product (c.g., a protein or fragment thereof) of MACIR.
  • kits for determining the likelihood of resistance to a cancer therapy in a subject with cancer comprising a reagent for detecting macrophage immunometabolism regulator (MACIR) expression in a sample obtained from the subject.
  • MACIR macrophage immunometabolism regulator
  • MACIR macrophage immunometabolism regulator
  • the kit comprises a nucleic acid for detecting MACIR mRNA or cDNA.
  • the nucleic acid may be, for example, an oligonucleotide probe or primer capable of hybridising to MACIR mRNA or cDNA.
  • the design of hybridisation probes and primers are well-known in the art.
  • the nucleic acid is an oligonucleotide probe for detecting MACIR mRNA.
  • Oligonucleotide probes herein are single-stranded DNA or RNA molecules designed to be substantially complementary to specific target nucleic acids (e.g., RNA), such that hybridisation of the target sequence and the probes occur. This complementarity need not be perfect, so long as the probe is able to hybridise with its target sequence under suitable hybridisation conditions.
  • an oligonucleotide probe can comprise a sequence having a complementarity to a corresponding target sequence of at least about 70%, at least about 75%>, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 99%, or 100%.
  • hybridisation will be influenced by the length of the probe, the pH, the temperature, the concentration of mono- and divalent cations, the proportion of G and C nucleotides in the region of hybridisation, and the possible presence of denaturants. Such variables also influence the time required for hybridisation. The preferred conditions will therefore depend upon the particular application. Such empirical conditions, however, can be routinely determined without undue experimentation.
  • the nucleic acid in the kit is a primer for reverse transcription of MACIR RNA to eDNA and/or for amplifying the RNA or eDNA product (e.g., primers for PCR amplification or isothermal amplification).
  • more than one oligonucleotide probe or primer is used per target sequence.
  • the probes or primers may target overlapping sections or separate sections of the target sequence. That is, two, three, four or more probes or primers may be used to build in a redundancy for a particular target.
  • the kit comprises an antigen-binding molecule for detecting MACIR protein.
  • the antigen-binding molecule may be, for example, an antibody or antigen-binding fragment thereof which binds specifically to MACIR.
  • the antibody may be a polyclonal or monoclonal antibody.
  • the kit may comprise a plurality of different antigen-binding molecules targeting MACIR.
  • the detection reagent in the kit may comprise a detectable label.
  • Detectable labels include, for example, chromogens, fluorophores, near-infrared dyes, chemiluminescent molecules, bioluminescent molecules, colloidal metal particles (such as gold or silver particles), lanthanide ions (e.g., Eu 3+ ), semiconductor nanocrystals (e.g., quantum dots), radioisotopes, epitopes, enzymes, and colored beads (such as glass or plastic beads).
  • Detectable labels also include barcodes such as molecular- barcodes and fluorescent barcodes.
  • the detection reagent may be immobilised on a solid substrate to form an array.
  • Suitable substrates include plastics (e.g., polytetrafluoroethylene, polystyrene, acrylic polymers), ceramics, silicon, glass, ferro- or paramagnetic materials, titanium dioxide, latex, crosslinked dextrans such as Sepharose, and cellulose.
  • Signal detection from an array may be performed using a chip or plate reader.
  • the reaction may be detected using flow cytometry.
  • kits may be provided together as a mix in dried form (e.g., a powder) and arc reconstituted with a liquid prior to use.
  • the reagents may be dried through lyophilisation or other methods known in the art.
  • the kit may further comprise an aqueous buffer for reconstituting the dried components.
  • Samples herein may be tissue samples, biological fluids, or cultures derived from tissue or fluid samples.
  • Methods herein may be used to predict treatment outcome in subjects with any type of cancer for which combination therapies based on R-CHOP or component agents thereof are suitable.
  • the cancer is a lymphoma.
  • Lymphomas refers to a group of blood cell cancers that develop from lymphocytes. Lymphomas include, but are not limited to, Hodgkin lymphoma, and nonHodgkin lymphoma, e.g., B cell lymphoma (e.g., diffuse large B cell lymphoma (DLBCL), follicular' lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphomas, Burkitt’s lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, primary central nervous system lymphoma and the like), T cell lymphoma (e.g., precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphomas and the like) and NK cell lymphoma.
  • the cancer is a non-Hodgkin lymphoma
  • Methods herein may be used to predict treatment outcome for various combination therapies based on R-CHOP, i.e., therapies based on two or more of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, or therapies incorporating two or more therapeutic agents that are equivalent to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.
  • an “equivalent” therapeutic agent refers to a drug that achieves substantially the same therapeutic effect as the reference drug, and may be substituted for the reference drug for treating a particular indication.
  • the equivalent drug may be a generic version of the reference drug, a drug with the same molecular target or the same targeted pathway as the reference drug, or a multivalent drug incorporating the reference drug.
  • the combination therapy comprises rituximab or an equivalent therapeutic agent.
  • the equivalent therapeutic agent may be an inhibitor of CD20, including but not limited to antibodies, antigen-binding fragments thereof, and other antigen-binding molecules capable of binding and inhibiting CD20.
  • rituximab examples include, for example, the CD20-targeting monoclonal antibodies ofatumumab, obinutuzumab and ublituximab, the bispccific antibodies mosunctuzumab and glofitamab targeting both CD20 and CD3, the antibody-drug conjugate loncastuximab tcsirinc (Zynlonta), and antigen-binding fragments thereof which bind CD20.
  • CD20-targeting monoclonal antibodies ofatumumab, obinutuzumab and ublituximab examples include, for example, the CD20-targeting monoclonal antibodies ofatumumab, obinutuzumab and ublituximab, the bispccific antibodies mosunctuzumab and glofitamab targeting both CD20 and CD3, the antibody-drug conjugate loncastuximab tcsirinc (Zy
  • the combination therapy comprises one or more of the chemotherapeutic agents cyclophosphamide, doxorubicin and vincristine, or equivalent compounds.
  • Therapeutic agents equivalent to cyclophosphamide include but are not limited to other DNA alkylating agents, such as ifosfamide, melphalan, chlorambucil andbendamustine.
  • Therapeutic agents equivalent to doxorubicin include but are not limited to other anthracycline compounds (e.g., daunorubicin, epirubicin, idarubicin and valrubicin), anthracenediones (e.g., mitoxantrone and pixantrone), and other topoisomerase II inhibitors (e.g., etoposide and teniposide).
  • Therapeutic agents equivalent to vincristine include but are not limited to other vinca alkaloids (e.g., vinblastine, vinorelbine and vindesine), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), and other microtubuletargeting and anti-mitotic agents (e.g., ixabepilone and eribulin).
  • vinca alkaloids e.g., vinblastine, vinorelbine and vindesine
  • taxanes e.g., paclitaxel, docetaxel, cabazitaxel
  • microtubuletargeting and anti-mitotic agents e.g., ixabepilone and eribulin.
  • the combination therapy comprises prednisone or an equivalent therapeutic agent.
  • the equivalent therapeutic agent may be a glucocorticoid or corticosteroid, including but not limited to prednisolone, methylprednisolone, hydrocortisone (cortisol), dexamethasone, betamethasone, and triamcinolone.
  • the equivalent therapeutic agent may be a non-corticostcroid immunosuppressant, such as azathioprine or methotrexate.
  • the cancer therapy is a combination therapy comprising two or more of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and additionally comprises etoposide and/or polatuzumab vedotin.
  • Polatuzumab vedotin is an antibody-drug conjugate consisting of an antibody specifically targeting CD79b (polatuzumab) linked to the anti-mitotic agent monomethyl auristatin E (MMAE).
  • the cancer therapy is CHOP (i.e., a combination of cyclophosphamide, doxorubicin, vincristine and prednisone) or R-CHOP (i.e., a combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).
  • the cancer therapy is a combination of rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (i.e., R-EPOCH).
  • the cancer therapy is a combination of polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin and prednisone (i.e., pola-R-CHP).
  • the expression level of MACIR may be used to identify cancer patients who are not likely to respond to R-CHOP-based combination therapies, or who are likely to relapse following R-CHOP-based combination therapies.
  • increased expression of MACIR is predictive of refractory cancers and poor response to R-CHOP-based combination therapies.
  • MACIR macrophage immunometabolism regulator
  • MACIR macrophage immunometabolism regulator
  • MACIR macrophage immunometabolism regulator
  • MACIR macrophage immunometabolism regulator
  • Normalisation can be performed using methods known in the art.
  • normalisation is performed by dividing the measured expression level of MACIR by the expression level of a reference or housekeeping gene.
  • Useful reference or housekeeping genes are genes that show a low variation in their expression level across a variety of different samples and subjects.
  • a useful reference gene will show the same expression level in samples derived from subjects who have cancer and in samples derived from subjects who do not have cancer.
  • Such reference or housekeeping genes are typically genes which are crucial for fundamental cellular processes such as metabolism and cell structure maintenance.
  • the term “increase” or “increased” with reference to a biomarker refers to a statistically significant and measurable increase in the biomarker as compared to a reference.
  • the increase may be an increase of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100%>.
  • an increase in the level of MACIR as compared to a reference is an increase of 1 .1 fold, 1 .2 fold, 1 .3 fold, 1 .4 fold, 1 .5 fold, 1 .6 fold, 1 .7 fold, 1 .8 fold, 1 .9 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 11 fold, 12 fold, 13 fold, 14 fold, 15 fold, 16 fold, 17 fold, 18 fold, 19 fold, 20 fold, 21 fold, 22 fold, 23 fold, 24 fold, 25 fold, 26 fold, 27 fold, 28 fold, 29 fold, 30 fold, 31 fold, 32 fold, 33 fold, 34 fold, 35 fold, 36 fold, 37 fold, 38 fold, 39 fold, 40 fold, 41 fold, 42 fold, 43 fold, 44 fold, 45 fold, 46 fold, 47 fold, 48 fold, 49 fold, 50 fold, 51 fold, 52 fold, 53 fold, 54 fold, 55 fold, 56 fold, 57 fold, 58 fold, 59 fold,
  • biomarkers may include non-genetic factors such as demographic or clinical variables, non-limiting examples of which include gender, age, lifestyle (e.g., diet, frequency of physical activity, alcohol intake, tobacco use), physiological parameters (e.g., body mass index, blood pressure), family history of disease, clinical history of cancer and/or other comorbid diseases or conditions, and other diagnostic indications of cancer (e.g., levels of other biomarkers, medical imaging).
  • Clinical methods may include imaging methods and histopathological analyses of biopsy samples.
  • Methods herein may be performed prior to, during or after a cancer therapy (such as R- CHOP therapy or similar combination therapies), and may be performed on multiple occasions over a period of time.
  • a cancer therapy such as R- CHOP therapy or similar combination therapies
  • treating the subject or refractory cancer comprises administering to the subject an adjusted regimen of CHOP or R-CHOP.
  • the adjustment may include, for example, a change in dose or dosage of one or more therapeutic agents in CHOP or R-CHOP, or a change in the schedule of CHOP or R-CHOP therapy.
  • CHOP or R-CHOP may be administered in combination with other therapeutic agents to subjects who are likely to be non-responsive to CHOP or R-CHOP therapy.
  • CHOP or R-CHOP may be administered in combination with an MACIR inhibitor.
  • treating the subject comprises administering to the subject a therapy other than CHOP or R-CHOP.
  • the therapy may be an equivalent combination therapy.
  • the therapy may comprise a variant of CHOP or R-CHOP where one or more components are substituted with an equivalent therapeutic agent, as provided in this disclosure.
  • the therapy may comprise therapeutic agents in addition to the components of CHOP or R-CHOP, such as other therapeutic agents indicated for the cancer.
  • the therapy may be, for example, R- EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) or pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin and prednisone).
  • R- EPOCH rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin
  • pola-R-CHP polyatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin and prednisone
  • one or more components of CHOP or R- CHOP may be substituted with an equivalent therapeutic agent, as provided in this disclosure.
  • the therapy may comprise any drug, pharmaceutical composition, combination therapy, or clinical intervention effective to treat the cancer of the subject.
  • a non-exhaustive list of anti-cancer therapies include surgery, chemotherapy, radiation therapy, photodynamic therapy, radionuclides, metal-containing compounds (c.g., platinum compounds), arsenic compounds, cytotoxic antibiotics, anti-metabolites, anti-mitotic agents, anti-angiogenic agents, alkylating agents, DNA topoisomerase inhibitors, signal transduction pathway inhibitors, cell cycle signalling inhibitors, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, HDAC inhibitors, protcasomc inhibitors, pro- apoptotic compounds, taxanes, nucleoside analogues, plant alkaloids, toxins, cytokines, hormones and hormonal analogues, proteolysis targeting chimeras (PROTACs), gene therapy (e.g., antisense polynucleotides, ribozymes, RNA interference molecules, triple helix polyn
  • the anti-cancer therapy may also be combinations of the aforementioned therapies.
  • the anti-cancer therapy may be administered in one or more doses, procedures or administrations.
  • a skilled person can select a suitable therapy based on, for example, the type of cancer to be treated, the assessment of the clinical history and clinical condition of the subject, and prevailing medical guidance.
  • treating the subject comprises administering to the subject an inhibitor of MACIR.
  • the MACIR inhibitor may be administered in combination with CHOP, R-CHOP or an equivalent therapy.
  • MACIR macrophage immunometabolism regulator
  • the cancer therapy may be a combination therapy comprising two or more of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.
  • the cancer therapy is CHOP or R-CHOP therapy.
  • MACIR macrophage immunometabolism regulator
  • compositions herein can further comprise a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable salt.
  • suitable carriers include isotonic saline solutions, for example phosphate-buffered saline.
  • Suitable diluents and excipients also include, for example, water, saline, dextrose, glycerol, and the like, and combinations thereof.
  • substances such as wetting, solubilising or emulsifying agents, stabilising or pH buffering agents, viscosity controlling agents. preservatives, antioxidants, emollients, odour controlling or fragrance compounds may also be present.
  • pharmaceutically acceptable carrier refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity.
  • Suitable carriers can be large, slowly metabolised macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, and amino acid copolymers.
  • salts can also be present, e.g., mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • compositions herein may be administered locally or systemically, such as via an oral, intra-adiposal, intra-arterial, intra-articular, intracranial, intradermal, intra-lesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intra-tumoral, intra- umbilical, intravaginal, intravenous, intravesicular, intravitreal, liposomal, local, mucosal, parenteral, subconjunctival, cutaneous, subcutaneous, sublingual, topical, transbuccal or transdermal route, or combinations thereof.
  • the pharmaceutical composition may be administered via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local deliver ⁇ ', via an implant, via a dressing, or via any combination thereof.
  • MACIR macrophage immunometabolism regulator
  • MACIR macrophage immunometabolism regulator
  • the subject is one who has an increased level of macrophage immunometabolism regulator (MACIR) expression in a sample as compared to a reference.
  • MACIR macrophage immunometabolism regulator
  • the MACIR inhibitor may be an inhibitory nucleic acid molecule, a site-specific nuclease (SSN) system, a peptide, a polypeptide, a proteolysis targeting chimera (PROTAC), or a small molecule capable of disrupting expression or activity of MACIR.
  • Methods herein may comprise administering a vector encoding the MACIR inhibitor to the subject, for inhibitors that comprise a nucleic acid, SSN system, peptide or polypeptide.
  • the MACIR inhibitor is a site-specific nuclease (SSN) system capable of modifying a gene encoding MACIR, or an RNA product of the gene, to reduce MACIR expression.
  • SSN systems generally comprise a sequence-specific nuclease that recognises a target nucleic acid sequence.
  • the sequence-specific nuclease may work in conjunction with one or more guide nucleic acids that target the nuclease to the target nucleic acid sequence.
  • the sequence- specific nuclease may be a wild-type, engineered or chimeric nuclease.
  • the SSN system may further comprise a donor template nucleic acid molecule for introducing specific sequence modifications (such as an insertion, deletion or substitution of one or more nucleotides) at or adjacent to the target nucleic acid sequence.
  • SSNs capable of being engineered to generate target nucleic acid scqucncc-spccific modifications include zine-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced palindromic repeats/CRISPR-associated nuclease (CRISPR/Cas) systems.
  • the MACTR inhibitor is a CRTSPR/Cas SSN system, such as a CRISPR/Cas9 system, CRISPR/Casl2 system or a CRISPR/Casl3 system.
  • Methods herein may comprise administering the MACIR inhibitor in combination with CHOP or R-CHOP therapy.
  • the MACIR inhibitor may be administered simultaneously or sequentially with the CHOP or R-CHOP therapy.
  • a combination and “in combination with” are not intended to imply that the therapy or the therapeutic agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope described herein.
  • the therapeutic agents in the combination can be administered concurrently with, prior to, or subsequent to, one or more other additional therapies or therapeutic agents.
  • the therapeutic agents or therapeutic protocol can be administered in any order. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. It will further be appreciated that the additional therapeutic agent utilised in the combination may be administered together or separately in different compositions. In general, it is expected that therapeutic agents utilised in combination be utilised at levels that do not exceed the levels at which they are utilised individually. In some embodiments, the levels utilised in combination are lower than those utilised individually.
  • MAC1R inhibitor may be administered before or after the CHOP or R-CHOP therapy.
  • a time delay may exist between sequential administration of the therapeutic agents.
  • the time interval may be any pre-determined time interval, but is preferably one that provides for a cooperative effect of the MACIR inhibitor and the CHOP or R-CHOP therapy.
  • the therapeutic agents may be administered simultaneously or sequentially via the same route or via different routes.
  • HEK293T cells were treated with siRNA targeting MACIR (sense: 5’- CUUCACGACUGGCGAGGAAdTdT-3’ [SEQ ID NO: 1], antisense: 5’- UUCCUCGCCAGUCGUGAAGdTdT-3’ [SEQ ID NO: 2J) and the knockdown was validated through Western blot ( Figure 3A). Additionally, MACIR knockout cell lines were generated with CRISPR (gRNA: 5’-
  • MACIR prognostic significance was also compared to known DLBCL prognostic markers MYC, BCL2 and BCL6. As shown in Figure 5 A, MACIR is more consistently and more strongly associated with poor survival when highly expressed than MYC, BCL2 or BCL6. Additionally, receiver operating characteristic (ROC) analysis indicated that MACIR accurately classifies patient survival in the NUH cohort, outperforming the cell-of-origin classification ( Figure 5B).
  • ROC receiver operating characteristic
  • MACIR is potentially a multifactorial biomarker that can predict for the likelihood of R-CHOP resistance, itself being a potential therapeutic target to improve the outcome of DLBCL.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Pathology (AREA)
  • Molecular Biology (AREA)
  • Analytical Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Genetics & Genomics (AREA)
  • Oncology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • General Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Cell Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne des procédés permettant de prédire l'évolution d'une thérapie anticancéreuse (en particulier une thérapie combinée avec CHOP ou R-CHOP) en détectant le niveau d'expression du régulateur de l'immunométabolisme des macrophages (MACIR) chez un sujet, une expression MACIR accrue indiquant une probable absence de réponse à la thérapie anticancéreuse. L'invention concerne également des méthodes de traitement du cancer réfractaire par l'utilisation d'inhibiteurs de MACIR.
PCT/SG2025/050013 2024-01-08 2025-01-08 Procédé de prédiction et de résistance cible à une chimiothérapie dans un cancer Pending WO2025151077A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SG10202400055R 2024-01-08
SG10202400055R 2024-01-08

Publications (1)

Publication Number Publication Date
WO2025151077A1 true WO2025151077A1 (fr) 2025-07-17

Family

ID=96387969

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SG2025/050013 Pending WO2025151077A1 (fr) 2024-01-08 2025-01-08 Procédé de prédiction et de résistance cible à une chimiothérapie dans un cancer

Country Status (1)

Country Link
WO (1) WO2025151077A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009149297A1 (fr) * 2008-06-04 2009-12-10 The Arizona Board Regents, On Behalf Of The University Of Arizona Marqueurs du lymphome diffus à grandes cellules b et utilisations associées
WO2013020690A1 (fr) * 2011-08-08 2013-02-14 Roche Diagnostics Gmbh Prédiction d'une sensibilité à une thérapie anti-cd20 chez des patients atteints de dlbcl
WO2022093910A1 (fr) * 2020-10-27 2022-05-05 The Children’S Mercy Hospital Signature du gène pronostique et procédé de pronostic et de traitement du lymphome diffus à grandes cellules b

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009149297A1 (fr) * 2008-06-04 2009-12-10 The Arizona Board Regents, On Behalf Of The University Of Arizona Marqueurs du lymphome diffus à grandes cellules b et utilisations associées
WO2013020690A1 (fr) * 2011-08-08 2013-02-14 Roche Diagnostics Gmbh Prédiction d'une sensibilité à une thérapie anti-cd20 chez des patients atteints de dlbcl
WO2022093910A1 (fr) * 2020-10-27 2022-05-05 The Children’S Mercy Hospital Signature du gène pronostique et procédé de pronostic et de traitement du lymphome diffus à grandes cellules b

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIANG XIPING; HU RENZHI; LI QIYING; WANG CHAOYU; LIU YAO: "Prognostic factors for diffuse large B-cell lymphoma: clinical and biological factors in the rituximab era", EXPERIMENTAL HEMATOLOGY, ELSEVIER INC., US, vol. 122, 16 March 2023 (2023-03-16), US , pages 1 - 9, XP087325750, ISSN: 0301-472X, DOI: 10.1016/j.exphem.2023.03.003 *

Similar Documents

Publication Publication Date Title
JP6807873B2 (ja) 癌の検出のためのバイオマーカーパネル
US11254986B2 (en) Gene signature for immune therapies in cancer
US9315869B2 (en) Marker for predicting gastric cancer prognosis and method for predicting gastric cancer prognosis using the same
US9663825B2 (en) Biomarkers to identify patients that will respond to treatment and treating such patients
US20140302042A1 (en) Methods of predicting prognosis in cancer
US20170058360A1 (en) Methods for Prediction of Clinical Response to Radiation Therapy in Cancer Patients
CN111630183B (zh) 透明细胞肾细胞癌生物标志物
US12398429B2 (en) Methods and systems for sequencing polynucleotides
EP2800821B1 (fr) Signature pour le diagnostic de l'agressivité du cancer du poumon
WO2010102195A2 (fr) Gène de l'annexine a11 et gènes associés en tant que biomarqueurs pour le cancer
Li et al. Reduced expression of PDCD5 is associated with high-grade astrocytic gliomas
Ines et al. Implication of K-ras and p53 in colorectal cancer carcinogenesis in Tunisian population cohort
US20170252364A1 (en) Compositions for treatment of acute lymphoblastic leukemia and methods of use thereof
US11519042B2 (en) Method for the diagnosis or prognosis, in vitro, of lung cancer
KR101657033B1 (ko) V-ATPase subunit V1E1의 단백질 발현 수준을 측정하여 식도암 환자의 생존율과 예후를 예측하는 방법
WO2025151077A1 (fr) Procédé de prédiction et de résistance cible à une chimiothérapie dans un cancer
TW202122584A (zh) 預測癌症預後之方法及其應用
KR20190037420A (ko) 위암의 예후 예측용 마커 및 이의 용도
KR20200089595A (ko) 항암제 반응성 예측용 바이오마커 및 이의 용도
US20060115834A1 (en) Methods of identifying metastatic potential in cancer
US20230272478A1 (en) Biomarker specific for liver cancer, and use thereof
US20220081719A1 (en) Method and application thereof for predicting prognosis of cancer
US20220081727A1 (en) Biomarker for predicting response to anticancer agent and use thereof
KR102879745B1 (ko) 갑상선 종양의 감별진단용 바이오마커 및 이의 용도
KR101860181B1 (ko) 융합유전자를 이용한 폐암 예후예측용 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25739211

Country of ref document: EP

Kind code of ref document: A1