HEDGEHOG PATHWAY INHIBITORS

• US 20120020876A1
• Filed: 01/22/2010
• Published: 01/26/2012
• Est. Priority Date: 01/23/2009
• Status: Abandoned Application

• Current Assignee: Cancer Research Technology Limited (Cancer Research UK)
• Original Assignee: Cancer Research Technology Limited (Cancer Research UK)
• Inventors: Olive, Kenneth Paul, Tuveson, David
• Application Number:
  US13/144,992
• Publication Number:
  US 20120020876A1
• Time in Patent Office: Days
• US Class Current: 424/1.11
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

This disclosure generally relates to methods useful for improving, for example, blood vessel density and/or blood vessel patency to a tissue by administration of a hedgehog pathway inhibitor. In certain embodiments, the hedgehog pathway inhibitor is administered with an agent to improve the delivery of the agent to the tissue. In certain embodiments, the tissue comprises tumor tissue.

Claims

1. A method of:

increasing delivery of an agent to a tissue, or treating or preventing tumor metastasis in a mammal, comprising administering a hedgehog pathway inhibitor and said agent to said tissue;

increasing blood density in a tissue, reducing stromal content in a tissue, increasing blood vessel patency in a tissue, or promoting angiogenesis in a tissue, comprising administering a hedgehog pathway inhibitor to said tissue;

or

imaging a tissue, comprising the steps of administering a hedgehog inhibitor to said tissue and using an imaging technique to image said tissue;

or

imaging a tissue comprises the steps of administering a hedgehog pathway inhibitor and an imaging agent to said tissue and using an imaging technique to image said tissue.

2. The method of claim 1, wherein said hedgehog pathway inhibitor and said agent are administered concurrently.

3. The method of claim 1, wherein said hedgehog pathway inhibitor and said agent are administered sequentially.

4. The method of claim 1, wherein said agent is a chemotherapeutic agent, a therapeutic agent or an imaging agent.

5. The method of claim 4, wherein said imaging agent is a magnetic resonance imaging (MRI) contrast agent, computerized axial tomography (CAT) contrast agent, or positron emission tomography (PET) contrast agent.

7. The method of claim 1, wherein said tissue comprises autochthonous tissue;

stromal tissue;

ischemic tissue;

tumor tissue;

tumor tissue exhibiting Hedgehog activation;

tumor tissue exhibiting Hedgehog activation characterized by one or more of phenotypes selected from group consisting of a Patched (Ptc) loss-of-function phenotype or a Smoothened (Smo) gain-of-function phenotype;

cardiac tissue;

or brain tissue.

17. The method of claim 7, wherein said autochthonous tumor is a pancreatic tumor, a prostate tumor, a breast tumor, a desmoplastic small round cell tumor, a colon tumor, an ovarion tumor, a bladder tumor, or an osteocarcinoma.

18. The method of claim 4, wherein said agent is a chemotherapeutic agent;

and wherein said administering comprises administering said hedgehog pathway inhibitor prior to initiating administration of said chemotherapeutic agent;

or

said administering comprises administering said hedgehog pathway inhibitor from about 3 days to about 21 days;

said administering comprises administering said hedgehog pathway inhibitor from about 3 days to about 21 days prior to initiating administration of said chemotherapeutic agent;

or

said administering comprises administering said hedgehog pathway inhibitor from about 3 days to about 14 days prior to initiating administration of said chemotherapeutic agent.

24. The method of claim 4, wherein said chemotherapeutic agent is selected from the group consisting of gemcitabine, capecitabine, 5-fluorouracil, floxuridine, doxifluridine, ratitrexed, methotrexate, trimetrexate, thapsigargin, taxol, paclitaxel, docetaxel, actinomycin D, dactinomycin, mercaptopurine, thioguanine, lovastatin, cytosine arabinoside, fludarabine, hydroxyurea, cytarabine, cytarabine, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, crisnatol, busulfan, mytomycin C, treosulfan, staurosporine, 1-methyl-4-phenylpyridinium, mercaptopurine, thioguanine, cyclophosphamide, ifosfamide, EB 1089, CB 1093, KH 1060, carmustine, lomustine, mycophenolic acid, tiazofurin, ribavirin, EICAR, cisplatin, carboplatin, oxaliplatin, bevacizumab, mitomycin, dacarbazine, procarbizine, etoposides, prednisolone, trofosfamide, chlorambucil, melphalan, estramustine, dexamethasone, cytarbine, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, doxorubicin, epirubicin, pirarubicin, zorubicin, verapamil, mitoxantrone, temozolomide, dactinomycin, plicamycin, bleomycin A2, bleomycin B2, peplomycin, asparaginase, vinblastine, vincristine, vindesine, vinorelbine, imatinib, thalidomide, leucovirin, deferoxamine, lenalidomide, bortezomib, erlotinib, gefitinib, sorafenib, erbitux, and sutinib.

34. The method of claim 1, wherein said administering comprises administering said hedgehog pathway inhibitor prior to initiating administration of said imaging agent.

40. The method of claim 1, wherein said imaging technique is ultrasound, X-ray, MRI, CAT, or PET.

74. The method of claim 1, wherein said hedgehog pathway inhibitor is selected from the group consisting of a compound of Formula I, Formula II, or Formula III:

75. The method of claim 74, wherein:

A is;

76. The method of claim 74, wherein the compound is a compound of formula I-32:

77. The method of claim 76, wherein the compound is

78. The method of claim 1, wherein said hedgehog pathway inhibitor is selected from MK-4101, GDC-0449, BMS-833923, LDE-225, PF-04449913, robotnikinin, and Cur-61414.

79. The method of claim 1, wherein said hedgehog pathway inhibitor is MK-4101

6. (canceled)

8-16. -16. (canceled)

19-23. -23. (canceled)

25-33. -33. (canceled)

35-39. -39. (canceled)

41-73. -73. (canceled)

80-106. -106. (canceled)