WO2019147839A1 - Procédés et compositions pour préserver la neurogenèse - Google Patents

Procédés et compositions pour préserver la neurogenèse Download PDF

Info

Publication number
WO2019147839A1
WO2019147839A1 PCT/US2019/014987 US2019014987W WO2019147839A1 WO 2019147839 A1 WO2019147839 A1 WO 2019147839A1 US 2019014987 W US2019014987 W US 2019014987W WO 2019147839 A1 WO2019147839 A1 WO 2019147839A1
Authority
WO
WIPO (PCT)
Prior art keywords
memory
analogue
subject
chemotherapy
pan
Prior art date
Application number
PCT/US2019/014987
Other languages
English (en)
Inventor
Hossein Ghanbari
Zhi-Gang Jiang
Original Assignee
Sensei Biotherapeutics, Inc.
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 Sensei Biotherapeutics, Inc. filed Critical Sensei Biotherapeutics, Inc.
Publication of WO2019147839A1 publication Critical patent/WO2019147839A1/fr

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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

Definitions

  • the present disclosure relates to methods for preserving neurogenesis in a subject treated with chemotherapy by administering to the subject a thiosemicarbazone compound, or an analogue thereof.
  • the disclosure also relates to methods for increasing the number of cells expressing doublecortin protein in a subject treated with chemotherapy by administering to a subject a thiosemicarbazone compound, or an analogue thereof.
  • the chemotherapy may be an anti-cancer therapeutic.
  • the disclosure relates to methods for correcting cancer therapy-impaired cognitive function by administering to a subject a thiosemicarbazone compound, or an analogue thereof.
  • Chemotherapies such as anti-cancer drugs, are usually associated with severe side effects that can affect quality of life and pose difficulties for the continuation of therapy.
  • One of the major adverse effects is the suppression of neurogenesis, which may lead to cognitive impairment in subjects treated with chemotherapy.
  • the disclosure provides a method for reducing chemotherapy-induced inhibition of neurogenesis in a subject, the method comprising administering to the subject a thiosemicarbazone compound, or an analogue thereof.
  • the disclosure further provides a method for preserving neurogenesis in a subject treated with chemotherapy, the method comprising administering to the subject a thiosemicarbazone compound, or an analogue thereof.
  • the disclosure further provides a method for increasing the number of cells expressing doublecortin (DCX) protein in a subject treated with chemotherapy, the method comprising administering to the subject a thiosemicarbazone compound, or an analogue thereof.
  • DCX doublecortin
  • the disclosure further provides a method for improving memory or learning in a subject treated with chemotherapy, the method comprising administering to the subject a thiosemicarbazone compound, or an analogue thereof.
  • the thiosemicarbazone compound is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (PAN-811).
  • the thiosemicarbazone compound is a compound of Formula (I):
  • R, R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, C1 - Salkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C1 -8haloalkyl, C6-10aryl, amino-C1 -8alkyl, hydroxy-C1 - 8alkyl, C1 -8alkoxye-C1-8alkyl, and C1-8alkanoyl, or NR1R2 taken in combination form a 3 to 7 member ring which may comprise 0, 1 , or 2 additional ring heteroatoms selected from N, O, and S;
  • R 6 is hydrogen, hydroxy, amino, or C1-8alkyl
  • R 5 and R 7 are independently selected from the group consisting of hydrogen, halide, hydroxy, thiol, amino, hydroxyamino, mono-C1 -8alkylamino, di(C1-8alkyl)amino, C1 -8alkoxy, C1-8alkyl, C1-8alkenyl, and C2-8alkynyl.
  • the thiosemicarbazone compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoemicarbazone compound
  • the administration of the thiosemicarbazone compound, or an analogue thereof is intravenous, intraperitoneal, subcutaneous, intramuscular, topical, transdermal or oral.
  • the subject is treated with the chemotherapy before or after the administration of the thiosemicarbazone compound, or an analogue thereof. In some embodiments, the subject is treated with the chemotherapy simultaneously with the administration of the thiosemicarbazone compound, or an analogue thereof.
  • the chemotherapy is an anti-cancer agent.
  • the anticancer agent is an immunotherapeutic agent (e.g., an immune checkpoint inhibitor).
  • the anti-cancer agent is a small molecule drug, a therapeutic antibody, an antibody-drug conjugate or a chimeric antigen receptor T-cell therapy.
  • the chemotherapy is a combination of two, three, four, or more than four anti-cancer agents.
  • the anti-cancer agent is an S- phase antimetabolite, G1/S phase inhibitor, topoisomerase II inhibitor, M phase inhibitors, G2/M phase inhibitor, alkylating agent, anthracycline, or topoisomerase I inhibitor.
  • the anticancer agent is 5-fluorouracil, methotrexate, leucovorin, cytarabine, fludarabine, gemcitabine, capecitabine, clofarabine, azacytidine, nelarabine, decitabine, pralatrexate, pemetrexed, etoposide, docetaxel, paclitaxel, ixabepilone, cabazitaxel, eribulin mesylate, vincristine, vinblastine, bleomycin, chlorambucil, procarbazine, dacarbazine, ifosfamide, temozolomide, oxaliplatin, bendamustine, daunorubicin, epirubicin, doxorubicin, irinotecan, topotecan, platinum analogue, cisplatin, pegaspargase, arsenic trioxide, lenalidomide or plerixa
  • the cells expressing DCX protein are located in the hippocampus. In some embodiments, the cells expressing DCX protein are in the dentate gyrus. In some embodiments, the cells expressing DCX protein are neural precursor cells, neural stem cells or immature neurons.
  • the memory improved by the methods described herein is spatial memory, short term memory, long term memory, working memory, episodic memory, semantic memory, remote memory, verbal memory, visual memory, procedural memory, topographic memory, autobiographical memory, implicit memory, retrospective memory or prospective memory.
  • the learning improved by the methods described herein is rule learning or discrimination learning.
  • the subject treated by the methods described herein has cancer.
  • the cancer is a solid tumor or a hematologic malignancy.
  • the cancer is a metastatic cancer.
  • FIG. 1 is an experimental timeline for the study described in Example 1 .
  • a combination of 5- fluorouracil (5-FU) and methotrexate (MTX) or equal volume of physiological saline was administered to 3- month old rats, i.p. (intraperitoneal), 3 times at 10-day intervals, and PAN-81 1 or equal volume of saline was injected, i.p., 10 min following each anticancer drug administration.
  • Chemo MTX/5-FU; PAN: PAN- 81 1 ; Inject: injection; Orient.: Orientation; SM: spatial memory test; PT: probe test; NMTS: nonmatching-to- sample test; DL: discrimination learning test; Perfus.: perfusion; IHC: imrnunohistochemistry.
  • FIG. 2A - FIG. 2D are line graphs and bar graphs showing that PAN-81 1 reverses MTX/5-FU- induced cognitive deficits. Rats received 3 i.p. injections of TX/5-FU or equal volume of saline at 10-day intervals, followed with PAN-81 1 or saline i.p. delivery.
  • FIG. 2A Effects of MTX/5-FU (Chemo) and PAN- 81 1 (Saline+PAN and Chemo+PAN) on spatial memory training. Data are presented as geometric means ⁇ SEM.
  • FIG. 2B Effects of MTX/5-FU and PAN-811 on performance in spatial memory probe test.
  • FIG. 2C Effects of MTX/5-FU and PAN-81 1 on performance in nonmatching-to-sample test. Data are expressed as arithmetic mean ⁇ SEM.
  • FIG. 2D Effects of MTX/5- FU and PAN-811 on discrimination learning. Data from 4 groups per day were statistically analyzed with One-Way ANOVA followed by Tukey HSD test, and paired group also analyzed with T-Test.
  • Figure symbols are #, p ⁇ 0.05, ##, p ⁇ 0.01 and ###, p ⁇ 0.005 compared with Saline control; * p ⁇ 0.05, ** p ⁇ 0.01 and *** p ⁇ 0.005 compared with Chemo group.
  • FIG. 3A - FIG. 3B are a set of fluorescent images and a bar graph showing that PAN-81 1 preserves neurogenesis against MTX/5-FU insult.
  • DCX doublecortin staining of hippocampus on Day 97.
  • FIG. 3A Representative fluorescent image of DCX, in which the abbreviations are: SGZ, subgranular zone; GCL, granule cell layer; and ML, molecular layer. Scale bars for photos in the top row, 100 ⁇ m; Scale bars for photos in the bottom row, 50 ⁇ m.
  • FIG. 3B Quantification of DCX+ cells in SGZ.
  • Chemo+PAN Chemo+PAN-81 1. Data were analyzed with both One- Way ANOVA as well as T-Test. Figure symbols are ##, P ⁇ 0.01 compared with Saline control; ** , P ⁇ 0.01 compared with Chemo group.
  • the disclosure provides methods for preserving neurogenesis in subjects treated with chemotherapy by administering to the subjects a thiosemicarbazone compound, or an analogue thereof.
  • a method for reducing chemotherapy-induced inhibition of neurogenesis in a subject comprising administering to the subject a thiosemicarbazone compound, or an analogue thereof.
  • a method for preserving neurogenesis in a subject treated with chemotherapy comprising administering to the subject a thiosemicarbazone compound, or an analogue thereof.
  • DCX doublecortin
  • a method for improving memory or learning in a subject treated with chemotherapy comprising administering to the subject a thiosemicarbazone compound, or an analogue thereof.
  • a subject may be a human, a non-human primate, a horse, a cow, a sheep, a goat, a pig, a dog, a cat, a rabbit, a hamster, a guinea pig, a rat or a mouse.
  • a subject is a human adult.
  • the subject is a human adolescent.
  • a subject is a human child.
  • the thiosemicarbazone compound may be 3-aminopyridine- 2-carboxaldehyde thiosemicarbazone (3-AP, also called Triapine), or a pharmaceutically acceptable salt thereof.
  • This compound is referred to herein as PAN-81 1.
  • PAN-81 1 is a ribonucleotide reductase inhibitor (see, e.g. , Finch et al., Biochem Pharmacol. 2000; 59: 983-991).
  • the thiosemicarbazone compound may be a compound of Formula (I):
  • R, R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, C1 - 8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C1 -8haloalkyl, C6-10aryl, amino-C1 -8alkyl, hydroxy-C1 - 8alkyl, C1 -8alkoxye-C1-8alkyl, and C1-8alkanoyl, or NR1R2 taken in combination form a 3 to 7 member ring which may comprise 0, 1 , or 2 additional ring heteroatoms selected from N, O, and S;
  • R 6 is hydrogen, hydroxy, amino, or C1-8alkyl
  • R 5 and R7 are independently selected from the group consisting of hydrogen, halide, hydroxy, thiol, amino, hydroxyamino, mono-C1 -8alkylamino, di(C1-8alkyl)amino, C1 -8alkoxy, C1-8alkyl, C1-8alkenyl, and C2-8alkynyl.
  • the thiosemicarbazone compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoemicarbazone compound
  • the administration to the subject of the thiosemicarbazone compound (for example, PAN-81 1), or an analogue thereof is intravenous, intraperitoneal, subcutaneous, intramuscular, topical, transdermal or oral.
  • a pharmaceutical composition comprising the thiosemicarbazone compound (for example, PAN-811), or an analogue thereof, and a pharmaceutically acceptable carrier, excipient or diluent is administered to the subject.
  • the pharmaceutical composition is formulated for intravenous, intraperitoneal, subcutaneous, intramuscular, topical, transdermal or oral delivery.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the type of carrier can be selected based upon the intended route of administration.
  • the carrier is suitable for intravenous, intraperitoneal, subcutaneous, intramuscular, topical, transdermal or oral administration.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • the compounds can be administered in a time release formulation, for example in a composition which includes a slow release polymer.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are generally known to those skilled in the art.
  • Sterile injectable solutions can be prepared by incorporating the thiosemicarbazone compound (for example, PAN-81 1), or an analogue thereof, in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the thiosemicarbazone compound (for example, PAN- 81 1), or an analogue thereof, may be coated in a material to protect it from the action of enzymes, acids and other natural conditions which may inactivate the agent.
  • the compound can be administered to a subject in an appropriate carrier or diluent co-administered with enzyme inhibitors or in an appropriate carrier such as liposomes.
  • Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
  • Enzyme inhibitors include pancreatic trypsin inhibitor, diisopropylfluoro-phosphate (DEP) and trasylol.
  • Liposomes include water-in-oil-in-water emulsions as well as conventional liposomes. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • the thiosemicarbazone compound for example, PAN-811
  • the thiosemicarbazone compound is formulated in the composition in a therapeutically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result to thereby influence the therapeutic course of a particular disease or disorder state.
  • a therapeutically effective amount of the thiosemicarbazone compound (for example, PAN-81 1), or an analogue thereof, may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the agent are outweighed by the therapeutically beneficial effects.
  • the thiosemicarbazone compound for example, PAN-811
  • the prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • the amount of the thiosemicarbazone compound (for example, PAN-81 1), or an analogue thereof, in the composition may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms used in the methods of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the thiosemicarbazone compound (for example, PAN-81 1), or an analogue thereof, and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the thiosemicarbazone compound (for example, PAN-811), or an analogue thereof, is administered to a subject (e.g,, a human subject) at a dose ranging from about 75 mg/rn 2 /day to about 100 mg/m 2 /day, from about 80 mg/m 2 /day to about 100 mg/m 2 /day or ranging from about 90 mg/m 2 /day to about 100 mg/m 2 /day.
  • the thiosemicarbazone compound (for example, PAN-811), or an analogue thereof, is administered to a subject (e.g, , a human subject) at a dose of about 96 mg/m 2 /day.
  • the chemotherapy is an anti-cancer agent (e.g., a cancer chemotherapeutic drug).
  • the anti-cancer agent is an immunotherapeutic agent (e.g., an immune checkpoint inhibitor).
  • an immunotherapeutic agent is a small molecule drug or a therapeutic antibody with immunomodulatory effects.
  • immune checkpoint inhibitors include inhibitors of PD-1 , PD-L1 , CTLA-4 and Lymphocyte Activation Gene 3 (LAG- 3).
  • the anti-cancer agent is a small molecule drug, a therapeutic antibody, an antibody-drug conjugate or a chimeric antigen receptor T-cell therapy.
  • the anticancer agent is, without limitation, an S-phase antimetabolite, G1/S phase inhibitor, topoisomerase II inhibitor, phase inhibitors, G2/ phase inhibitor, alkylating agent, anthracycline, or topoisomerase I inhibitor.
  • the anti-cancer agent is 5-fluorouracil, methotrexate, leucovorin, cytarabine, fludarabine, gemcitabine, capecitabine, clofarabine, azacytidine, nelarabine, decitabine, pralatrexate, pemetrexed, etoposide, docetaxel, paclitaxel, ixabepilone, cabazitaxel, eribulin mesylate, vincristine, vinblastine, bleomycin, chlorambucil, procarbazine, dacarbazine, ifosfamide, temozolomide, oxaliplatin, bendamustine, daunorubicin, epirubicin, doxorubicin, irinotecan, topotecan, platinum analogue, cisplatin, pegaspargase, arsenic trioxide, lenalidomide or
  • the chemotherapy is a combination of two or more, three or more, four or more, or five or more anti-cancer agents (i.e., different anti-cancer agents).
  • the chemotherapy is a combination of 5-fluorouracil and methotrexate.
  • the chemotherapy is a combination of 5-fluorouracil and cisplatin.
  • the chemotherapy is a combination of methotrexate and cisplatin.
  • the subject is treated with the chemotherapy before or after the administration of the thiosemicarbazone compound (for example, PAN- 81 1), or an analogue thereof.
  • administration of the thiosemicarbazone compound and administration of the chemotherapy may be separated by about 0.5 hours, about 1 hour or about 2 hours.
  • the subject is treated with the chemotherapy simultaneously with the administration of the thiosemicarbazone compound (for example, PAN-811), or an analogue thereof.
  • the chemotherapy and the thiosemicarbazone compound may be in the same composition.
  • the chemotherapy and the thiosemicarbazone compound may be in different compositions.
  • the thiosemicarbazone compound for example, PAN-811
  • an anti-cancer agent may inhibit or kill cancer cells at a substantially similar level in the absence of and in the presence of the thiosemicarbazone compound (for example, PAN-81 1), or an analogue thereof.
  • the cells expressing DCX protein are located in the hippocampus.
  • the cells expressing DCX protein are in the dentate gyrus (for example, in the subgranular zone, the granule cell layer or the molecular layer of the dentate gyrus).
  • the DCX protein is human DCX protein.
  • the cells expressing DCX protein are neural precursor cells, neural stem cells or immature neurons. Immature neurons may be adult or embryonic immature neurons.
  • administration of the thiosemicarbazone compound (for example, PAN-811), or an analogue thereof to a subject treated with chemotherapy increases the number of cells expressing DCX by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% compared to the number of cells expressing DCX in a subject treated with the same chemotherapy and not administered the thiosemicarbazone compound.
  • the memory improved by any of the methods of the disclosure is spatial memory, short term memory, long term memory, working memory, episodic memory, semantic memory, remote memory, verbal memory, visual memory, procedural memory, topographic memory, autobiographical memory, implicit memory, retrospective memory or prospective memory, or any combination of types of memory.
  • the memory improved by any of the methods of the disclosure may be evaluated in human subjects with clinically used tests (e.g., the Mini-Mental State Exam (MMSE) or the Mini-Cog test), or computerized tests using CANTAB Mobile, COGNIGRAM®, COGNIVUE®, COGNISION® and Automated Neuropsychological Assessment Metrics (ANAM) devices.
  • MMSE Mini-Mental State Exam
  • ANAM Automated Neuropsychological Assessment Metrics
  • the learning improved by the methods described herein is rule learning or discrimination learning, or a combination of these.
  • the subject treated by any of the methods of the disclosure has cancer.
  • the cancer is a solid tumor.
  • the cancer is skin, brain, head-and-neck, lung, stomach, colon, pancreatic, liver, kidney, bladder, breast, ovarian, uterine, cervical, prostate or testicular cancer.
  • the cancer is melanoma or basal cell carcinoma.
  • the cancer is a hematologic malignancy.
  • the cancer is leukemia, lymphoma or multiple myeloma.
  • the cancer is metastatic cancer.
  • the subject has experienced cognitive impairment (for example, memory loss, attention deficit, learning impairment or confused thought processes, or any combination of these) before being treated by a method of the disclosure.
  • cognitive impairment for example, memory loss, attention deficit, learning impairment or confused thought processes, or any combination of these.
  • the disclosure also provides a use of a thiosemicarbazone compound (for example PAN-81 1), or an analogue thereof, for preserving neurogenesis in a subject treated with chemotherapy.
  • the disclosure further provides a use of a thiosemicarbazone compound (for example PAN-81 1), or an analogue thereof, for reducing chemotherapy-induced inhibition of neurogenesis in a subject.
  • the disclosure further provides a use of a thiosemicarbazone compound (for example PAN-81 1), or an analogue thereof, for increasing the number of cells expressing doublecortin (DCX) protein in a subject treated with chemotherapy.
  • the disclosure yet further provides a use of a thiosemicarbazone compound (for example PAN-81 1), or an analogue thereof, for improving memory or learning in a subject treated with chemotherapy.
  • the term "about” when immediately preceding a numerical value means ⁇ 0% to 10% of the numerical value, ⁇ 0% to 10%, ⁇ 0% to 9%, ⁇ 0% to 8%, ⁇ 0% to 7%, ⁇ 0% to 6%, ⁇ 0% to 5%, ⁇ 0% to 4%, ⁇ 0% to 3%, ⁇ 0% to 2%, ⁇ 0% to 1 %, ⁇ 0% to less than 1 %, or any other value or range of values therein.
  • "about 40” means ⁇ 0% to 10% of 40 (i.e., from 36 to 44).
  • EXAMPLE 1 EFFECTS OF PAN-811 ON COGNITIVE TASKS AND NEUROGENESIS IN RATS TREATED WITH 5-FLUOROURACIL (5-FU) AND METHOTREXATE (MTX)
  • PAN-811 Cl ⁇ H 2 O was produced by Kimia Corp, Santa Clara for Panacea Pharmaceuticals Inc.
  • MTX and 5-FU were purchased from Wyeth Canada, Thornhill, Ontario, and Mayne Pharma, Kirkland, Quebec, respectively.
  • SM Spatial learning and memory
  • the SM test is a widely used, highly sensitive test of hippocampal dysfunction [Morris et al., Nature. 1982; 297: 681-683].
  • the test was conducted in a circular pool (130 cm diameter and 30 cm high), located in the center of a standard testing room. The pool was filled with opaque water and maintained at 21 °C. An inverted flowerpot (10cm diameter), situated a few cm below the surface, served as a platform on which the rats could climb to escape the water. Throughout testing, the water was cleaned after each trial and changed every 2-3 days. The pool was divided into 6 zones of approximately equal size.
  • swimming patterns were monitored by an overhead video camera connected to a recorder and data processing system.
  • the system recorded swimming routes that were used to count errors. An error was recorded each time the rat entered a zone not containing the platform.
  • the rats received one day of orientation training (5 trials/day) in which they learned to swim to the platform that was visible and in a different location on each trial.
  • SM testing began the following day (Day 32).
  • the platform was now submerged and always located in the center of the northeast zone.
  • the rat was placed in the water at the edge of the pool, facing the wall, at a different location, but never in the northeast zone. A trial continued until the rat mounted the platform with all four paws.
  • PT or probe trial provided an additional test of memory for the location of the platform.
  • trials 1 & 2 were conducted in the usual manner.
  • the platform was removed and the rats were allowed to swim for 60 sec.
  • Time spent in the target zone for each group was expressed as a percentage of the 60-sec period.
  • the number of rats in each group was same as that in SM test. Data were expressed as arithmetic means ⁇ SEM.
  • Nonmatching-to-sample learning (NMTS).
  • the NMTS test consists of a series of paired sample (or study) - test trials in a water maze.
  • the stimuli for the sample and test trials were black and white cylinders (30 cm long x 3 cm in diameter), suspended 5 centimeters above the surface of the water.
  • one of the stimuli signaled the platform's location.
  • the sample stimulus was presented along with the other stimulus in new locations.
  • the cylinder that was not present during the preceding sample trial now signaled the platform's location.
  • NMTS and related rule- learning tasks incorporate conditional and working memory components and are known to be sensitive to frontal-lobe impairment [Winocur, Neuropsychologia. 1992; 30: 769-781].
  • NMTS testing began on Day 39.
  • the rat was placed in the southeast zone of the pool and allowed to swim to the submerged platform under a sample cylinder.
  • the rat remained on the platform for 20 sec. and then placed under the heat lamp while the platform together with the cylinders were re-located to different zones.
  • the test trial which began 10 sec. later, the rat was placed in the pool at a different location (with the exceptions of the zone containing either cylinder and the target zone in the preceding sample trial), and allowed to swim to the submerged platform. If the rat failed to find the platform within 60 sec, it was guided to the platform and given an error score of 15. After 20 sec.
  • Discrimination learning (PL).
  • the DL test requires the rat to discriminate between horizontal vs vertical, black and white striped cylinders (30 cm long x 3 cm in diameter) in order to find the submerged platform.
  • the task measures non-conditional, stimulus-response learning and is sensitive to impairment in the striatal system [McDonald et al., Functional dissociation of bain regions in learning and memory: Evidence for multiple systems. In: Foster JK, Jelicic M, editors. Memory: Systems, Process or Function. New York: Oxford University Press; 1999. p. 66-103].
  • the pool was fitted with a gray, plastic cross-maze with walls that extended 10 cm above the surface of the water.
  • Each arm of the maze was 55 cm long.
  • Orientation training started on Day 50 (Day 30 following the final drug administration), and lasted for 2 days.
  • the rat was placed in the pool at the end of one of the arms and allowed to swim to a submerged platform which was located at the end of each goal arm.
  • Each orientation session consisted of 5 trials/day. For these trials, there was no discrete cue to direct the animal.
  • DL began the day following orientation (on Day 52 or Day 32 following the final drug administration), and consisted of 10 trials/day.
  • the rat was placed in the pool at the end of one of the arms and allowed to swim to the choice point, where it encountered the black and white cylinders.
  • the cylinder with horizontal stripes was positive, and for the other half, the cylinder with vertical stripes was positive.
  • the selection of the start arm for each trial and the positioning of the cylinders were determined by a random schedule.
  • a submerged platform was located at the end of the correct arm.
  • the rat made a correct response if, at the choice point, it turned in the direction of the correct stimulus and swam down that arm. An error was scored when a rat entered an incorrect arm with its whole body (less the tail) or left the correct arm. Between trials of orientation training and discrimination learning, animals were placed under the heat lamp to await the next trial.
  • Rats were tested on the DL task until they reached a criterion of 0.5 errors/trial/day averaged over two consecutive days. Testing was terminated if an animal failed to reach this criterion after 15 days (by the end of Day 66 orthe end of Day 46 following final drug administration), and a score of 150 was assigned. The number of rats in each group was same as that in NMTS test.
  • Doublecortin is a reliable marker of immature neurons and has become a standard method for quantification of neurogenesis.
  • Rats were sacrificed on Day 97 by an overdose i.p. injection of Euthansol (Day 77 following the final drug administration). Brain tissue was fixed by pre-intracardiac perfusion and post-fixed with 4% paraformaldehyde for 24 hrs. Brains were cut in half and the hippocampus was isolated from the right hemisphere of each rat.
  • Isolated hippocampi were sectioned serially along the dorso-ventral axis using a vibratome (VT1000S, Leica Microsystems, Heidelberg, Germany) into sections 30 ⁇ thick.
  • the sections were stored in phosphate-buffered saline (PBS) with 0.1% sodium azide for further processing. Twelve sections from each animal were sampled using a systematic random sampling procedure previously described [Morris et al., Nature. 1982; 297: 681-683].
  • DCX staining was performed on free-floating sections. Importantly, sections were rinsed extensively in PBS before processing and between each incubation. All primary and secondary antibody incubations were conducted in PBS containing 0.3% Triton X-100.
  • the sections were incubated with a primary goat anti-DCX antibody (1 :200, sc-8066, Santa Cruz Biotechnology, 24 hours at 4°C), followed by secondary antibody donkey anti-goat IgG Alexa 488 (1 :200; A11055, Life Technologies; 2 hours at room temperature (RT) in the dark). Then sections were mounted onto glass slides using double-distilled water (ddH20), and coverslipped using PermaFluo (Thermo Scientific, Fremont, CA, USA).
  • Immunohistochemical controls included the omission of primary antibody, which resulted in lack of staining at the corresponding wavelength. Sections were examined and immunolabelled cells in the dentate gyrus (DG) of hippocampus were counted using a Leica TCS-SL confocal microscope (Leica Microsystems (Canada) Inc.; Richmond Hill, ON, Canada) with a 63x oil immersion objective lens. The experimenter was blinded with respect to the group and animal identification number to avoid bias. Immuno-positive cells (DCX+) were counted in the subgranular zone (SGZ) of DG.
  • DCX+ subgranular zone
  • the SGZ was defined as a two-cell width wide (approximately 20 ⁇ ) region just below the granule cell layer (GCL). All cells within each section were counted, but excluding top and bottom surfaces of the sections in order to avoid counting cells that were dissected or damaged. The average number of cells per section was multiplied by the total number of sections to obtain total cell numbers per DG [Morris et al., Nature. 1982; 297: 681-683; Wojtowicz et al., Nat Protoc. 2006; 1 : 1399-1405].
  • Figure symbols are as follows: #, p ⁇ 0.05; ##, p ⁇ 0.01 ; ###, p ⁇ 0.005 for comparisons with the Saline group; * , p ⁇ 0.05; ** , p ⁇ 0.01 ; *** , p ⁇ 0.005 for comparisons with the Chemo group.
  • the PT which was carried out on Day 6 of the SM test, measured time spent in the zone where the platform was previously present, provides an additional measure of hippocampus-sensitive spatial memory (FIG. 2B).
  • PAN-81 1 treatment protected rats against the effects of chemotherapy on spatial memory.
  • PAN-811 reduces MTX/5-FU-induced deficits in NMTS rule learning
  • PAN-811 reduces MTX/5-FU-induced deficit in discrimination learning
  • the DL test assessed discrimination capability that is sensitive to impairment of the striatal system.
  • the measure of learning was the number of trials required to achieve a criterion of 0.5 errors/trial on two consecutive days of testing.
  • PAN-811 by itself did not affect discrimination learning in comparison with Saline control (no statistically significant difference between the two groups).
  • PAN-811 blocks MTX/5-FU-elicited damage to neurogenesis in the subgranular zone
  • DCX is a protein that expresses in both neural precursor cells and immature neurons, which involves neurogenesis in adult brain.
  • DCX positive cells were labeled with green fluorescence (FIG. 3A), which not only shown in cell body but also in cell processes in the subgranular zone (SGZ) of DG.
  • the density of DCX+ cells in the Saline+PAN group was about same as that in the Saline group. However, the number of DCX+ cells was clearly less in the Chemo group, in comparison with that in the Saline control. There were more DCX+ cells in the Chemo+PAN group than in the Chemo group. The density of cell processes in the PAN and Chemo+PAN groups appeared also higher.
  • DCX+ cells in SGZ were manually quantified in blind way to avoid bias (FIG. 3B).
  • PAN-811 did not cause any decrease of DCX+ cells in number.
  • PAN-811 provided a full preservation of neurogenesis in the SGZ under MTX/5-FU stress.
  • MTX and 5-FU have dual effects. It can damage both cancer cells and neural stem cells [Winocur et al., Behav Neurosci. 2016; 130: 428-436; Winocur et al., Behav Brain Res. 2015; 281 : 239-244].
  • the former introduces a therapeutic benefit with respect to the disease while the latter has negative side effects on the nervous system.
  • oxidative stress (OS) is a common factor in cytotoxicity, and both MTX and 5-FU increase in vivo OS and result in damage [Miketova et al., Biol Res Nurs. 2005; 6: 187-195; Caron et al., Pediatr Blood Cancer.
  • PAN-811 at a dose of 12 mg/kg does not introduce any neurotoxicity by comparison with control group, as shown with cognitive tests and IHC examination. Furthermore, PAN-81 1 at this dose does not show fatal toxicity to rats, since rat number in Saline+PAN group remained same as that in Saline group by the end of experiment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés pour réduire l'inhibition de la neurogenèse induite par un traitement chimiothérapeutique par l'administration à un sujet d'un composé thiosemicarbazone, ou d'un analogue de celui-ci. L'invention concerne également des procédés permettant d'augmenter le nombre de cellules exprimant la protéine de la double protéine chez un sujet traité avec une chimiothérapie par administration à un sujet d'un composé thiosemicarbazone, ou d'un analogue de celui-ci.
PCT/US2019/014987 2018-01-24 2019-01-24 Procédés et compositions pour préserver la neurogenèse WO2019147839A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862621079P 2018-01-24 2018-01-24
US62/621,079 2018-01-24

Publications (1)

Publication Number Publication Date
WO2019147839A1 true WO2019147839A1 (fr) 2019-08-01

Family

ID=67396244

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/014987 WO2019147839A1 (fr) 2018-01-24 2019-01-24 Procédés et compositions pour préserver la neurogenèse

Country Status (1)

Country Link
WO (1) WO2019147839A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090286799A1 (en) * 2008-05-16 2009-11-19 Zhi-Gang Jiang Methods for the treatment of brain edema
US20140271812A1 (en) * 2013-03-14 2014-09-18 Panacea Pharmaceuticals Treatment for chemotherapy-induced cognitive impairment

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090286799A1 (en) * 2008-05-16 2009-11-19 Zhi-Gang Jiang Methods for the treatment of brain edema
US20140271812A1 (en) * 2013-03-14 2014-09-18 Panacea Pharmaceuticals Treatment for chemotherapy-induced cognitive impairment

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JIANG, ZG ET AL.: "PAN-811 prevents chemotherapy-induced cognitive impairment and preserves neurogenesis in the hippocampus of adult rat s", PLOS ON E, vol. 13, no. 1, 25 January 2018 (2018-01-25), pages 1 - 13, XP055627149 *

Similar Documents

Publication Publication Date Title
US20240050459A1 (en) Nicotinyl Riboside Compounds and Their Uses
US20180311308A1 (en) Methods of treating myeloid leukemia
CA2994544C (fr) Compositions et procedes pour traiter des cancers associes a l'activation d'etbr
EP3062809B1 (fr) Un inhibiteur peptidique de cxcr4 pour le traitement de la leucémie myéloïde aiguë avec mutation de la flt3
Neale et al. Combination chemotherapy for choroidal melanoma: ex vivo sensitivity to treosulfan with gemcitabine or cytosine arabinoside
US20140005122A1 (en) Gemcitabine combination therapy
BR112020000196A2 (pt) composições para administração parenteral de agentes terapêuticos
KR20110110355A (ko) 암 치료용 조성물 및 방법
JP2004532883A (ja) 抗腫瘍コンビネーション
EP4313067A1 (fr) Traitement de troubles liés à l?immunité, de troubles rénaux, de troubles hépatiques, de troubles hémolytiques et de troubles liés au stress oxydatif à l'aide de nrh, narh et de leurs dérivés réduits
JP2019536783A (ja) チロシン誘導体及びそれらを含む組成物
US8507518B2 (en) Method of treating mantle cell lymphoma
US11583509B2 (en) Compound for treating cancer and diabetes
AU2017290047A1 (en) TATĸ-CDKL5 fusion proteins, compositions, formulations, and use thereof
WO2019147839A1 (fr) Procédés et compositions pour préserver la neurogenèse
US20230087078A1 (en) Compositions and methods for the treatment of pancreatic cancer
US20240100107A1 (en) Seneca valley virus combination therapy to treat a cancer refractory to a checkpoint inhibitor
US20150087677A1 (en) Methods for treating vestibulotoxicty
US20200170978A1 (en) Methods of treating disease with dichlorphenamide
KR102676323B1 (ko) Fis1 활성화에 의한 조골세포 활성화를 통한 골형성 촉진 유도용 또는 골질환 치료용 조성물
CN116745619A (zh) 靶向pacs1的化合物及其使用方法
CN116745421A (zh) 靶向wdr37的化合物及其使用方法
CN112843033A (zh) Chmp2b蛋白靶向抑制剂及在缺血性心脏病中的应用
EA044434B1 (ru) Композиции для парентерального введения терапевтических средств
Allison Delivery of oseltamivir phosphate and gemcibatine from implantable poly (D, L-lactic-co-glycolic acid) cylinders for the treatment of pancreatic cancer

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: 19743622

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19743622

Country of ref document: EP

Kind code of ref document: A1