WO2013103792A2 - Procédé de traitement du cancer par administration de faibles taux de protéine de choc thermique 70 (hsp70) - Google Patents

Procédé de traitement du cancer par administration de faibles taux de protéine de choc thermique 70 (hsp70) Download PDF

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Publication number
WO2013103792A2
WO2013103792A2 PCT/US2013/020252 US2013020252W WO2013103792A2 WO 2013103792 A2 WO2013103792 A2 WO 2013103792A2 US 2013020252 W US2013020252 W US 2013020252W WO 2013103792 A2 WO2013103792 A2 WO 2013103792A2
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WO
WIPO (PCT)
Prior art keywords
hsp70
tumors
carcinoma
administered
cancer
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PCT/US2013/020252
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English (en)
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WO2013103792A3 (fr
Inventor
John Mcmichael
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Beech Tree Labs, 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.)
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Publication date
Application filed by Beech Tree Labs, Inc. filed Critical Beech Tree Labs, Inc.
Priority to JP2014551330A priority Critical patent/JP2015515445A/ja
Priority to EP13733755.6A priority patent/EP2800577A2/fr
Priority to AU2013207466A priority patent/AU2013207466A1/en
Priority to CA2858427A priority patent/CA2858427A1/fr
Publication of WO2013103792A2 publication Critical patent/WO2013103792A2/fr
Priority to IL232732A priority patent/IL232732A0/en
Publication of WO2013103792A3 publication Critical patent/WO2013103792A3/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
    • A61K38/1703—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. There are several different heat shock proteins which are named according to their weights. Heat shock proteins are expressed when cells are exposed to elevated temperatures or other stresses such as infection, inflammation, exposure to toxins, starvation and water deprivation, hypoxia, radiation exposure and the like.
  • Hsp 60, Hsp 70, Hsp90 and Hsp 100 are different proteins where the number reflects their approximate molecular weight in kilodaltons.
  • the major heat shock proteins are expressed at high levels in stressed cells but occur at low to moderate levels in cells which have not been stressed.
  • Hsp70 is hardly detectable at normal temperatures but is highly expressed in cells upon heat shock.
  • Hsp60 and Hsp90 are more highly expressed under normal conditions but have their expression further induced by heat.
  • Heat Shock Protein 70 is a chaperone protein with an approximate weight of 70 kilodaltons that acts as a quality control mechanism to protect amino acids as they align to become a protein. It appears to be up-regulated in transformed cells, consistent with the tendency of those cells to exhibit an increased metabolic rate compared to normal cells. Because of their apparent relationship to cancer there is much interest in heat shock proteins as a target for cancer prevention and treatment.
  • Heat shock proteins are used as immunologic adjuvants in boosting responses to vaccine.
  • Multhoff, U.S. Patent No. 7,700,737 discloses anti-Hsp70 antibodies for use in diagnosis and therapy of primary and metastatic neoplastic diseases.
  • a potential limitation of such therapy is that treating a cancer patient with anti-Hsp70 monoclonal antibodies may well destroy the cancer cell target, but would simultaneously damage healthy cells for which Hsp70 activity is essential.
  • Hsp preparation is said to comprise "HSP-peptide complexes which display the antigenicity of an agent of the infectious disease.” (col. 8, lines 31-33).
  • Dosages of HSP's are said to range from O. ⁇ g to 1000 ⁇ g per administration with preferred dosages of Hsp70 said to be in the range of from 10 to 600 ⁇ g per administration if administered intradermally. (col. 50, lines 36-49)
  • the present invention relates to the discovery that administration of small dosages of HSP70 is useful in the treatment of various cancers. While not wishing to be bound by any particular theory of the invention it is believed that the introduction of low levels of HSP70 may induce a negative feedback loop in transformed cells such that the endogenous production of HSP70 in those cells would be decreased. Such a reduction would render the cancer cells more susceptible to attacks by the subject's own immune system and other cancer therapies.
  • the invention provides a method of treating cancer in a subject in need thereof comprising: administering an effective amount of heat shock protein 70 (Hsp70) to said subject.
  • the subject can be any mammal including a human and the cancer is selected from the group of cancers comprising brain tumors (including meningiomas, glioblastoma multiforme, anaplastic astrocytomas, cerebellar astrocytomas, other high-grade or low-grade astrocytomas, brain stem gliomas, oligodendrogliomas, mixed gliomas, other gliomas, cerebral neuroblastomas, craniopharyngiomas, diencephalic gliomas, germinomas, medulloblastomas, ependymomas, choroid plexus tumors, pineal parenchymal tumors, gangliogliomas, neuroepithelial tumors, neuronal or mixed neuronal glial tumors), lung tumors (including small cell carcinomas
  • the Hsp70 is preferably administered in the absence of any vaccine and more preferably is not complexed to any other molecule.
  • the method is particularly useful because the Hsp70 is administered at a relatively low dosages.
  • the Hsp70 can be administered at daily dosages of from 0.0003 micrograms to 3 micrograms per day, with daily dosages of from 0.003 micrograms to 0.3 micrograms per day being particularly preferred.
  • the dosage is preferably administered in one or more doses during the day with four dosages totaling about 0.03 micrograms per day being particularly preferred.
  • the Hsp70 may be administered by a variety of modes including a mode selected from the group consisting of sublingual, bucal, oral drench, subcutaneous, intramuscular, intradermal, or intravenous administration although sublingual administration is particularly preferred.
  • FIG. 1 depicts transcription levels of Hsp70 mRNA in cancerous cell lines treated with Hsp70 protein.
  • the present invention relates to the discovery that administration of small dosages of HSP70 is useful in the treatment of various cancers.
  • the cancer is selected from the group of cancers comprising brain tumors (including meningiomas, glioblastoma multiforme, anaplastic astrocytomas, cerebellar astrocytomas, other high-grade or low-grade astrocytomas, brain stem gliomas, oligodendrogliomas, mixed gliomas, other gliomas, cerebral neuroblastomas, craniopharyngiomas, diencephalic gliomas, germinomas, medulloblastomas, ependymomas, choroid plexus tumors, pineal parenchymal tumors, gangliogliomas, neuroepithelial tumors, neuronal or mixed neuronal glial tumors), lung tumors (including small cell carcinomas, epidermoid carcinomas, adenocarcinomas, large cell carcinomas, car
  • RNA samples were collected to determine endogenous production of Hsp 70 RNA.
  • the cells were subjected to RNA extraction by Trizol and RNA quality and quantity were measured by a Nano-drop spectrophotometer (Thermo-Fisher Scientific, Wilmington, DE).
  • RT-PCR Real-time PCR
  • qPCR were conducted according to the manufacturer's protocol (Quigen) to determine levels of Hsp70 mRNA.
  • the results presented in Fig. 1 show that treatment with Hsp70 reduced endogenous Hsp70 transcription by 40-60% in the treated breast cancer cells.
  • the presence of the exogenous Hsp 70 functions to downregulate the production of endogenous Hsp 70 by the tumor. Because the Hsp 70 is a required protein for the tumor cells, remission is thereby induced.
  • a 33 year old male was diagnosed with a stage 4 glioblastoma multiform following a seizure and was treated in accordance with the invention.
  • sequential MRIs showed a rapidly progressing tumor.
  • Two rounds of surgery and one round each of chemotherapy and radiation failed to eliminate the cancer.
  • Eight months after the original diagnosis the patient was admitted to the hospital in a rapidly deteriorating progressing over a 3-4 hour period during which he suffered loss of motor skills, speech, and finally consciousness. He was labeled "comatose" upon admission. Following aggressive intervention of several types, he was discharged four days later in a weakened state with impaired cognition and both gross and fine motor function.
  • peripheral blood mononuclear cells were treated with various doses of Hsp70 (0. IX, IX or 10X) for 24 hours.
  • Hsp70 (0. IX, IX or 10X)
  • Cancer Pathway Finder qPCR arrays were utilized to determine gene expression of the PBMCs compared to untreated controls.
  • SERPINB2 urokinase plasminogen activator
  • expression of ARNT and/or SERPINB2 is associated with tumor development and invasiveness.
  • this data confirms the that Hsp70 is useful in treating cancer a subject by downregulating the expression of at least two tumor-expressing genes (e.g., ARNT and SERPINB2).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des procédés de traitement du cancer par administration de protéine de choc thermique 70 (Hsp70) au sujet atteint de cancer.
PCT/US2013/020252 2012-01-05 2013-01-04 Procédé de traitement du cancer par administration de faibles taux de protéine de choc thermique 70 (hsp70) WO2013103792A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2014551330A JP2015515445A (ja) 2012-01-05 2013-01-04 低レベルの熱ショックタンパク質７０（Ｈｓｐ７０）を投与することによって癌を処置する方法
EP13733755.6A EP2800577A2 (fr) 2012-01-05 2013-01-04 Procédé de traitement du cancer par administration de faibles taux de protéine de choc thermique 70 (hsp70)
AU2013207466A AU2013207466A1 (en) 2012-01-05 2013-01-04 Method of treating cancer by administration of low levels of heat shock protein 70 (Hsp70)
CA2858427A CA2858427A1 (fr) 2012-01-05 2013-01-04 Procede de traitement du cancer par administration de faibles taux de proteine de choc thermique 70 (hsp70)
IL232732A IL232732A0 (en) 2012-01-05 2014-05-21 A method of treating cancer by administering low levels of heat shock protein 70

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261583535P 2012-01-05 2012-01-05
US61/583,535 2012-01-05

Publications (2)

Publication Number Publication Date
WO2013103792A2 true WO2013103792A2 (fr) 2013-07-11
WO2013103792A3 WO2013103792A3 (fr) 2015-01-22

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PCT/US2013/020252 WO2013103792A2 (fr) 2012-01-05 2013-01-04 Procédé de traitement du cancer par administration de faibles taux de protéine de choc thermique 70 (hsp70)

Country Status (6)

Country Link
EP (1) EP2800577A2 (fr)
JP (1) JP2015515445A (fr)
AU (1) AU2013207466A1 (fr)
CA (1) CA2858427A1 (fr)
IL (1) IL232732A0 (fr)
WO (1) WO2013103792A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202019398A (zh) * 2018-06-28 2020-06-01 張翔毓 用於治療或預防構形疾病之方法及藥物篩選方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396681B1 (en) * 1998-03-27 2008-07-08 Gabriele Multhoff Application of Hsp70 proteins
US20110286993A1 (en) * 2008-06-26 2011-11-24 Orphazyme ApS c/o COBIS A/S Use of hsp70 as a regulator of enzymatic activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396681B1 (en) * 1998-03-27 2008-07-08 Gabriele Multhoff Application of Hsp70 proteins
US20110286993A1 (en) * 2008-06-26 2011-11-24 Orphazyme ApS c/o COBIS A/S Use of hsp70 as a regulator of enzymatic activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ISHIKAWA ET AL.: 'Intratumoral injection of IL -2-activated NK cells enhances the antitumor effect of intradermally injected paraformaldehyde-fixed tumor vaccine in a rat intracranial brain tumor model.' CANCER SCI. vol. 95, no. 1, January 2004, pages 98 - 103, XP055173453 *

Also Published As

Publication number Publication date
JP2015515445A (ja) 2015-05-28
CA2858427A1 (fr) 2013-07-11
AU2013207466A1 (en) 2014-06-12
WO2013103792A3 (fr) 2015-01-22
EP2800577A2 (fr) 2014-11-12
IL232732A0 (en) 2014-07-31

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