WO2022031859A2 - Acide méthylmalonique et son métabolisme en tant que biomarqueur du cancer et cible - Google Patents

Acide méthylmalonique et son métabolisme en tant que biomarqueur du cancer et cible Download PDF

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Publication number
WO2022031859A2
WO2022031859A2 PCT/US2021/044560 US2021044560W WO2022031859A2 WO 2022031859 A2 WO2022031859 A2 WO 2022031859A2 US 2021044560 W US2021044560 W US 2021044560W WO 2022031859 A2 WO2022031859 A2 WO 2022031859A2
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WO
WIPO (PCT)
Prior art keywords
mma
metabolite
sample
cancer
methylmalonic acid
Prior art date
Application number
PCT/US2021/044560
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English (en)
Other versions
WO2022031859A3 (fr
Inventor
John Blenis
Ana Patricia DA SILVA GOMES
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Cornell University
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 Cornell University filed Critical Cornell University
Publication of WO2022031859A2 publication Critical patent/WO2022031859A2/fr
Publication of WO2022031859A3 publication Critical patent/WO2022031859A3/fr

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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
    • 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
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids

Definitions

  • HEBCH human hydroxyisobutyryl-CoA hydrolase
  • total MMA or related metabolite concentration in a sample can be used as a marker for metastasis, by comparing the MMA or related metabolite levels in the sample compared to a reference normal tissue or adjacent normal tissue taken from the same patient.
  • MMA or related metabolite concentrations in pre-therapy and shortly post therapy samples is a marker for cancer cell responses.
  • the determination of metastatic disease is based on the measured level of MMA or related metabolites as compared to a reference control level or personalized longitudinal time points.
  • the control level is indicative of the level of the one in a control subject who does not have metastatic disease, or before and after treatment.
  • Solid animal tumors include cancers of the head and neck, lung, mesothelioma, mediastinum, esophagus, stomach, pancreas, hepatobiliary system, small intestine, colon, colorectal, rectum, anus, kidney, urethra, bladder, prostate, urethra, penis, testis, gynecological organs, ovaries, breast, endocrine system, skin central nervous system; sarcomas of the soft tissue and bone; and melanoma of cutaneous and intraocular origin.
  • a metastatic cancer at any stage of progression can be treated, such as micrometastatic tumors, megametastatic tumors, and recurrent cancers.
  • inventive methods and compositions can also be used to treat cancer of the adrenal cortex, cancer of the cervix, cancer of the endometrium, cancer of the esophagus, cancer of the head and neck, cancer of the liver, cancer of the pancreas, cancer of the prostate, cancer of the thymus, carcinoid tumors, chronic lymphocytic leukemia, Ewing's sarcoma, gestational trophoblastic tumors, hepatoblastoma, multiple myeloma, non-small cell lung cancer, retinoblastoma, or tumors in the ovaries.
  • compositions described herein for treatment of cancer can include additional therapeutic agents such as additional anti-cancer or chemotherapeutic agents, vitamins, pain reducing agents, and anti-microbial agents.
  • Alkylating agents and the platinum anti-tumor compounds form strong chemical bonds with electron-rich atoms (nucleophiles), such as sulfur in proteins and nitrogen in DNA. Although these compounds react with many biologic molecules, the primary cytotoxic actions of both classes of agents appear to be the inhibition of DNA replication and cell division produced by their reactions with DNA. However, the chemical differences between these two classes of agents produce significant differences in their anti-tumor and toxic effects.
  • the most frequently used alkylating agents are the nitrogen mustards. Although thousands of nitrogen mustards have been synthesized and tested, only five are commonly used in cancer therapy today. These are mechlorethamine (the original "nitrogen mustard”), cyclophosphamide, ifosfamide, melphalan, and chlorambucil.
  • Clinically useful plant products that target microtubules include the Vinca alkaloids, primarily vinblastine (VLB), vincristine (VCR), vinorelbine (Navelbine, VRLB), and a newer Vinca alkaloid, vinflunine (VFL; 20’,20'-difluoro-3',4'-dihydrovinorelbine), as well as the two taxanes, paclitaxel and docetaxel (Taxotere).
  • VLB vinblastine
  • VCR vincristine
  • VFL vinflunine
  • VFL vinflunine
  • paclitaxel and docetaxel docetaxel
  • the structure of paclitaxel is provided below.
  • Steric blocking inhibitory nucleic acids which are RNase -H independent, interfere with gene expression or other mRNA-dependent cellular processes by binding to a target mRNA and getting m the way of other processes.
  • Steric blocking inhibitory nucleic acids include 2'-0 alkyl (usually in chimeras with RNase-H dependent antisense), peptide nucleic acid (PNA), locked nucleic acid (LNA) and morpholino antisense.
  • an inhibitory nucleic acid such as a short hairpin RNA, siRNA or an antisense oligonucleotide may be prepared using methods such as by expression from an expression vector or expression cassette that includes the sequence of the inhibitory nucleic acid. Alternatively, it may be prepared by chemical synthesis using naturally occurring nucleotides, modified nucleotides or any combinations thereof.
  • the inhibitory nucleic acids are made from modified nucleotides or non-phosphodiester bonds, for example, that are designed to increase biological stabili ty of the inhibitory nucleic acid or to increase intracellular stability of the duplex formed between the inhibitory nucleic acid and the target HIBCH, ACOT13, SOX4, PCC, and/or TGF ⁇ -2 nucleic acid.
  • Methods are also described herein for screening metastatic tumor samples for susceptibility to treatment with candidate compounds.
  • the methods can include assay steps tor identifying a candidate compound that selectively reduces the level of MM A or related metabolites in cancer calls, or that interferes with HIBCH, ACOT13, SOX4, PCC, and/or TGF ⁇ -2 activity or expression.
  • proliferation level of MMA or a related metabolite is decreased in the presence of a test compound as compared to a normal control cell then that test compound has utility for reducing the growth and/or metastasis of cancer cells.
  • one method can include (a) obtaining a fluid, cell or tissue sample from a patient; (b) measuring the amount or concentration of MMA or a related metabolite levels within a selected amount of the fluid, cell or tissue sample to generate a reference fluid, ceil or tissue sample value; (c) mixing the same selected (known) amount of the fluid, cell or tissue sample with a test compound to generate a test assay; (d) measuring the MMA or a related metabolite levels, amount or concentration in the test assay to generate a test assay the MMA or a related metabolite value; (e) optionally repeating steps (c) and (d): and selecting a test compound with a lower test assay the MMA or a related metabolite value than the reference the MMA or a related metabolite value.
  • active agent-lipid particles can be prepared and incorporated into a broad range of lipid-containing dosage forms.
  • the suspension containing the active agent-lipid particles can be formulated and administered as liposomes, gels, oils, emulsions, topical creams, pastes, ointments, lotions, foams, mousses, and the like.
  • MCF-10A, HCC1806, MDA-MB-231 -luciferase and A549 cells were seeded and the next day treatment was initiated with indicated concentrations of MMA (Tocris) or vehicle (double distilled water) for the time frames indicated.
  • Peptides were labeled with 10-plex amine reactive TAIT labeling reagents (Thermo Fisher, Rockford, IL) by re-suspending in 100 ⁇ l of 0.2 M HEPES pH 8 and adding 0.2 mg of each TMT label in 10 pl of anhydrous acetonitrile and incubating at RT for 1 hr. Reactions were quenched with 8 pl of 5% hydroxylamine and then acidified with 16 pl neat FA. Test mixtures for each 1 Oplex set were generated by mixing 5 pl from each channel and analyzed with a 75 min gradient version of the final analysis method (described below). The final mix was adjusted based on this analysis to generate equal total reporter ion intensities from each TMT channel.
  • 10-plex amine reactive TAIT labeling reagents Thermo Fisher, Rockford, IL
  • A549 cells were treated with 5 mM MMA for selected (indicated) amounts of time and then the conditioned culture media were collected. The samples were centrifuged for 3 minutes at 300 g to remove any cells and debris and activated using the Sample Activation Kit 1 (R&D Systems) according to the manufacturer’s protocol. Human TGF ⁇ - 2levels in these conditioned media were measured with the Human TGFB2 Quantikine ELISA Kit (R&D Systems) according to the manufacturer’s protocol.
  • a composition comprising one or more agents that deplete, degrade, or inhibit the expression or activity of hydroxyisobutyryl-CoA hydrolase (HIBCH), Acyl-CoA thioesterase 13 (ACOT13), SOX4, PCC, TG,F ⁇ -2 or a combination thereof in a subject.
  • the composition of statement 23 wherein the one or more agents comprises a nucleic acid that binds to a hydroxyisobutyryl-CoA hydrolase (HIBCH) nucleic acid, an Acyl -Co A thioesterase 13 (ACOT13) nucleic acid, a SOX4 nucleic acid, or a TGF n ⁇ u-2cleic acid.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Cell Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Oncology (AREA)
  • Food Science & Technology (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Hospice & Palliative Care (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Selon l'invention des taux accrus d'acide méthylmalonique (MMA) ou de métabolites apparentés sont corrélés au cancer. L'invention concerne des méthodes et des compositions pour détecter et traiter des sujets affichant des taux élevés d'acide méthylmalonique (MMA) ou d'un métabolite apparenté par rapport à un niveau témoin ou standard d'acide méthylmalonique (MMA) ou d'un métabolite apparenté.
PCT/US2021/044560 2020-08-05 2021-08-04 Acide méthylmalonique et son métabolisme en tant que biomarqueur du cancer et cible WO2022031859A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063061523P 2020-08-05 2020-08-05
US63/061,523 2020-08-05

Publications (2)

Publication Number Publication Date
WO2022031859A2 true WO2022031859A2 (fr) 2022-02-10
WO2022031859A3 WO2022031859A3 (fr) 2022-03-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118360253A (zh) * 2024-05-11 2024-07-19 中山大学附属第六医院 一种干扰甲基丙二酰辅酶a变位酶表达的细胞系及其构建方法与应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10837972B2 (en) * 2010-06-09 2020-11-17 Quest Diagnostics Investments Incorporated Mass spectrometric determination of derivatized methylmalonic acid
ES2711814T3 (es) * 2015-02-27 2019-05-07 Hosmotic Srl Método para el diagnóstico de carcinoma endometrial

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118360253A (zh) * 2024-05-11 2024-07-19 中山大学附属第六医院 一种干扰甲基丙二酰辅酶a变位酶表达的细胞系及其构建方法与应用

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