WO2007011339A1 - Methodes de traitement et de prevention des cancers du cerveau - Google Patents

Methodes de traitement et de prevention des cancers du cerveau Download PDF

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Publication number
WO2007011339A1
WO2007011339A1 PCT/US2005/025132 US2005025132W WO2007011339A1 WO 2007011339 A1 WO2007011339 A1 WO 2007011339A1 US 2005025132 W US2005025132 W US 2005025132W WO 2007011339 A1 WO2007011339 A1 WO 2007011339A1
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patient
brain cancer
gnrh
leuprolide
brain
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PCT/US2005/025132
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English (en)
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Richard Lloyd Bowen
Christopher W. Gregory
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Voyager Pharmaceutical Corporation
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Priority to PCT/US2005/025132 priority Critical patent/WO2007011339A1/fr
Publication of WO2007011339A1 publication Critical patent/WO2007011339A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord

Definitions

  • the present invention relates to methods for treating, preventing, delaying, or mitigating brain cancer, for decreasing the level of brain cancer-specific markers, or for preventing or slowing proliferation of cells of brain origin.
  • Brain cancer means any abnormally increased proliferation of any type of neuronal cells, or any other cancer that has metastasized into the central nervous system.
  • Examples of brain cancers include, but are not limited to, neuroma, anaplastic astrocytoma, neuroblastoma, glioma, glioblastoma multiforme, astrocytoma, meningioma, pituitary adenoma, primary CNS lymphoma, medulloblastoma, ependymoma, sarcoma, oligodendroglioma, medulloblastoma, spinal cord tumor, and schwannoma.
  • neuronal cells - that is, cells that comprise or are found in the central nervous system, including, for example, neurons, microglia, and astrocytes - are "terminally differentiated,” meaning that they no longer possess the ability to complete the cell cycle.
  • terminally differentiated neuronal cells may be able to enter the cell cycle, they are unable to complete the process and usually undergo apoptosis (cell death).
  • Brain cancers may result when terminally differentiated neuronal cells lose the protective ability to apoptose and are able to complete the cell cycle, resulting in abnormally increased cell proliferation.
  • Hahn W C Meyerson M, Telomerase activation, cellular immortalization and cancer, Ann Med Mar;33(2): 123-9 (2001)).
  • an upregulation in the cell cycle contributes to the development of brain cancers by causing abnormally increased proliferation of neuronal cells that have lost the ability to apoptose.
  • an upregulation of the cell cycle associated with abnormally increased proliferation of neuronal cells is caused, at least in part, by an increase in blood level, production, function, or activity of luteinizing hormone (LH) or follicle stimulating hormone (FSH).
  • LH luteinizing hormone
  • FSH follicle stimulating hormone
  • the present invention encompasses preventing or treating brain cancer by administering an agent that decreases or regulates levels, production, function, or activity of LH or FSH.
  • the present invention provides that suppression of autocrine/paracrine gonadotropin releasing hormone (GnRH) signaling in the brain requires doses of GnRH agonists that are significantly higher than those required to suppress endocrine GnRH signaling at the level of the pituitary.
  • the present invention further provides that hormones of the hypothalami c-pituitary-gonadal (HPG) axis function not only in an endocrine fashion to modulate brain cell function but also in an autocrine/paracrine fashion to regulate brain cell function.
  • HPG hypothalami c-pituitary-gonadal
  • hypothalamic-pituitary-gonadal (HPG) hormonal axis is presented with reference to FIG. 11.
  • the centrally produced hormones include gonadotropin releasing hormone (GnRH) from the hypothalamus; and gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone (FSH) from the pituitary.
  • GnRH gonadotropin releasing hormone
  • LH luteinizing hormone
  • FSH follicle stimulating hormone
  • Peripherally produced hormones include estrogen, progesterone, testosterone, and inhibins that are primarily of gonadal origin, while activins and follistatin are produced in all tissues including the gonads (Carr BR, in Williams Textbook of Endocrinology, JD Wilson, DW Foster, HM Kronenberg, and PR Larsen, eds. (Philadelphia PA, WB Saunders Co.), pp. 751-817 (1998)). The levels of each of these hormones are regulated by a complex feedback loop.
  • GnRH gonadotropin releasing hormone
  • Receptors for luteinizing hormone releasing hormone have been detected in meningiomata, glioblastoma multiforme, gliomata and chordoma using LHRH binding assays, demonstrating a possible autocrine signaling loop in brain cancers (van Groeninghen JC, Kiesel L, Winkler D, Zwirner M. Effects of luteinising-hormone- releasing hormone on nervous-system tumors. Lancet 352:372-373, 1998).
  • GnRH agonists are the most commonly used type of hormonal therapy for prostate cancer. These are analogues of the endogenous GnRH decapeptide with specific amino acid substitutions. Replacement of the GnRH carboxy-terminal glycinamide residue with an ethylamide group greatly increases the affinity these analogues possess for the GnRH receptor compared to the endogenous peptide. Many of these analogues also have a longer half-life than endogenous GnRH (Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocrine Reviews 25:235-275, 2004).
  • GnRH agonists and antagonists may generally be considered to be adequate to suppress endocrine influences of hormones of the HPG axis by lowering their serum concentrations
  • these same doses of GnRH antagonists and agonists are believed to be subtherapeutic when it comes to adequately suppressing local tissue production of these hormones.
  • abnormal cell division in malignant brain tissues may be driven by elevated levels of gonadotropins. It is believed that, by reducing the level of gonadotropins in the serum and brain tissue of patients with brain cancers, brain cancer can be treated, prevented, delayed, or mitigated.
  • Among the goals of the present invention is treatment, mitigation, slowing the progression of, or preventing brain cancers by achieving higher tissue levels of GnRH agonists and/or GnRH antagonists, whether by administering more of such drugs, by preventing degradation of such drugs once administered, by delivering the drugs at a site where they are needed, by a combination of these methods, or by other methods.
  • the present invention relates to methods for treating, mitigating, slowing the progression of, or preventing brain cancer, or preventing or slowing proliferation of cells of brain origin, or for decreasing the level of a brain cancer-specific marker in a patient, by administering high doses of at least one physiological agent, such as a GnRH agonist or a GnRH antagonist, that decreases or regulates the blood or tissue levels, expression, production, function, or activity of LH, LH receptors, FSH, FSH receptors, androgenic steroids, androgenic steroid receptors, activins, or activin receptors, or administering a physiological agent that increases or regulates the blood or tissue levels, expression, production, function, or activity of GnRH, inhibins, beta-glycan, or follistatins.
  • a physiological agent such as a GnRH agonist or a GnRH antagonist
  • the invention further encompasses, for example, a method of preventing or inhibiting an upregulation of the cell cycle in brain-derived cells by administering high doses of at least one physiological agent that is a GnRH agonist or antagonist, effective to reduce local tissue production of hormones of the hypothalamic-pituitary-gonadal (HPG) axis.
  • the physiological agent is leuprolide
  • the amount administered is in the range of approximately at least 15 mg/month.
  • the amount of leuprolide administered is in the range of at least about 20 mg/month, or at least 37.5 mg/month.
  • the physiological agent is an agent other than leuprolide
  • the amount administered is an amount sufficient to produce the same or similar physiological effects as at least about 15 mg of leuprolide per month, or at least about 20 mg of leuprolide per month, or at least about 37.5 mg of leuprolide per month.
  • physiologically equivalent dose to a dose of a first physiological agent means a dose of a second physiological agent that achieves the same or similar physiological responses as the dose of the first physiological agent.
  • the invention also encompasses, as another example, a method for treating brain cancer in a patient having brain cancer comprising administering to the patient a physiological agent that decreases the degradation of GnRH agonists or GnRH antagonists, increases the half- life of GnRH agonists or GnRH antagonists, or increases brain tissue levels of GnRH agonists or GnRH antagonists within the patient.
  • the invention also encompasses, as another example, a method for treating brain cancer in a patient having brain cancer comprising administering to the patient a physiological agent that decreases the degradation of GnRH agonists or GnRH antagonists, increases the half-life of GnRH agonists or GnRH antagonists, or increases brain tissue levels of GnRH agonists or GnRH antagonists within the patient.
  • Leuprolide acetate is an example of a GnRH agonist used in the treatment of a cancer, i.e., prostate cancer.
  • Approved GnRH agonists and antagonists, dosage levels and plasma/serum levels of active medication are as follows (according to their approved labelling): LUPRON ® DEPOT 3.75mg 1 month injection gives a mean plasma leuprolide concentration of 4.6-10.2 ng/ml at 4 hours postdosing; LUPRON ® DEPOT 7.5mg 1 month injection gives a mean plasma leuprolide concentration of 20 ng/ml at 4 hours and 0.36 ng/ml at 4 weeks; LUPRON ® DEPOT-PED 11.25mg 1 month injection gives a mean plasma leuprolide concentration of 1.25 ng/ml at 4 weeks; LUPRON ® DEPOT-PED 15mg injection gives a mean plasma leuprolide concentration of 1.59 ng/ml at 4 weeks; LUPRON ® DEP
  • FIG. IA presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the LN229 adult glioblastoma brain cancer cell line on the initial day of a seven-day period.
  • FIG. IB presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the LN229 adult glioblastoma brain cancer cell line on each day of a five-day period.
  • FIG. 1 C presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the LN229 adult glioblastoma brain cancer cell line on each day of a seven-day period.
  • FIG. 2A presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the U87-MG adult astrocytoma brain cancer cell line on each day of a seven-day period.
  • FIG. 2B presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the U87-MG adult astrocytoma brain cancer cell line on each day of a seven-day period.
  • FIG. 2C presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the U87-MG adult astrocytoma brain cancer cell line twice per day of a five-day period.
  • FIG. 3 presents results of two in vitro experiments (averaged) in which leuprolide acetate was administered to cells of the Ul 18-MG adult glioblastoma brain cancer cell line twice daily for five days.
  • FIG. 4A presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the DAOY pediatric medulloblastoma brain cancer cell line on the first day of a seven-day period.
  • FIG. 4B presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the DAOY pediatric medulloblastoma brain cancer cell line on each day of a six-day period.
  • FIG. 4C presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the DAOY pediatric medulloblastoma brain cancer cell line on each day of a seven-day period.
  • FIG. 5 A presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the SK-N-MC pediatric neuroblastoma brain cancer cell line on the first day of a seven-day period.
  • FIG. 5B presents results of an in vitro experiment in which leuprolide acetate was administered to cells of the SK-N-MC pediatric neuroblastoma brain cancer cell line on each day of a six-day period.
  • FIG. 5C presents results of a replicate in vitro experiment in which leuprolide acetate was administered to cells of the SK-N-MC pediatric neuroblastoma brain cancer cell line on each day of a seven-day period.
  • FIG. 6A presents tumor growth data from an experiment in which human LN229 brain cancer cells were injected as xenografts into nude mice that were one week prior treated with placebo or leuprolide implants.
  • FIG. 6B presents tumor growth rates from tumors represented in FIG. 6A.
  • FIG. 7A presents tumor growth data from an experiment in which human U87-
  • MG brain cancer cells were injected as xenografts into nude mice that were concurrently implanted with placebo or leuprolide implants.
  • FIG. 7B presents tumor growth rates from tumors represented in FIG. 7A.
  • FIG. 8A presents tumor growth data for small tumors ( ⁇ 4x Vo) from an experiment in which human U87-MG brain cancer cells were injected as xenografts into nude mice that were one week prior implanted with placebo or leuprolide implants.
  • FIG. 8B presents tumor growth rates from the small tumors represented in FIG. 8A.
  • FIG. 8C presents tumor growth data for large tumors ( >4x V 0 ) from an experiment in which human U87-MG brain cancer cells were injected as xenografts into nude mice that were one week prior implanted with placebo or leuprolide implants.
  • FIG. 8D presents tumor growth rates from the large tumors represented in FIG. 8C.
  • FIG. 9A presents tumor growth data from an experiment in which human DAOY brain cancer cells were injected as xenografts into nude mice that were subsequently dosed with placebo or leuprolide implants one week after injection.
  • FIG. 9B presents tumor growth rates from tumors represented in FIG. 9 A.
  • FIG. 1OA presents tumor growth data for small tumors from an experiment in which SK-N-MC brain cancer cells were injected as xenografts into nude mice that were subsequently dosed with placebo or leuprolide implants one week after injection.
  • FIG. 1OB presents tumor growth rates from tumors represented in FIG. 1OA.
  • FIG. 1OC presents tumor growth data for large tumors from an experiment in which SK-N-MC brain cancer cells were injected as xenografts into nude mice that were subsequently dosed with placebo or leuprolide implants one week after injection.
  • FIG. 1OD presents tumor growth rates from tumors represented in FIG. 1OC.
  • FIG. 11 is a schematic overview of the hypothalamic-pituitary-gonadal hormonal axis.
  • the present invention encompasses methods of preventing or treating brain cancer, or preventing or slowing proliferation of neuronal cells, or inhibiting or preventing upregulation of the cell cycle by administering an agent that decreases or regulates blood and brain levels, production, function, or activity of LH or FSH (an "LH/FSH-inhibiting agent")-
  • the LH/FSH-inhibiting agent comprises one or more of gonadotropin releasing hormone (GnRH); leuprolide; triptorelin; buserelin; nafarelin; desorelin; histrelin; goserelin; follistatin; a compound that stimulates the production of follistatin; a GnRH antagonist; a GnRH receptor blocker; citrorelix; abarelix; a vaccine or antibody that stimulates the production of antibodies that inhibit the activity of any of LH, FSH, or GnRH; a vaccine or antibody that stimulates the production of antibodies that block an LH receptor
  • the blood level, production, function, or activity of LH or FSH is decreased or regulated to be near a target blood level, a target production, a target function, or a target activity of LH or FSH, respectively, occurring at or near the time of greatest reproductive function, which in humans corresponds to 18 to 35 years of age.
  • the blood level, production, function, or activity of LH or FSH is decreased or regulated to be approximately as low as possible without unacceptable adverse side effects.
  • An unacceptable adverse side effect is an adverse side effect that, in the reasonable judgment of one of ordinary skill in the art, has costs that outweigh the benefits of treatment.
  • the blood level, production, function, or activity of LH or FSH is decreased or regulated to be undetectable or nearly undetectable by conventional means known in the art, meaning less than 0.7 mIU/mL for both LH and FSH in a clinical laboratory, and lower in a commercial laboratory.
  • Embodiments of the present invention include administration of one or more LH/FSH-inhibiting agents that can be used to decrease or regulate the blood level, production, function, or activity of LH or FSH.
  • GnRH or a GnRH analog can be administered to decrease or regulate the brain or blood level, production, function, or activity of LH or FSH.
  • Studies have shown that increased levels of GnRH or its analogs will result in significant decreases in LH and FSH levels. (Thorner MO, et al., The anterior pituitary, in Williams Textbook of Endocrinology 9 th edition, eds. Wilson JD, Foster DW, Kronenberg H, Larsen PR, 269, W.B.
  • leuprolide a GnRH analog
  • TEP-144-SR Advanced Prostatic Cancer: A Dose Response Evaluation, Drugs in Experimental and Clinical Research, 15:373-387 (1989)
  • pituitary GnRH receptors are down-regulated, resulting in a significant decrease in LH and FSH secretion.
  • GnRH analogs that are useful in the present invention include leuprolide, triptorelin, buserelin, nafarelin, desorelin, histrelin, and goserelin.
  • LH/FSH-inhibiting agents include GnRH antagonists, GnRH receptor blockers, such as citrorelix and abberelix, and LH or FSH receptor blockers.
  • LUPRON ® DEPOT 3.75mg 1 month injection gives a mean plasma leuprolide concentration of 4.6-10.2 ng/ml at 4 hours postdosing
  • LUPRON ® DEPOT 7.5mg 1 month injection gives a mean plasma leuprolide concentration of 20 ng/ml at 4 hours and 0.36 ng/ml at 4 weeks
  • LUPRON ® DEPOT-PED 11.25mg 1 month injection gives a mean plasma leuprolide concentration of 1.25 ng/ml at 4 weeks
  • LUPRON ® DEPOT- PED 15mg injection gives a mean plasma leuprolide concentration of 1.59 ng/ml at 4 weeks
  • LUPRON ® DEPOT 22.5mg 3 month injection gives a mean plasma leuprolide concentration of 48.9 ng/ml at 4 hours and 0.67 ng/
  • vaccines or antibodies can be employed to stimulate the production of antibodies that recognize, bind to, block or substantially reduce the activity of LH, FSH, or GnRH.
  • vaccines or antibodies can be employed to stimulate the production of antibodies that recognize, bind to, or block the receptors for one of LH, FSH, or GnRH. Examples of such vaccines include the Talwar vaccine and the vaccine marketed under the trade name GONADIMMUNE ® by Aphton Corporation.
  • Other LH/FSH-inhibiting agents include compounds that regulate expression of LH and FSH receptors and agents that regulate post-receptor signaling of LH and FSH receptors.
  • a sex steroid hormone such as estrogen, progesterone, or testosterone, or an analog thereof
  • an LH/FSH-inhibiting agent may be co-administered with an LH/FSH-inhibiting agent.
  • the presence of estrogen, progesterone, or testosterone signals the hypothalamus to decrease the secretion of GnRH.
  • the present invention also encompasses co-administration of sex steroids in order to replenish the sex steroids.
  • GnRH agonists are peptides, they are generally not amenable to oral administration. Therefore, they are usually administered subcutaneously, intra- muscularly, or via nasal spray. GnRH agonists are highly potent with serum concentrations of less than 1 ng/ml of leuprolide acetate required for testosterone suppression (Fowler, J. E., Flanagan, M., Gleason, D. M., Klimberg, I.W., Gottesman, J. E., and Sharifi, R. (2000) Evaluation of an implant that delivers leuprolide for 1 year for the palliative treatment of prostate cancer. Urol. 55:639-642).
  • GnRH agonists are also often considered to be ideal for use in long-acting depot delivery systems. At least ten such products are currently marketed in the United States. The duration of action of these products ranges from one month to one year. Leuprolide acetate has been on the market for close to two decades and continues to demonstrate a favorable side effect profile. Most of the side effects such as hot flashes and osteoporosis can be attributed to the loss of sex steroid production (Stege, R. (2000). Potential side-effects of endocrine treatment of long duration in prostate cancer. Prostate Suppl. 10:38-42). Experimental Design
  • LN229 ATCC CRL-2611 cells were prepared by plating in Dulbecco's modified Eagle's medium with 4 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate and 4.5 g/L glucose, 95%; fetal bovine serum, 5%.
  • U87-MG ATCC HTB- 14 cells were prepared by plating in Minimum essential medium (Eagle) with 2 mM L-glutamine and Earle's BSS adjusted to contain 1.5 g/L sodium bicarbonate, 0.1 mM non-essential amino acids, and 1.0 mM sodium pyruvate, 90%; fetal bovine serum, 10%.
  • Ul 18-MG (ATCC HTB-15) cells were prepared by plating in Dulbecco's modified Eagle's medium with 4 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate and 4.5 g/L glucose, 90%; fetal bovine serum, 10%.
  • DAOY (ATCC HTB- 186) cells were prepared by plating in Minimum essential medium (Eagle) with 2 mM L- glutamine and Earle's BSS adjusted to contain 1.5 g/L sodium bicarbonate, 0.1 mM nonessential amino acids, and 1.0 mM sodium pyruvate, 90%; fetal bovine serum, 10%.
  • SK- N-MC ATCC HTB- 10 cells were prepared by plating in Minimum essential medium (Eagle) with 2 mM L-glutamine and Earle's BSS adjusted to contain 1.5 g/L sodium bicarbonate, 0.1 mM non-essential amino acids, and 1.0 mM sodium pyruvate, 90%; fetal bovine serum, 10%.
  • Minimum essential medium Eagle
  • Treatment concentrations were 0 M (control), 10 "11 M (shown as l.OOE-11, 0.012 ng/ml), 10 "9 M (shown as 1.00E-9, 0.0012 ⁇ g/ml), 10 "8 M (shown as 1.00E-8, 0.012 ⁇ g/ml), 10 "7 M (shown as 1.00E-7, 0.12 ⁇ g/ml) and 10 "5 M (shown as 1.00E-5, 12.25 ⁇ g/ml).
  • the number of cells in each group was measured by incubating cells with WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H- tetrazolium, monosodium salt) which produces a water soluble formazan dye that was detected by measuring optical density (at 450 nm) using a ⁇ QuantTM Universal Microplate Spectrophotometer (Bio-Tek ® Instruments, Inc., Winooski, Vermont).
  • WST-8 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H- tetrazolium, monosodium salt
  • mice Male nude:nude athymic mice from Harlan Sprague Dawley (Indianapolis, Indiana) were used. Mice were anesthetized with Domitor/Ketaset and placed under a warming lamp. Tumor cells were injected in Matrigel (BD Biosciences, Bedford, Maryland) and implants were placed subcutaneously into anesthetized mice. Tumor measurements were carried out twice weekly using calipers, and length (1) and width (w) were converted to tumor volumes using the following equation: (w 2 x l)/2. All tumors within one treatment group were used to calculate average tumor volumes ⁇ standard deviations. To calculate tumor growth rates, tumor volumes were normalized to the initial tumor volume (V 0 ).
  • mice were sacrificed by cervical dislocation, and tissues and blood were collected.
  • the DURIN- Leuprolide 2-month implant available from Durect Corporation (Cupertino, California), is a solid formulation comprising approximately 25-30 weight % leuprolide acetate dispersed in a matrix of poly (DL-lactide-co-glycolide).
  • the implant is a cylindrical, opaque rod with nominal dimensions of 1.5 mm (diameter) x 2.0 cm
  • the formulation provides 11.25 mg of leuprolide acetate per 2 cm rod, with a substantially uniform release profile.
  • doses were used: placebo (2 cm of formulation, 0 mg leuprolide acetate); low dose (2 cm of formulation, 11.25 mg leuprolide acetate); medium dose (3 cm of formulation; 16.875 mg leuprolide acetate); high dose (4 cm of formulation; 22.5 mg leuprolide acetate).
  • the dimension on the right-hand axis refers to the length of these implants used for the particular experimental group, and the designations "LA” and “PL” refer respectively to leuprolide acetate and placebo.
  • FIGs. IA-C present results of a series of three experiments on the effects of administration of leuprolide acetate at various molar concentrations on the growth in number of cells of the LN229 adult glioblastoma brain cancer cell line.
  • the source of this cell line was from a glioblastoma in the right frontal parieto-occipital cortex of a 60- year-old female patient.
  • each of five groups of cells from the LN229 cell line was prepared as described above and respectively treated with final concentrations of OM (phosphate buffered saline control), 10 "11 M , 10 “9 M, 10 "7 M, or 10 "5 M leuprolide acetate solution at experiment commencement.
  • the number of cells in each group was measured by incubating cells with WST-8 (as described in Experimental Design) at day 0 (experiment commencement) and on the first, third, and seventh days following commencement.
  • FIG. IA presents the results of this experiment. For each concentration of leuprolide acetate used in this experiment, and for each day on which absorbance was measured, FIG. IA shows, on the vertical axis, the absorbance (450 nm), which indicates cell number as a function of optical density of the formazan dye product.
  • each of five groups of cells from the LN229 cell line was prepared as described above and respectively treated with final concentrations of OM (phosphate buffered saline control), 10 "11 M , 10 “9 M, 10 "7 M, or 10 "5 M leuprolide acetate solution at experiment commencement and every day after commencement out to five days.
  • the number of cells in each group was measured by incubating cells with WST-8 (as described in Experimental Design) at day 0 (experiment commencement) and on the first, second, and fifth days following commencement.
  • FIG. IB presents the results of this experiment. For each concentration of leuprolide acetate used in this experiment, and for each day on which absorbance was measured, FIG. IB shows, on the vertical axis, the absorbance (450 nm), which indicates cell number as a function of optical density of the formazan dye product.
  • each of four groups of cells from the LN229 cell line was prepared as described above and respectively treated with final concentrations of OM (culture medium control), 10 "11 M, 10 "8 M, or 10 "5 M leuprolide acetate solution at experiment commencement and every day after commencement up to seven days.
  • the number of cells was measured by counting at experiment commencement and on the third and seventh days following commencement, using a hemacytometer and microscope by a blinded observer.
  • FIG. 1C presents the results of this experiment. For each concentration of leuprolide acetate used in this experiment, and for each day on which cells were counted, FIG. 1 C shows, on the vertical axis, the number of cells per plate.
  • FIGs. 2A-C present results of a series of three experiments on the effects of administration of leuprolide acetate at various molar concentrations on the growth of cells of the U87-MG adult astrocytoma brain cancer cell line.
  • the source of this cell line was from the brain of an adult female with a malignant glioma (astrocytoma).
  • FIG. 2A presents the results of the cell growth experiment with groups of U87- MG cells respectively administered the concentrations of leuprolide acetate identified in FIG. 2A at experiment commencement and on each day after commencement (0 M, 10 "11 M, 10 "8 M, 10 '5 M).
  • FIG. 2B presents the results of the cell growth experiment with groups of U87- MG cells respectively administered the concentrations of leuprolide acetate identified in FIG. 2B at experiment commencement and on each day after commencement (0 M, 10 "11 M, 10 "8 M, 10 "5 M).
  • FIG. 2C presents the results of the cell growth experiment with groups of U87-
  • MG cells respectively administered the concentrations of leuprolide acetate identified in FIG. 2C at experiment commencement and twice per day after commencement (0 M, 10 " 11 M, 10 "8 M, 10 "5 M).
  • FIG. 3 presents results of two experiments on the effects of administration of leuprolide acetate at various molar concentrations on the growth of cells of the UIl 8-MG adult glioblastoma cell line.
  • the source of this cell line was from a stage III glioblastoma (astrocytoma) from the brain of a 50-year-old male patient.
  • FIG. 3 presents the results of two cell growth experiments (averaged) with groups of Ul 18-MG cells respectively administered the concentrations of leuprolide acetate identified in FIG. 3 at experiment commencement and twice per day after commencement (O M 5 IO- 11 M 5 IO- 8 M 5 IO- 5 M).
  • FIGs. 4A-C present results of a series of three experiments on the effects of administration of leuprolide acetate at various molar concentrations on the growth of cells of the DAOY pediatric medulloblastoma brain cancer cell line.
  • the source of this cell line was from the brain of a 4-year-old male with a desmoplastic cerebellar medulloblastoma.
  • FIG. 4A presents the results of the cell growth experiment with groups of DAOY cells respectively administered the concentrations of leuprolide acetate identified in FIG. 4A at experiment commencement (0 M 5 10 "11 M 5 10 "9 M, 10 "7 M 5 and lO "5 M).
  • FIG. 4B presents the results of the cell growth experiment with groups of DAOY cells respectively administered the concentrations of leuprolide acetate identified in FIG. 4B at experiment commencement and on each day after commencement (0 M 5 10 "11 M, 10 "9 M 5 10 "7 M, and 10 ⁇ s M).
  • FIG. 4C presents the results of a replicate cell growth expeiiment with groups of DAOY cells respectively administered the concentrations of leuprolide acetate identified in FIG. 4C at experiment commencement and on each day after commencement (0 M 5 10 " 11 M 5 IO- 8 M 5 IO- 5 M).
  • administration of the highest concentration (10 " 5 M) of leuprolide acetate once each day inhibited growth of DAOY brain cancer cells by 40% compared to control cells growing in culture medium without leuprolide.
  • FIGs. 5A-C present the results of a series of three experiments on the effects of administration of leuprolide acetate at various molar concentrations on the growth of cells of the SK-N-MC brain cancer cell line.
  • the source of this cell line is from a neuroepithelioma from the supra-orbital area of a 14-year-old female.
  • FIG. 5 A presents the results of the cell growth experiment with groups of SK-N- MC cells respectively administered the concentrations of leuprolide acetate identified in FIG. 5A at experiment commencement (0 M, 10 "u M, 10 "9 M, 10 "7 M, and 10 "5 M).
  • FIG. 5B presents the results of the cell growth experiment with groups of SK-N- MC cells respectively administered the concentrations of leuprolide acetate identified in FIG. 5 A at experiment commencement and each day after commencement (0 M, 10 "11 M, 10 "9 M, 10 "7 M, and 10 "5 M).
  • FIG. 5C presents the results of the cell growth experiment with groups of SK-N- MC cells respectively administered the concentrations of leuprolide acetate identified in FIG. 5C at experiment commencement (0 M, 10 "11 M, 10 "8 M, 10 "5 M).
  • FIGs. 6A and 6B present results of experiments in which 5 x 10 6 cells of the LN229 human glioblastoma brain cancer cell line were injected bilaterally into three groups (two treatment groups and a control group), each with three mice.
  • a controlled-release leuprolide acetate formulation was implanted into each mouse from one of the groups.
  • Two centimeters of leuprolide rod, providing 11.25 mg of leuprolide, or four centimeters of leuprolide rod, providing 22.5 mg of leuprolide, were implanted in each mouse of the treatment groups.
  • Four centimeters of placebo rod (without leuprolide) were implanted one week prior to injection into each mouse of the control group.
  • FIG. 6A presents results of tumor xenograft growth over time in a placebo group and two leuprolide implant groups.
  • tumor volume measurements were commenced on the fourteenth day following injection, when tumors were detectable in all groups.
  • FIG. 6B presents results of measurement of tumor growth rate in each of the treatment and control groups for this experiment.
  • tumors were first observed in all groups and these tumor sizes were used as V 0 for a calculation of growth rate (see Experimental Design). Tumor growth rates were similar in both groups until day 31 after injection, at which time tumors in the placebo group began to grow at a more rapid rate compared to tumors in leuprolide-treated mice.
  • tumors growing in mice treated with leuprolide were smaller by 25% compared to tumors growing in placebo mice, and the tumors in mice treated with 4 cm of leuprolide had doubled in size while tumors growing in placebo mice had increased almost three times over the initial tumor size (Vo).
  • FIGs. 7 A and 7B present results of experiments in which 5 x 10 6 cells of the U87- MG human glioblastoma brain cancer cell line were injected bilaterally into three groups (two treatment groups and a control group), each with three mice. Concurrently with the cell injection, a controlled-release leuprolide acetate formulation was implanted into each mouse from one of the groups. Two centimeters of leuprolide rod, providing 11.25 mg of leuprolide, or four centimeters of leuprolide rod, providing 22.5 mg of leuprolide, were implanted in each mouse of the treatment groups. Four centimeters of placebo rod (without leuprolide) were implanted one week prior to injection into each mouse of the control group.
  • FIG. 7 A presents results of tumor xenograft growth over time in the placebo group and the two leuprolide implant groups.
  • FIG. 7A shows, tumor volume measurements were commenced on the tenth day following injection, when tumors were detectable in all groups.
  • FIG. 7B presents results of measurement of tumor growth rate in each of the treatment and control groups for this experiment.
  • tumors were first observed in all groups and these tumor sizes were used as V 0 for a calculation of growth rate (see Experimental Design). Tumor growth rates were similar in both groups until day 28 after injection, at which time tumors in the placebo group began to grow at a more rapid rate compared to tumors in leuprolide-treated mice.
  • tumors growing in mice treated with leuprolide were smaller by 57% compared to rumors growing in placebo mice, and the tumors in mice treated with 4 cm of leuprolide had grown five times while tumors in the placebo mice had grown twelve times over the initial tumor size (V 0 ).
  • FIGs. 8A-D present results of experiments in which 5 x 10 6 cells of the U87-MG human glioblastoma brain cancer cell line were injected bilaterally into three groups (two treatment groups and a control group), each with four mice.
  • a controlled-release leuprolide acetate formulation was implanted into each mouse from one of the groups.
  • Four centimeters of placebo rod (without leuprolide) was implanted one week prior to injection into each mouse of the control group.
  • Table 1 presents the number of tumors formed and a subgroup analysis of small ( ⁇ 4x V 0 ) and large ( >4x V 0 ) tumors. This data demonstrates that higher doses of leuprolide inhibit the formation of large tumors of the U87-MG cell line.
  • FIG. 8 A presents results of tumor xenograft growth over time in the placebo group and the two leuprolide implant groups.
  • FIG. 8A shows, tumor volume measurements for small tumors were commenced on the fourteenth day following injection, when tumors were detectable in all groups.
  • tumors in the 4 cm treatment group (n 6) had grown to 800 mm 3 on average.
  • FIG. 8B presents results of measurement of tumor growth rate in each of the treatment and control groups for this experiment.
  • tumors were first observed in all groups and these tumor sizes were used as V 0 for a calculation of growth rate (see Experimental Design). Tumor growth rates were similar in both groups until day 34 after injection, at which time tumors in the 2 cm leuprolide group began to grow at a more rapid rate compared to tumors in the placebo and 4 cm leuprolide-treated mice.
  • mice treated with 4 cm leuprolide were smaller by 25 % compared to tumors growing in placebo mice; and the tumors in mice treated with 4 cm of leuprolide had grown seven times, tumors in the placebo mice had grown seven times, and tumors in mice treated with 2 cm of leuprolide had grown twelve times over the initial tumor size (V 0 ).
  • FIG. 8C presents results of tumor xenograft growth over time in the placebo group and the two leuprolide implant groups.
  • FIG. 8C shows, tumor volume measurements for large tumors were commenced on the fourteenth day following injection, when tumors were detectable in all groups. By the thirty-ninth day following injection, large tumors in all groups had grown to approximately 2250 mm 3 .
  • FIG. 8D presents results of measurement of tumor growth rate for large tumors in each of the treatment and control groups for this experiment.
  • tumors were first observed in all groups and these tumor sizes were used as V 0 for a calculation of growth rate (see Experimental Design). Tumor growth rates were similar in all groups until day 39 after injection.
  • mice treated with leuprolide far fewer large tumors formed in mice treated with leuprolide.
  • tumors growing in placebo or leuprolide-treated mice were of a similar volume and grew at similar rates.
  • FIGs. 9A and 9B present results of experiments in which 5 x 10 6 cells of the DAOY human pediatric medulloblastoma brain cancer cell line were injected bilaterally into three groups (two treatment groups and a control group), each with three mice.
  • a controlled-release leuprolide acetate formulation was implanted into each mouse from one of the groups.
  • Two centimeters of leuprolide rod, providing 11.25 mg of leuprolide, or four centimeters of leuprolide rod, providing 22.5 mg of leuprolide, were implanted in each mouse of the treatment groups.
  • Four centimeters of placebo rod (without leuprolide) were implanted one week prior to injection into each mouse of the control group.
  • FIG. 9A presents results of tumor xenograft growth over time in the placebo group and the two leuprolide implant groups.
  • FIG. 9A shows, tumor volume measurements for all tumors were commenced on the seventh day following injection, when tumors were detectable in all groups.
  • FIG. 9B presents results of measurement of tumor growth rate in each of the treatment and control groups for this experiment.
  • tumors were first observed in all groups, and these tumor sizes were used as V 0 for a calculation of growth rate (see Experimental Design).
  • Tumor growth rates were similar in both groups until day 24 after injection, at which time tumors in the placebo and 4 cm leuprolide groups began to grow at a more rapid rate compared to tumors in the 2 cm leuprolide-treated mice.
  • FIGs. 10A-D present results of experiments in which 5 x 10 6 cells of the SK-N- MC human pediatric neuroblastoma brain cancer cell line were injected bilaterally into three groups (two treatment groups and a control group), each with three mice.
  • a controlled-release leuprolide acetate formulation was implanted into each mouse from one of the groups.
  • Two centimeters of leuprolide rod, providing 11.25 mg of leuprolide, or four centimeters of leuprolide rod, providing 22.5 mg of leuprolide, were implanted in each mouse of the treatment groups.
  • Four centimeters of placebo rod (without leuprolide) were implanted one week prior to injection into each mouse of the control group.
  • Table 2 presents the number of tumors formed in three mice per group, percent of large tumors ( >10x V 0 ), and the average volumes of large and small tumors. While leuprolide (LA) treated mice had more large tumors, the large tumors in those mice were smaller than the large tumors in the placebo (PL) group.
  • LA leuprolide
  • FIG. 1OA presents results of tumor xenograft growth for small tumors over time in a placebo group and two leuprolide implant groups.
  • FIG. 1OA shows, tumor volume measurements for small tumors were commenced on the sixth day following injection, when tumors were detectable in all groups.
  • FIG. 1OB presents results of measurement of tumor growth rate for small tumors in each of the treatment and control groups for this experiment.
  • tumors were first observed in all groups, and these tumor sizes were used as V 0 for a calculation of growth rate (see Experimental Design).
  • Tumor growth rates were similar in both groups until day 16 after injection, at which time tumors in the placebo group began to grow at a more rapid rate compared to tumors in the 2 cm and 4 cm leuprolide-treated mice.
  • Tumors in the placebo group had increased by almost eight fold while tumors in the leuprolide-treated mice had increased by only 3.5 fold.
  • FIG. 1OC presents results of tumor xenograft growth over time in the placebo group and the two leuprolide implant groups.
  • FIG. 1OC shows, tumor volume measurements for large tumors were commenced on the sixth day following injection, when tumors were detectable in all groups.
  • large tumors in the placebo group had grown to 8200 mm 3 on average, while tumors in the mice treated with 2 cm leuprolide were 3200 mm 3 on average, and tumors in the mice treated with 4 cm leuprolide were 4200 mm 3 on average.
  • FIG. 1OD presents results of measurement of tumor growth rate for large tumors in each of the treatment and control groups for this experiment.
  • tumors were first observed in all groups, and these tumor sizes were used as V 0 for a calculation of growth rate (see Experimental Design).
  • Tumor growth rates were similar in both groups until day 20 after injection, at which time tumors in the placebo group began to grow at a more rapid rate compared to tumors in the 2 cm and 4 cm leuprolide-treated mice.
  • Tumors in the placebo group had increased by almost thirty- five fold while tumors in the leuprolide-treated mice had increased by only twenty-five fold.
  • brain cancer is prevented, treated, delayed, or mitigated by administering a dosage regimen of GnRH agonists or antagonists that is at least about two to three times higher, and in other embodiments more than three times higher, than is currently approved for other indications. Since no toxic dose of GnRH agonists is believed to have been documented, other embodiments of this invention include treating, preventing, slowing the progression of, or mitigation of brain cancer by continually increasing the dose of the GnRH agonist or antagonist until a decrease in a brain cancer-specific marker is achieved, or until the patient develops adverse effects that represent greater risk or discomfort than does the risk or discomfort of the brain cancer.
  • brain cancer would be prevented, treated, delayed, or mitigated by directly and constantly infusing GnRH agonists or antagonists into the affected tissue, for example, from a reservoir into the spinal cavity via a catheter (such as a fenestrated catheter) embedded directly into the spine of a patient.
  • the drug is thus directly delivered to the brain through the cerebrospinal fluid rather than indirectly delivered through the bloodstream. It is well known in the art to deliver drugs by infusion through a catheter embedded directly in a part of a patient's body requiring treatment, for example, in the liver of a patient requiring chemotherapy drugs for the treatment of liver cancer.
  • controlled release formulations of GnRH agonists or antagonists would be implanted directly into or near the brain tissue in order to prevent, treat, delay, or mitigate brain cancer, for example by implantation directly into the brain following a surgical resection of a tumor. This would allow for high brain concentrations of the GnRH agonist or antagonist while minimizing peripheral exposure.
  • a needle may be used to inject about 1 mg/day of GnRH agonists or antagonists into a patient.
  • a dose of a GnRH agonist or antagonist administered for the prevention, treatment, delay, or mitigation of brain cancer, when delivered by implantation of controlled release formulations directly into or near the brain results in serum and/or brain tissue levels up to 3 ng/ml or more.
  • the dosage regime of GnRH agonist or antagonist to treat, prevent, mitigate, or slow the progression of brain cancer would be a physiologically equivalent dose to a dose of leuprolide in the range of 11.25 mg/month to 22.5 mg/month, or a dose of an agent resulting in daily dosages physiologically equivalent to a dose of leuprolide of approximately 0.375 mg/day to approximately 0.75 mg/day.
  • the controlled release formulation would be formulated to maintain the tissue concentration of the GnRH agonist or antagonist at levels that produce the same or similar physiological effects as dosages of leuprolide of 7.5 mg/month, 11.25 mg/month, 22.5 mg/month, or more.
  • the higher tissue concentration would be substantially sustained at a high level instead of spiking initially and briefly to a very high level and then dropping substantially.
  • implanted controlled release formulations of GnRH agonists or antagonists would achieve a release profile that provides a substantially stable serum concentration of GnRH agonists or antagonists that is at least about two to five times the serum concentration provided by currently-known cancer treatments using GnRH agonists or antagonists (for example, treatments for prostate cancer), in which the serum concentration is substantially sustained at the higher level instead of spiking initially and briefly to a very high level and then dropping substantially.
  • an implanted controlled release formulation of the present invention for preventing, treating, delaying, or mitigating brain cancer would provide a GnRH agonist or antagonist serum concentration of at least about 3 ng/ml, in embodiments up to 10 ng/ml or more over the lifetime of the formulation.
  • GnRH agonist or antagonist serum concentration of at least about 3 ng/ml, in embodiments up to 10 ng/ml or more over the lifetime of the formulation.
  • GnRH agonists or antagonists include but are not limited to Antide ® brand of iturelix; Lupron ® brand of leuprolide acetate; Zoladex ® brand of goserelin acetate; Synarel ® brand of nafarelin acetate; Trelstar Depot brand of triptorelin; Supprelin brand of histrelin; Suprefact brand ofbuserelin; Cetrotide ® brand of cetrorelix; Plenaxis ® brand of abarelix; Antagon brand of ganirelix; and degarelix (FE200486).
  • Embodiments of the present invention also include treating, mitigating, slowing the progression of, or preventing brain cancer by co-administering a GnRH agonist or antagonist with standard chemotherapeutic treatment.
  • Embodiments of the present invention further include treating, mitigating, slowing the progression of, or preventing brain cancer by co-administering a GnRH agonist or antagonist with standard radiation therapy or high-dose radiation delivered by a "gamma knife.”
  • Embodiments of the present invention also include treating, mitigating, slowing the progression of, or preventing brain cancer by administering a GnRH agonist or antagonist prior to surgical resection of a brain tumor.
  • Embodiments of the present invention additionally include treating, mitigating, slowing the progression of, or preventing brain cancer by administering a GnRH agonist or antagonist during the immediate period after a surgical resection and indefinitely thereafter to prevent tumor recurrence.
  • Embodiments of the present invention also include treating, mitigating, slowing the progression of, or preventing brain cancer by co-administering a GnRH agonist or antagonist with LH receptor blockers or analogues thereof, which include but are not limited to interleukin-1 and anti-LH receptor immunoglobulins; co-administering a GnRH agonist or antagonist with activin receptor blockers or analogues thereof; and administering other agents, including agents not yet known, that decrease the degradation of, increase the half-life of, or increase brain tissue levels of GnRH agonists or antagonists.
  • a GnRH agonist or antagonist with LH receptor blockers or analogues thereof, which include but are not limited to interleukin-1 and anti-LH receptor immunoglobulins
  • co-administering a GnRH agonist or antagonist with activin receptor blockers or analogues thereof and administering other agents, including agents not yet known, that decrease the degradation of, increase the half-life of
  • the present invention encompasses pharmaceutical formulations containing GnRH agonists and/or GnRH antagonists and which are configured to be implanted in or near brain tissue and to provide serum concentrations or certain tissue concentrations of the GnRH agonists and/or GnRH antagonists substantially higher than serum levels resulting from conventional cancer treatments using GnRH agonists or antagonists, such as, for example, conventional prostate cancer treatments.
  • the pharmaceutical formulations could be used, for example, to treat, delay, mitigate, or prevent brain cancer.

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Abstract

L'invention concerne des méthodes permettant de traiter le cancer du cerveau, de prévenir ou de ralentir la prolifération des cellules d'origine cérébrale, de prévenir le cancer du cerveau chez un patient présentant un risque de contracter un tel cancer, de prévenir ou d'inhiber une dérégulation à la hausse du cycle cellulaire des cellules d'origine cérébrale chez un patient, et de réduire le taux d'antigène spécifique du cerveau chez un patient.
PCT/US2005/025132 2005-07-14 2005-07-14 Methodes de traitement et de prevention des cancers du cerveau WO2007011339A1 (fr)

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US20110201563A1 (en) * 2008-05-13 2011-08-18 Yale University Chimeric small molecules for the recruitment of antibodies to cancer cells

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Publication number Priority date Publication date Assignee Title
US20110201563A1 (en) * 2008-05-13 2011-08-18 Yale University Chimeric small molecules for the recruitment of antibodies to cancer cells
US8859509B2 (en) * 2008-05-13 2014-10-14 Yale University Chimeric small molecules for the recruitment of antibodies to cancer cells

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