WO2011063309A1 - Procédés et compositions de traitement de cancers associés à hedgehog - Google Patents

Procédés et compositions de traitement de cancers associés à hedgehog Download PDF

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Publication number
WO2011063309A1
WO2011063309A1 PCT/US2010/057534 US2010057534W WO2011063309A1 WO 2011063309 A1 WO2011063309 A1 WO 2011063309A1 US 2010057534 W US2010057534 W US 2010057534W WO 2011063309 A1 WO2011063309 A1 WO 2011063309A1
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Prior art keywords
cancer
inhibitor
hedgehog
tumor
agent
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PCT/US2010/057534
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English (en)
Inventor
Veronica Travaglione
John Macdougall
Karen J. Mcgovern
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Infinity Pharmaceuticals, Inc.
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Filing date
Publication date
Priority claimed from US12/762,008 external-priority patent/US20100297118A1/en
Application filed by Infinity Pharmaceuticals, Inc. filed Critical Infinity Pharmaceuticals, Inc.
Priority to JP2012540121A priority Critical patent/JP2013511549A/ja
Priority to AU2010321773A priority patent/AU2010321773A1/en
Priority to EP10832305A priority patent/EP2502078A1/fr
Priority to CA2781300A priority patent/CA2781300A1/fr
Publication of WO2011063309A1 publication Critical patent/WO2011063309A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Hedgehog signaling plays a role in many stages of development, especially in formation of left-right symmetry. Loss or reduction of hedgehog signaling leads to multiple developmental deficits and malformations, one of the most striking of which is cyclopia.
  • the invention discloses, at least in part, that a hedgehog (Hh) inhibitor, as a single agent or in combination with other anti-cancer agents, can reduce hedgehog-associated cancer cell growth.
  • a hedgehog inhibitor alone or in combination with a tyrosine kinase inhibitor ⁇ e.g., sunitinib
  • administration of the hedgehog inhibitor reduced the expression of hedgehog-dependent markers (e.g., genes) in stroma surrounding neuroendocrine cancers, while no significant effect was detected on hedgehog dependent markers (e.g., genes) in the neuroendocrine tumor cells.
  • a hedgehog inhibitor in other embodiments, administration of a hedgehog inhibitor, alone or in combination with an mTOR inhibitor or other anti-cancer agents (e.g., one or more of: doxorubicin, cisplatin, ifosfamide, or methotrexate (e.g., high dose methotrexate)) reduced the growth and/or tumor progression of musculoskeletal sarcomas, such as chondrosarcomas and osteosarcomas.
  • methotrexate e.g., high dose methotrexate
  • administration of a hedgehog inhibitor in combination with paclitaxel or a paclitaxel agent reduces the growth and/or tumor progression of a pancreatic cancer, e.g., metastatic pancreatic cancer, to a greater extent than
  • the combination of the hedgehog inhibitor and paclitaxel or paclitaxel agent can further include gemcitabine (e.g., GEMZAR®). It is Attorney Docket No. I2041-7000WO/3020PCT believed that administration of the hedgehog inhibitor results in enhancement of the delivery of the paclitaxel or the paclitaxel agent and/or gemcitabine, when used in combination, compared to the use of the paclitaxel or paclitaxel agent (and/or gemcitabine) without the hedgehog inhibitor.
  • the subject is a patient with metastastatic pancreatic cancer.
  • the subject is a patient with pancreatic or metastastatic pancreatic cancer who has received no prior cancer treatment (e.g., no prior exposure to other anti-cancer agent, surgical or radiation procedure for, e.g., no prior cancer treatment for their disease).
  • no prior cancer treatment e.g., no prior exposure to other anti-cancer agent, surgical or radiation procedure for, e.g., no prior cancer treatment for their disease.
  • a hedgehog inhibitor in combination with a VEGF (Vascular Endothelial Growth Factor) antagonist e.g., an anti-VEGF antibody (e.g., bevacizumab)
  • VEGF Vascular Endothelial Growth Factor
  • an anti-VEGF antibody e.g., bevacizumab
  • a hedgehog inhibitor in combination with a tyrosine kinase inhibitor (e.g., a receptor tyrosine kinase (RTK) inhibitor, such as an EGFR inhibitor) reduces the growth and/or tumor progression of a head and neck cancer and/or lung cancer (e.g., non-small cell lung cancer).
  • a tyrosine kinase inhibitor e.g., a receptor tyrosine kinase (RTK) inhibitor, such as an EGFR inhibitor
  • RTK receptor tyrosine kinase
  • lung cancer e.g., non-small cell lung cancer
  • the hedgehog inhibitor extends the relapse free survival of a subject who is undergoing, or has been previously treated with, another anti-cancer agent (e.g., a tyrosine kinase inhibitor).
  • the tyrosine kinase inhibitor is geftinib or cetuximab.
  • the hedgehog inhibitor reduces or inhibits tumor re-growth of a hedgehog-associated cancer after therapy with a tyrosine kinase inhibitor is less effective or ineffective (e.g., a subject having a relapse after therapy with, or a tumor developing resistance to, a tyrosine kinase inhibitor).
  • the subject is a patient with lung cancer (e.g., non-small cell lung cancer) who relapses after geftinib therapy.
  • the subject is a patient with head and neck squamous cell carcinoma (FINSCC) who is undergoing or has undergone therapy with a tyrosine kinase inhibitor (e.g., an EGFR tyrosine kinase inhibitor such as cetuximab).
  • a tyrosine kinase inhibitor e.g., an EGFR tyrosine kinase inhibitor such as cetuximab.
  • a hedgehog-associated cancer e.g., a hedgehog ligand-dependent cancer cell growth chosen from a
  • a sarcoma e.g., a musculoskeletal or soft-tissue sarcoma, such as chondrosarcoma, osteosarcoma, synovial sarcoma or liposarcoma
  • a head and neck Attorney Docket No. I2041-7000WO/3020PCT cancer
  • a lung cancer by administering to a subject a hedgehog inhibitor, alone or combination with another anti-cancer agent (e.g., paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor (e.g., receptor tyrosine kinase (RTK) inhibitor) or an mTOR inhibitor) are disclosed.
  • another anti-cancer agent e.g., paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor (e.g., receptor tyrosine kinase (RTK) inhibitor) or an mTOR inhibitor
  • the invention features a method of reducing or inhibiting growth of a tumor or cancer, e.g., a hedgehog-associated tumor or cancer, in a subject.
  • the invention also features a method of treating a subject having, or at risk of having, a tumor or cancer, e.g., a hedgehog-associated cancer or tumor.
  • the method includes administering to the subject a hedgehog inhibitor, e.g., one or more hedgehog inhibitors as described herein, in an amount sufficient to reduce or inhibit the tumor cell growth, and/or treat or prevent the cancer or tumor, in the subject.
  • a hedgehog inhibitor e.g., one or more hedgehog inhibitors as described herein
  • the hedgehog inhibitor is administered as a single agent, or in combination with other anti-cancer agents (e.g., in combination with a paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor (e.g., receptor tyrosine kinase (RTK) inhibitor), an mTOR inhibitoror a VEGF inhibitor).
  • anti-cancer agents e.g., in combination with a paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor (e.g., receptor tyrosine kinase (RTK) inhibitor), an mTOR inhibitoror a VEGF inhibitor).
  • the hedgehog-associated tumor or cancer is a hedgehog ligand-dependent cancer cell growth chosen from one or more of a neuroendocrine cancer, a sarcoma (e.g., a musculoskeletal or soft- tissue sarcoma, such as chondrosarcoma, osteosarcoma, synovial sarcoma or liposarcoma), a pancreatic cancer, a head and neck cancer, prostate cancer, ovarian cancer, or a lung cancer (e.g., a small cell or a non-small cell lung cancer).
  • a neuroendocrine cancer e.g., a sarcoma (e.g., a musculoskeletal or soft- tissue sarcoma, such as chondrosarcoma, osteosarcoma, synovial sarcoma or liposarcoma), a pancreatic cancer, a head and neck cancer, prostate cancer, ovarian cancer, or a lung cancer (e.g.,
  • the invention features a method of treating a hedgehog- associated cancer or tumor, in a subject in need of hedgehog inhibition.
  • the method includes administering to the subject a first anti-cancer agent and a second anti-cancer agent, in an amount sufficient to treat the cancer or tumor, wherein the first anti-cancer agent is a hedgehog inhibitor.
  • the hedgehog-associated cancer or tumor and the second anti-cancer agent are each chosen from: (i) the hedgehog- associated cancer or tumor is a sarcoma and the second anti-cancer agent is chosen from one or more of: mTOR inhibitor, doxorubicin, cisplatin, ifosfamide, or methotrexate; (ii) the hedgehog-associated cancer or tumor is a neuroendocrine cancer and the second anti- cancer agent is a tyrosine kinase inhibitor; (iii) the hedgehog-associated cancer or tumor is a head and neck squamous cell cancer and the second anti-cancer agent is a tyrosine Attorney Docket No.
  • the hedgehog-associated cancer or tumor is a pancreatic cancer and the second anti-cancer agent is a paclitaxel agent;
  • the hedgehog-associated cancer or tumor is a pancreatic cancer and the second anti-cancer agent is a VEGF inhibitor; or
  • the hedgehog-associated cancer or tumor is a lung cancer and the second anti-cancer agent is a tyrosine kinase inhibitor is chosen from sunitinib, erlotinib, gefitinib, or sorafenib.
  • the invention features a method of reducing or preventing a relapse in a subject having a tumor or cancer, e.g., a hedgehog-associated tumor or cancer.
  • the method includes administering to the subject a hedgehog inhibitor, e.g., one or more hedgehog inhibitors as described herein, in an amount sufficient to reduce or inhibit the tumor or cancer re-growth or relapse, in the subject.
  • a hedgehog inhibitor e.g., one or more hedgehog inhibitors as described herein
  • the hedgehog inhibitor is administered as a single agent, or in combination with other anti-cancer agents (e.g., in combination with a paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor (e.g., receptor tyrosine kinase (RTK) inhibitor) or an mTOR inhibitor).
  • anti-cancer agents e.g., in combination with a paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor (e.g., receptor tyrosine kinase (RTK) inhibitor) or an mTOR inhibitor).
  • the hedgehog-associated tumor or cancer is a hedgehog ligand- dependent cancer cell growth chosen from one or more of a neuroendocrine cancer, a sarcoma (e.g., a musculoskeletal sarcoma, such as chondrosarcoma and osteosarcoma, or soft-tissue sarcoma, such as synovial sarcoma or liposarcoma), a pancreatic cancer, a head and neck cancer, or a lung cancer (e.g., a small cell or a non-small cell lung cancer).
  • the subject is a patient who is undergoing cancer therapy (e.g., treatment with other anti-cancer agents, surgery and/or radiation).
  • cancer therapy e.g., treatment with other anti-cancer agents, surgery and/or radiation.
  • the subject is a patient who has undergone cancer therapy (e.g., treatment with other anti-cancer agents, surgery and/or radiation).
  • cancer therapy e.g., treatment with other anti-cancer agents, surgery and/or radiation.
  • the relapse reduced or prevented occurs after tyrosine kinase inhibitor therapy, e.g., a subject that has undergone or is undergoing therapy with a tyrosine kinase inhibitor therapy.
  • the cancer is a lung cancer (e.g., a non-small cell lung cancer) or a head and neck squamous cell cancer.
  • treatment can include, but is not limited to, inhibiting tumor growth; reducing tumor mass or volume; reducing Attorney Docket No. I2041-7000WO/3020PCT size or number of metastatic lesions; inhibiting the development of new metastatic lesions; reducing one or more of non-invasive tumor volume, metabolism; prolonged survival; prolonged progression-free survival; prolonged time to progression; and/or enhanced quality of life.
  • the hedgehog inhibitor reduces or inhibits a hedgehog signaling pathway.
  • the hedgehog inhibitor reduces or inhibits the activity of a hedgehog receptor, e.g., Smoothened.
  • the hedgehog inhibitor reduces or inhibits the binding of a hedgehog ligand to a hedgehog receptor, e.g., Patched.
  • the hedgehog inhibitor is a Smoothened inhibitor.
  • the hedgehog inhibitor targets a hedgehog ligand-dependent cancer or tumor, e.g., targets one or more of the tumor cell, the tumor microenvironment, or other residual diseases that is responsive to a hedgehog ligand (e.g., a target tumor cell, a target tumor microenviroment, and/or a target residual disease as shown in Figure 19).
  • a hedgehog ligand-dependent cancer or tumor e.g., targets one or more of the tumor cell, the tumor microenvironment, or other residual diseases that is responsive to a hedgehog ligand (e.g., a target tumor cell, a target tumor microenviroment, and/or a target residual disease as shown in Figure 19).
  • the hedgehog inhibitor targets the tumor microenvironment of a hedgehog ligand-dependent cancer or tumor (e.g., a desmoplastic tumor, such as pancreatic cancer and/or neurodendocrine tumors) thereby causing one or more of: (i) depleting or reducing desmoplastic stroma and/or the stroma support provided to the tumor; (ii) increasing the vascularity of the tumor; or (iii) rendering the tumor more accessible to chemotherapy.
  • a hedgehog ligand-dependent cancer or tumor e.g., a desmoplastic tumor, such as pancreatic cancer and/or neurodendocrine tumors
  • the hedgehog inhibitor can decrease fibrosis, thus leading to improved drug delivery and/or survival.
  • the hedgehog inhibitor targets a hedgehog ligand- independent cancer or tumor, e.g., a cancer or tumor having a genetic mutation in a hedgehog receptor (e.g., a Patched mutant tumor).
  • a hedgehog ligand- independent cancers or tumors include, but are not limited to, basal cell carcinoma (e.g., advanced basal cell carcinoma) and medulloblastoma.
  • the tumor or cancer e.g., the hedgehog-associated cancer or tumor
  • treated includes, but is not limited to, a solid tumor, a soft tissue tumor (e.g., a heme malignancy), and a metastatic lesion, e.g., a metastatic lesion of any of the cancers disclosed herein.
  • the tumor or cancer, e.g., the hedgehog-associated cancer or tumor, treated with the hedgehog inhibitor is a sarcoma, e.g., a bone or soft tissue Attorney Docket No. I2041-7000WO/3020PCT sarcoma (e.g., a synovial sarcoma, a liposarcoma, a musculoskeletal sarcoma, such as bone and cartilage sarcoma, chondrosarcoma and osteosarcoma).
  • a sarcoma e.g., a bone or soft tissue Attorney Docket No. I2041-7000WO/3020PCT sarcoma (e.g., a synovial sarcoma, a liposarcoma, a musculoskeletal sarcoma, such as bone and cartilage sarcoma, chondrosarcoma and osteosarcoma).
  • the hedgehog inhibitor alone or combination with a second agent reduces or inhibits local or metastatic sarcoma invasion.
  • a second agent e.g., an mTOR inhibitor and/or other anti-cancer agents (e.g., one or more of: doxorubicin, cisplatin, ifosfamide, or methotrexate (e.g., high dose methotrexate))
  • the hedgehog inhibitor, alone or combination with the mTOR inhibitor treats or prevents a chondrosarcoma.
  • the hedgehog inhibitor alone or combination with the mTOR inhibitor treats or prevents an osteosarcoma, e.g., a relapsed or refractory osteosarcoma.
  • the tumor or cancer, e.g., the hedgehog-associated cancer or tumor, treated with the hedgehog inhibitor is a neuroendocrine cancer or tumor.
  • the cancer or tumor treated is a neuroendocrine cancer chosen from one or more of, e.g., a neuroendocrine cancer of the pancreas (e.g., a pancreatic endocrine tumor), lung, appendix, duodenum, ileum, rectum, small intestine; or a neuroendocrine cancer from the adrenal medulla, the pituitary, the parathyroids, thyroid endocrine islets, pancreatic endocrine islets, or dispersed endocrine cells in the respiratory or
  • the cancer or tumor treated is a carcinoid tumor, e.g., a functional or a non- functional carcinoid neuroendocrine cancer.
  • the hedgehog inhibitor is administered in combination with a tyrosine kinase inhibitor (e.g., one or more of a receptor tyrosine inhibitor (RTK), e.g., sunitinib) in an amount sufficient to treat or prevent the neuroendocrine tumor.
  • a tyrosine kinase inhibitor e.g., one or more of a receptor tyrosine inhibitor (RTK), e.g., sunitinib
  • RTK receptor tyrosine inhibitor
  • the hedgehog inhibitor and the tyrosine kinase inhibitor are administered concurrently.
  • the hedgehog inhibitor and the tyrosine kinase inhibitor are administered sequentially.
  • the hedgehog inhibitor can be administered before initiating treatment with, or after ceasing treatment with, the tyrosine kinase inhibitor.
  • Administration of the hedgehog inhibitor and the tyrosine kinase inhibitor can overlap in part with each other, and either of which can be continued as a single agent after cessation of treatment with the other.
  • the tumor or cancer e.g., the hedgehog-associated cancer or tumor
  • TAXOL® an albumin-stabilized nanoparticle paclitaxel formulation
  • albumin-stabilized nanoparticle paclitaxel formulation e.g.,
  • the hedgehog inhibitor is administered concurrently with the paclitaxel or the paclitaxel agent.
  • the hedgehog inhibitor and the paclitaxel or the paclitaxel agent are administered sequentially.
  • the hedgehog inhibitor can be administered before initiating treatment with, or after ceasing treatment with, the paclitaxel or the paclitaxel agent.
  • administration of the hedgehog inhibitor overlaps with the treatment with the paclitaxel or the paclitaxel agent, and continues after treatment with the paclitaxel or the paclitaxel agent has ceased.
  • the hedgehog inhibitor and the paclitaxel are administered in combination with an additional therapeutic agent (e.g., a third anti-cancer agent chosen from gemcitabine, cisplatin, epirubicin, 5-fluorouracil, leucovorin, oxaplatin, a VEGF antagonist, e.g., an anti-VEGF antibody (e.g., bevacizumab), or a combination thereof).
  • an additional therapeutic agent e.g., a third anti-cancer agent chosen from gemcitabine, cisplatin, epirubicin, 5-fluorouracil, leucovorin, oxaplatin, a VEGF antagonist, e.g., an anti-VEGF antibody (e.g., bevacizumab), or a combination thereof.
  • the hedgehog inhibitor, the paclitaxel agent and the third anti- cancer agent are administered concurrently, sequentially, or in a partially overlapping schedule.
  • the third anti-cancer agent is administered prior to initiating treatment with, or after ceasing treatment with, the hedgehog inhibitor and the paclitaxel or the paclitaxel agent.
  • the combination of the hedgehog inhibitor and paclitaxel or paclitaxel agent can further include gemcitabine (e.g., GEMZAR®).
  • the subject is a patient with metastastatic pancreatic cancer.
  • the subject is a patient with pancreatic or metastastatic pancreatic cancer who has received no prior cancer treatment (e.g., no prior exposure to other anti-cancer agent, surgical or radiation procedure for, e.g., no prior cancer treatment for their disease, e.g., their metastatic disease).
  • the tumor or cancer e.g., the hedgehog-associated cancer or tumor
  • paclitaxel e.g., paclitaxel agent
  • a VEGF antagonist e.g., an anti- VEGF antibody (e.g., bevacizumab), 5-fluorouracil, or oxaplatin.
  • the tumor or cancer e.g., the hedgehog-associated cancer or tumor
  • a VEGF antagonist e.g., an anti-VEGF antibody (e.g., bevacizumab), 5-fluorouracil, or oxaplatin.
  • the tumor or cancer, e.g., the hedgehog-associated cancer or tumor, treated with the hedgehog inhibitor is a head and neck squamous cell cancer.
  • the hedgehog inhibitor is administered in combination with a tyrosine kinase inhibitor (e.g., in combination with one or more of a receptor tyrosine inhibitor (RTK), e.g., an EGFR-tyrosine kinase inhibitor such as an anti-EGFR antibody (e.g., cetuximab)) to treat or prevent the head and neck squamous cell cancer.
  • RTK receptor tyrosine inhibitor
  • an EGFR-tyrosine kinase inhibitor such as an anti-EGFR antibody (e.g., cetuximab)
  • the hedgehog inhibitor and the tyrosine kinase inhibitor are administered concurrently.
  • the hedgehog inhibitor and the tyrosine kinase inhibitor are administered sequentially.
  • the hedgehog inhibitor can be administered before initiating treatment with, or after ceasing treatment with, the tyrosine kinase inhibitor.
  • the administration of the hedgehog inhibitor overlaps with the treatment with the tyrosine kinase inhibitor, and continues after treatment with the tyrosine kinase inhibitor has ceased.
  • the tumor or cancer, e.g., the hedgehog-associated cancer or tumor, treated with the hedgehog inhibitor is a lung cancer, e.g., a small or a non-small lung cancer.
  • the lung cancer is non-small lung cancer.
  • the hedgehog inhibitor is administered in combination with a tyrosine kinase inhibitor (e.g., in combination with one or more of a receptor tyrosine inhibitor (RTK), e.g., gefitinib or a VEGF inhibitor) to treat or prevent the lung cancer.
  • a tyrosine kinase inhibitor e.g., in combination with one or more of a receptor tyrosine inhibitor (RTK), e.g., gefitinib or a VEGF inhibitor
  • the lung cancer is non-small cell lung cancer and the hedghehog inhibitor is administered in combination with a VEGF inhibitor (e.g., an anti-VEGF antibody such as bevacizumab) in combination with carboplatin and/or paclitaxel or a paclitaxel agent.
  • a VEGF inhibitor e.g., an anti-VEGF antibody such as bevacizumab
  • the hedgehog inhibitor and the tyrosine kinase or other agent inhibitor are administered concurrently.
  • the hedgehog inhibitor and the tyrosine kinase inhibitor or other agent are administered sequentially.
  • the hedgehog inhibitor can be administered before initiating treatment with, or after ceasing treatment with, the tyrosine kinase inhibitor.
  • the administration of the hedgehog inhibitor overlaps with the treatment with the tyrosine Attorney Docket No. I2041-7000WO/3020PCT kinase inhibitor or other agent, and continues after treatment with the tyrosine kinase inhibitor or other agent has ceased.
  • the tyrosine kinase inhibitor is a receptor tyrosine kinase inhibitor. In one embodiment, the tyrosine kinase inhibitor is chosen from sunitinib, erlotinib, gefitinib, or sorafenib. In certain embodiment, the tyrosine kinase inhibitor is an EGFR-tyrosine kinase inhibitor. In certain embodiments, the EGFR-tyrosine kinase inhibitor is a small molecule EGFR-tyrosine kinase inhibitor.
  • the small molecule EGFR-tyrosine kinase inhibitor is chosen from one or more of erlotinib, gefitinib, icotinib, lapatinib, neratinib, vandetanib, BIBW 2992 or XL-647. In other embodiments, the small molecule EGFR-tyrosine kinase inhibitor is gefitinib or erlotinib. In certain embodiments, the small molecule EGFR-tyrosine kinase inhibitor is gefitinib. In other embodiments, the small molecule EGFR-tyrosine kinase inhibitor is erlotinib.
  • the EGFR-tyrosine kinase inhibitor is a monoclonal antibody.
  • the monoclonal antibody is chosen from cetuximab, panitumumab, zalutumumab, nimotuzumab necitumumab or matuzumab. In one embodiment, the monoclonal antibody is cetuximab.
  • compositions of the invention can optionally be used in combination with other therapeutic modalities, e.g., one or more anti-cancer agents, and/or in combination with surgical and/or radiation procedures as described herein.
  • the subject treated is a mammal, e.g., a primate, typically a human (e.g., a patient having, or at risk of, a cancer or tumor as described herein).
  • the subject treated is in need of hedgehog inhibition (e.g., has been evaluated to show elevated hedgehog levels).
  • the subject is a human having, or at risk of having, a hedgehog-associated tumor or cancer.
  • the subject is a human having, or at risk of having, a hedgehog ligand- independent tumor or cancer.
  • the subject is a human having, or at risk of having, a hedgehog ligand-dependent cancer or tumor.
  • the subject is a human having, or at risk of having, a hedgehog ligand-dependent cancer or tumor chosen from one or more of a neuroendocrine cancer, a sarcoma (e.g., a Attorney Docket No. I2041-7000WO/3020PCT musculoskeletal sarcoma, such as chondrosarcoma and osteosarcoma), a pancreatic cancer, a head and neck cancer, or a lung cancer (e.g., a small cell or a non-small cell lung cancer).
  • the subject is a patient suffering from multiple endocrine neoplasia type 1.
  • the subject is a patient suffering from a chondrosarcoma, or an osteosarcoma, e.g., a relapsed or refractory osteosarcoma.
  • the subject is in need of, or being considered for, treatment with a hedgehog inhibitor, alone or in combination, with any of the anti-cancer agents disclosed herein.
  • the subject can be one at risk of having the disorder, e.g., a subject having a relative afflicted with the disorder, or a subject having a genetic trait associated with risk for the disorder.
  • the subject can be symptomatic or asymptomatic.
  • the subject harbors an alteration in an EGFR gene or gene product.
  • the subject is a patient who is undergoing cancer therapy (e.g., other anti-cancer agents, surgery and/or radiation).
  • the subject is a patient who has undergone cancer therapy (e.g., other anti- cancer agents, surgery and/or radiation).
  • the subject has been treated with a tyrosine kinase inhibitor (e.g., sunitinib, cetuximab or geftinib).
  • a tyrosine kinase inhibitor e.g., sunitinib, cetuximab or geftinib.
  • the subject has developed a partial or complete resistance to a previous anti-cancer treatment, e.g., the subject does not respond well to treatment with a tyrosine kinase inhibitor (e.g., sunitinib, cetuximab or geftinib).
  • the subject is a patient with a metastatic cancer, e.g., metastastatic pancreatic cancer.
  • the subject is a patient with a cancer or a metastatic cancer (e.g., pancreatic or metastastatic pancreatic cancer) who has received no prior cancer treatment (e.g., no prior exposure to other anti-cancer agent, surgical or radiation procedure for, e.g., no prior cancer treatment for their disease, e.g., their metastatic disease).
  • no prior cancer treatment e.g., no prior exposure to other anti-cancer agent, surgical or radiation procedure for, e.g., no prior cancer treatment for their disease, e.g., their metastatic disease.
  • the hedgehog inhibitor used in the methods or compositions of the invention is a compound of formula I: Attorney Docket No. I2041-7000WO/3020PCT
  • a pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt.
  • the hedgehog inhibitor is administered as a pharmaceutical composition comprising the hedgehog inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the hedgehog inhibitor is administered, or is present in the composition, e.g., the pharmaceutical composition.
  • the hedgehog inhibitors described herein can be administered to the subject systemically (e.g., orally, parenterally, subcutaneous ly, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or intracavitary installation). Typically, the hedgehog inhibitors are administered orally.
  • the hedgehog inhibitor is IPI-926.
  • IPI-926 can be administered orally in a daily schedule at a dose of about 20 mg to 200 mg, typically about 50 to 150 mg, 75 to 140 mg, and more typically 120 to 130 mg, alone or in combination with a second agent as described herein.
  • the methods and compositions of the invention can, optionally, be used in combination with other therapeutic modalities, e.g., one or more additional anti-cancer agents, and/or in combination with surgical and/or radiation procedures. In other embodiments, the methods and compositions of the invention are used in combination with surgical and/or radiation procedures. Any combination of the hedgehog inhibitor and other therapeutic modalities can be used.
  • the hedgehog inhibitor and the other therapeutic modalities can be administered during periods of active disorder, or during a period of remission or less active disorder.
  • the hedgehog inhibitor and other therapeutic modalities can be administered before treatment, concurrently with treatment, Attorney Docket No. I2041-7000WO/3020PCT post-treatment, or during remission of the disorder.
  • the anti-cancer agent is administered simultaneously or sequentially with the hedgehog inhibitor.
  • the hedgehog inhibitor and the anti-cancer agent are administered as separate compositions, e.g., pharmaceutical compositions.
  • the hedgehog inhibitor and the anti-cancer agent are administered separately, but via the same route (e.g., both orally or both intravenously).
  • the hedgehog inhibitor and the anti-cancer agent are administered in the same composition, e.g., pharmaceutical composition.
  • the hedgehog inhibitor is a first line treatment for the cancer, e.g., the hedgehog-associated cancer or tumor, i.e., it is used in a subject who has not been previously administered another drug intended to treat the cancer.
  • the hedgehog inhibitor is a second line treatment for the cancer, e.g., hedgehog-associated cancer or tumor, i.e., it is used in a subject who has been previously administered another drug intended to treat the cancer.
  • the hedgehog inhibitor is a third or fourth line treatment for the cancer, e.g., the hedgehog-associated cancer or tumor, i.e., it is used in a subject who has been previously administered two or three other drugs intended to treat the cancer.
  • the hedgehog inhibitor is administered as neoadjuvant therapy, i.e., prior to another treatment.
  • the hedgehog inhibitor is administered as adjuvant therapy, i.e., a treatment in addition to a primary therapy.
  • the hedgehog inhibitor is administered to a subject prior to, or following surgical excision/removal of the cancer, e.g., the hedgehog-associated cancer or tumor.
  • the hedgehog inhibitor is administered to a subject before, during, and/or after radiation treatment of the cancer, e.g., the hedgehog-associated cancer or tumor.
  • the hedgehog inhibitor is administered to a subject, e.g., a cancer patient who is undergoing or has undergone cancer therapy (e.g., treatment with another anti-cancer agent, radiation therapy and/or surgery).
  • cancer therapy e.g., treatment with another anti-cancer agent, radiation therapy and/or surgery.
  • the Attorney Docket No. I2041-7000WO/3020PCT hedgehog inhibitor is administered concurrently with the cancer therapy.
  • the hedgehog inhibitor can continue to be administered after the cancer therapy has ceased.
  • the hedgehog inhibitor is administered sequentially with the cancer therapy.
  • the hedgehog inhibitor can be administered before initiating treatment with, or after ceasing treatment with, the cancer therapy.
  • the administration of the hedgehog inhibitor overlaps with the cancer therapy, and continues after the cancer therapy has ceased.
  • the hedgehog inhibitor is administered after cancer therapy has ceased (i.e., with no period of overlap with the cancer treatment).
  • the cancer therapy and the hedgehog inhibitor can be administered concurrently, sequentially, or as a combination of concurrent administration followed by monotherapy with either the anticancer agent, or the hedgehog inhibitor.
  • the method includes administering the hedgehog inhibitor as a first therapeutic agent, followed by administration of a cancer therapy (e.g., treatment with a second therapeutic agent (e.g., another anti-cancer agent), radiation therapy and/or surgery).
  • a cancer therapy e.g., treatment with a second therapeutic agent (e.g., another anti-cancer agent), radiation therapy and/or surgery
  • the method includes administering a cancer therapy first (e.g., treatment with a first therapeutic agent (e.g., another anti-cancer agent), radiation therapy and/or surgery), followed by administering the hedgehog inhibitor as a second therapeutic agent.
  • the method includes administering the hedgehog inhibitor in combination with a second, third or more additional therapeutic agents (e.g., anti-cancer agents as described herein).
  • a second anti-cancer agent e.g., a second anti-cancer agent chosen from a tyrosine kinase inhibitor, paclitaxel or a paclitaxel agent, an mTOR inhibitor
  • yet another therapeutic agent e.g., a third anti-cancer agent chosen from gemcitabine, cisplatin, epirubicin, 5-fluorouracil, a VEGF antagonist (e.g., an anti- VEGF antibody (bevacizumab), leucovorin, oxaplatin, or a combination thereof).
  • a VEGF antagonist e.g., an anti- VEGF antibody (bevacizumab), leucovorin, oxaplatin, or a combination thereof.
  • the hedgehog inhibitor, the second and third anti-cancer agents are administered concurrently.
  • the third anti-cancer agent is administered prior to initiating treatment with, or after ceasing treatment with, the hedgehog inhibitor and the second anti-cancer agents. Any order and combination of the Attorney Docket No. I2041-7000WO/3020PCT administration of the hedgehog inhibitor, with a second, third or more anti-cancer agent is within the scope of the present invention.
  • one or more hedgehog inhibitors are administered in combination.
  • the hedgehog inhibitors are administed concurrently.
  • the inhibitors are administered sequentially.
  • a combination of e.g., IPI-926 and GDC-0449 can be administered concurrently or sequentially.
  • GDC-0449 is administered first, followed, with or without a period of overlap, by administration of IPI-926.
  • IPI-926 is administered first, followed, with or without a period of overlap, by administration of GDC-0449.
  • the anti-cancer agent used in combination with the hedgehog inhibitor is a cytotoxic or a cytostatic agent.
  • cytotoxic agents include antimicrotubule agents, topoisomerase inhibitors (e.g., irinotecan), or taxanes (e.g., docetaxel), antimetabolites, mitotic inhibitors, alkylating agents, intercalating agents, agents capable of interfering with a signal transduction pathway, agents that promote apoptosis and radiation.
  • the methods can be used in combination with immunodulatory agents, e.g., IL-1 , 2, 4, 6, or 12, or interferon alpha or gamma, or immune cell growth factors such as GM-CSF.
  • the anticancer agent is a topoisomerase inhibitor, e.g., irinotecan.
  • the anti-cancer agent used in combination with the hedgehog inhibitor is paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor (e.g., a receptor tyrosine kinase (RTK) inhibitor, e.g., an EGFR inhibitor, gefitinib, sunitinib) or an mTOR inhibitor.
  • a tyrosine kinase inhibitor e.g., a receptor tyrosine kinase (RTK) inhibitor, e.g., an EGFR inhibitor, gefitinib, sunitinib
  • RTK receptor tyrosine kinase
  • the anti-cancer agent is a tyrosine kinase inhibitor (e.g., a receptor tyrosine kinase (RTK) inhibitor).
  • a tyrosine kinase inhibitor e.g., a receptor tyrosine kinase (RTK) inhibitor
  • the methods of the invention include administering to the subject in need of treatment, or at risk of having the cancer, a hedgehog inhibitor as described herein, in combination with a tyrosine kinase inhibitor (e.g., a receptor tyrosine kinase (RTK) inhibitor) in an amount effective to reduce or treat the cancer or tumor, e.g., the hedgehog ligand dependent cancer or tumor described herein.
  • a tyrosine kinase inhibitor e.g., a receptor tyrosine kinase (RTK) inhibitor
  • the tyrosine kinase inhibitor include, but is not limited to, an epidermal growth factor (EGF) pathway inhibitor (e.g., Attorney Docket No. I2041-7000WO/3020PCT an epidermal growth factor receptor (EGFR) inhibitor), a vascular endothelial growth factor (VEGF) pathway inhibitor (e.g., a vascular endothelial growth factor receptor (VEGFR) inhibitor (e.g., a VEGFR-1 inhibitor, a VEGFR-2 inhibitor, a VEGFR-3 inhibitor)), a platelet derived growth factor (PDGF) pathway inhibitor (e.g., a platelet derived growth factor receptor (PDGFR) inhibitor (e.g., a PDGFR- ⁇ inhibitor)), a RAF-1 inhibitor, a KIT inhibitor and a RET inhibitor.
  • EGF epidermal growth factor
  • VEGF vascular endothelial growth factor
  • VEGFR-1 inhibitor vascular endothelial growth factor receptor
  • the anti-cancer agent used in combination with the hedgehog inhibitor is selected from the group consisting of: axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU1 1248), toceranib
  • PALLADIA® vandetanib
  • ZACTIMA® vandetanib
  • ZD6474 vatalanib
  • PTK787 PTK/ZK
  • trastuzumab HERCEPTIN®
  • bevacizumab AVASTIN®
  • rituximab RITUXAN®
  • cetuximab ERBITUX®
  • panitumumab VECTIBIX®
  • ranibizumab (Lucentis®
  • TASIGNA® sorafenib
  • NEXAVAR® alemtuzumab
  • CAMPATH® gemtuzumab ozogamicin
  • MYLOTARG® ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF- 02341066, PF-299804, BMS-777607, ABT
  • Selected tyrosine kinase inhibitors are chosen from sunitinib, erlotinib, gefitinib, or sorafenib.
  • the tyrosine kinase inhibitor is chosen from cetuximab, bevacizumab, panitumumab, zalutumumab, nimotuzumab necitumumab or matuzumab.
  • the monoclonal antibody is cetuximab.
  • the hedgehog inhibitor is administered in combination with an mTOR inhibitor, e.g., one or more mTOR inhibitors chosen from one or more of rapamycin, temsirolimus (TORISEL®), everolimus (RAD001 , AFINITOR®), ridaforolimus, AP23573, AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1 126, OSI-027, GSK1059615, KU-0063794, WYE-354, INK128, temsirolimus (CCI- 779), Palomid 529 (P529), PF-04691502, or PKI-587.
  • an mTOR inhibitor e.g., one or more mTOR inhibitors chosen from one or more of rapamycin, temsirolimus (TORISEL®), everolimus (RAD001 , AFINITOR®), ridaforolimus, AP23573, AZD8055
  • the mTOR Attorney Docket No. I2041-7000WO/3020PCT inhibitor inhibits TORC1 and TORC2.
  • TORC1 and TORC2 dual inhibitors include, e.g., OSI-027, XL765, Palomid 529, and INK128.
  • the hedgehog inhibitor can be administered via the same or a different route than the mTOR inhibitor.
  • the mTOR inhibitor is administered systemically, e.g., orally,
  • the hedgehog inhibitor is administered with an inhibitor of insulin-like growth factor receptor (IGF-1R).
  • IGF-1R inhibitors include, but are not limited to, small molecule IGF-1R antagonists ⁇ e.g., GSK1904529A), antibody antagonists, IGF-1R peptide antagonists, or anti-sense or other nucleic acid antagonists.
  • the hedgehog inhibitor is administered in combination with an ALK kinase inhibitor(s).
  • ALK inhibitors include TAE-684 (also referred to herein as "NVP-TAE694"), PF02341066 (also referred to herein as
  • crizotinib or “1066”
  • AP26113 Additional examples of ALK kinase inhibitors are described in example 3-39 of WO 2005016894 by Garcia-Echeverria C, et al.
  • the hedgehog inhibitor is administered in combination with folfirinox.
  • Folfirinox comprises oxaliplatin 85 mg/m2 and irinotecan 180 mg/m2 plus leucovorin 400 mg/m2 followed by bolus fluorouracil (5-FU) 400 mg/m2 on day 1 , then 5-FU 2,400 mg/m2 as a 46-hour continuous infusion.
  • the hedgehog inhibitor is administered in combination with a PI3K inhibitor.
  • the PI3K inhibitor is an inhibitor of delta and gamma isoforms of PI3K.
  • the PI3K inhibitor is a dual inhibitor of PI3K and mTOR.
  • Exemplary PI3K inhibitors that can be used in combination with the hedgehog inhibitor include but are not limited to, GSK 2126458, GDC-0980, GDC- 0941, Sanofi XL147, XL756, XL147, PF-46915032, BKM 120, CAL-101 , CAL 263, SF1126, PX-886, and a dual PI3K inhibitor ⁇ e.g., Novartis BEZ235).
  • GSK 2126458 GDC-0980
  • GDC- 0941 Sanofi XL147, XL756, XL147, PF-46915032
  • BKM 120 CAL-101
  • CAL 263, SF1126, PX-886 a dual PI3K inhibitor ⁇ e.g., Novartis BEZ235.
  • the PI3K inhibitor is an isoquinolinone. In one embodiment, the PI3K inhibitor is INKl 197 or a derivative thereof. In other embodiments, the PI3K inhibitor is INKl 1 17 or a derivative thereof.
  • the hedgehog inhibitor is administered in combination with a BRAF inhibitor, e.g., GSK2118436, RG7204, PLX4032, GDC-0879, PLX4720, and sorafenib tosylate (Bay 43-9006).
  • a BRAF inhibitor e.g., GSK2118436, RG7204, PLX4032, GDC-0879, PLX4720, and sorafenib tosylate (Bay 43-9006).
  • the hedgehog inhibitor is administered in combination with a MEK inhibitor, e.g., ARRY-142886, GSKl 120212, RDEA436, RDEAl 19/BAY 869766, AS703026, AZD6244 (selumetinib), BIX 02188, BIX 02189, CI-1040
  • a MEK inhibitor e.g., ARRY-142886, GSKl 120212, RDEA436, RDEAl 19/BAY 869766, AS703026, AZD6244 (selumetinib), BIX 02188, BIX 02189, CI-1040
  • the hedgehog inhibitor is administered in combination with a JAK2 inhibitor, e.g., CEP-701, INCB 18424, CP-690550 (tasocitinib).
  • a JAK2 inhibitor e.g., CEP-701, INCB 18424, CP-690550 (tasocitinib).
  • the hedgehog inhibitor is administered in combination with a vascular disrupting agent (e.g., DMXAA, vadimezan).
  • a vascular disrupting agent e.g., DMXAA, vadimezan
  • the aforesaid combinations can be used to treat any of the cancers and metastic growths described herein.
  • the combinations described herein can be administered in any order.
  • the use herein of the term "first,” “second,” or “third” agent is not intended to imply a particular order of administration. It is intended to clarify the different classes of agents used.
  • the hedgehog inhibitor alone or combination with the anti-cancer agent is administered in a therapeutically effective amount, e.g., at a predetermined dosage schedule.
  • the method includes administering the hedgehog inhibitor and/or the tyrosine kinase inhibitor at sub-cytotoxic levels.
  • the tyrosine kinase inhibitor is administered to a subject at a dose (e.g., oral dose) of at least about 10 mg, about 25 mg, about 37.5 mg, about 50 mg, about 70 mg, about 87.5 mg, about 100 mg, about 125 mg, or about 150 mg per day. In some embodiments, the tyrosine kinase inhibitor is administered to a subject at a dose (e.g., oral dose) of about 37.5 mg, about 50 mg, or about 87.5 mg per day. In some embodiments, the tyrosine kinase inhibitor is administered to a subject at a dose (e.g., oral dose) of about 50 mg per day. In some embodiments, the tyrosine kinase inhibitor is administered to a subject once, twice, three, or more times per day. In some
  • the tyrosine kinase inhibitor is administered to a subject once per day. In some embodiments, the tyrosine kinase inhibitor is administered to a subject daily for about one, two, three, four or more weeks. In some embodiments, the tyrosine kinase inhibitor is administered to a subject daily for about four weeks.
  • Attorney Docket No. I2041-7000WO/3020PCT is administered to a subject once per day. In some embodiments, the tyrosine kinase inhibitor is administered to a subject daily for about one, two, three, four or more weeks. In some embodiments, the tyrosine kinase inhibitor is administered to a subject daily for about four weeks.
  • sunitinib is the tyrosine kinase inhibitor administered in combination with the hedgehog inhibitor
  • it can be administered at a dose of about 50 mg daily; less than 50 mg daily, e.g., 37.5 mg daily; or greater than 50 mg daily, e.g., 62.5 mg daily.
  • the tyrosine kinase inhibitor e.g., sunitinib
  • sunitinib is administered daily for one, two, three, four or five weeks, followed by one, two, or three weeks without administration.
  • sunitinib is administered orally.
  • the methods of the invention can further include the step of evaluating a sample from the tumor, the cancer cell or the subject, e.g., to detect the presence or absence of an alteration in an EGFR gene or gene product.
  • the method can be used to identify or select a tumor, a cancer cell, or a subject (e.g., a subject having a cancer or tumor, or at risk for developing a cancer or tumor) as having a likelihood (e.g., increased or decreased likelihood), to respond to a treatment comprising an EGFR inhibitor in combination with a hedgehog inhibitor.
  • Exemplary alterations in an EGFR gene or gene product that can be evaluated and/or treated include but are not limited to, an EGFR exon deletion (e.g., EGFR exon 19 deletion, E746-A750 deletion), and/or exon mutation (e.g., an EGFR exon deletion (e.g., EGFR exon 19 deletion, E746-A750 deletion), and/or exon mutation (e.g., an EGFR exon deletion (e.g., EGFR exon 19 deletion, E746-A750 deletion), and/or exon mutation (e.g., an EGFR exon deletion), and/or exon mutation (e.g., an EGFR exon deletion), and/or exon mutation (e.g., an EGFR exon deletion), and/or exon mutation (e.g., an EGFR exon deletion (e.g., EGFR exon 19 deletion, E746-A750 deletion), and/or exon mutation (e.g., an
  • L858R/T790M EGFR mutation include, but are not limited to, EGFR_ D770_N771>AGG; EGFR_D770_N771 insG; EGFR_D770_N771insG;
  • EGFR_D770_N771insN EGFR E709A
  • EGFR E709G EGFR 709H
  • EGFR E709K EGFR E709V
  • EGFR_E746_A750del EGFR_E746_A750del, T751 A;
  • EGFR_E746_A750del V ins; EGFR_E746_T751 del, I ins; EGFR_E746_T751 del,
  • the methods of the invention can further include the step of monitoring the subject, e.g., for a change (e.g., an increase or decrease) in one or more of: tumor size; Attorney Docket No. I2041-7000WO/3020PCT hedgehog levels or signaling; stromal activation; levels of one or more cancer markers; the rate of appearance of new lesions, e.g., in a bone scan; one or more of non-invasive ly tumor volume, metabolism, hypoxia evolution and/or tumor bone synthesis; the appearance of new disease-related symptoms; the size of soft tissue mass, e.g., a decreased or stabilization; quality of life, e.g., amount of disease associated pain, e.g., bone pain; histological analysis, e.g., synthesis of cartilage, lobular pattern, and/or the presence or absence of mitotic cells; tumor aggressivity, vascularization of primary tumor, metastatic spread; tumor size and location can be visualized using multimodal imaging techniques (e.g 18 F
  • the subject can be monitored in one or more of the following periods: prior to beginning of treatment; during the treatment; or after one or more elements of the treatment have been administered. Monitoring can be used to evaluate the need for further treatment with the same hedgehog inhibitor, alone or in combination with, the same anti-cancer agent, or for additional treatment with additional agents. Generally, a decrease in one or more of the parameters described above is indicative of the improved condition of the subject, although with serum hemoglobin levels, an increase can be associated with the improved condition of the subject.
  • the methods of the invention can further include the step of analyzing a nucleic acid or protein from the subject, e.g., analyzing the genotype of the subject.
  • a hedgehog protein, or a nucleic acid encoding a hedgehog ligand and/or an upstream or downstream component(s) of the hedgehog signaling, e.g., a receptor, activator or inhibitor of hedgehog is analyzed.
  • the elevated hedgehog ligand can be detected in blood, urine, circulating tumor cells, a tumor biopsy or a bone marrow biopsy.
  • the elevated hedgehog ligand can also be detected by systemic administration of a labeled form of an antibody to a hedgehog ligand followed by imaging.
  • the analysis can be used, e.g., to evaluate the suitability of, or to choose between alternative treatments, e.g., a particular dosage, mode of delivery, time of delivery, inclusion of adjunctive therapy, e.g., administration in combination with a second agent, or generally to determine the subject's probable drug response phenotype or genotype.
  • the nucleic acid or protein can be analyzed at any stage of treatment, but preferably, prior to
  • the methods of the invention further include the step of detecting elevated hedgehog ligand in the subject, prior to, or after, administering a hedgehog inhibitor to the patient.
  • the elevated hedgehog ligand can be detected in blood, urine, circulating tumor cells, a tumor biopsy or a bone marrow biopsy.
  • the elevated hedgehog ligand can also be detected by systemic administration of a labeled form of an antibody to a hedgehog ligand followed by imaging.
  • the step of detecting elevated hedgehog ligand can include the steps of measuring hedgehog ligand in the patient prior to administration of the other cancer therapy, measuring hedgehog ligand in the patient after administration of the other cancer therapy, and determining if the amount of hedgehog ligand after administration of the other chemotherapy is greater than the amount of hedgehog ligand before administration of the other chemotherapy.
  • the other cancer therapy can be, for example, a chemo therapeutic or radiation therapy.
  • the method further includes the step of identifying one or more anti-cancer agents that elevate hedgehog ligand expression in a tumor (e.g., a tumor).
  • the step of identifying the anti-cancer agent that elevate hedgehog expression can include the steps of exposing cells from the tumor to one or more anti-cancer agents in vitro and measuring hedgehog ligand in the cells.
  • the invention features a composition, e.g., a pharmaceutical composition, that includes one or more hedgehog inhibitors, e.g., a hedgehog inhibitor as described herein, and one or more anti-cancer agents (e.g. , an anti-cancer agent as disclosed herein).
  • the composition can further include a pharmaceutically-acceptable carrier or excipient.
  • the invention features a composition for use, or the use, of a hedgehog inhibitor, alone or in combination with an anti-cancer agent described herein (e.g., a paclitaxel or a paclitaxel agent, tyrosine kinase inhibitor, mTOR inhibitor, and/or Attorney Docket No. I2041-7000WO/3020PCT
  • an anti-cancer agent described herein e.g., a paclitaxel or a paclitaxel agent, tyrosine kinase inhibitor, mTOR inhibitor, and/or Attorney Docket No. I2041-7000WO/3020PCT
  • IGF-1R antagonist for the treatment of a cancer or tumor, e.g., a hedgehog associated cancer or tumor described herein.
  • the invention features therapeutic kits that include the hedgehog inhibitor, alone or in combination with an anti-cancer agent described herein (e.g., a paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor, mTOR inhibitor, and/or IGF- 1R antagonist), and instructions for use the treatment of cancer, e.g., a hedgehog
  • an anti-cancer agent described herein e.g., a paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor, mTOR inhibitor, and/or IGF- 1R antagonist
  • Certain compounds of the present invention can comprise one or more
  • compounds and pharmaceutical compositions thereof can be in the form of an individual enantiomer, diastereomer or other geometric isomer, or can be in the form of a mixture of stereoisomers.
  • Enantiomers, diastereomers and other geometric isomers can be isolated from mixtures (including racemic mixtures) by any method known to those skilled in the Attorney Docket No.
  • I2041-7000WO/3020PCT art including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses; see, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
  • HPLC high pressure liquid chromatography
  • Carbon atoms can optionally be substituted with one or more substituents.
  • the number of substituents is typically limited by the number of available valences on the carbon atom, and can be substituted by replacement of one or more of the hydrogen atoms that would be available on the unsubstituted group.
  • alkyl alkenyl, alkynyl, alkoxy, alkoxy, aryl, aryloxy, arylthio, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocyclyl, halo,
  • an alkyl group containing 1-6 carbon atoms (Ci_ 6 alkyl) is intended to encompass, Ci, C 2 , C 3 , C4, C 5 , C 6 , Ci_ 6 , C 2 _ 6 , C 3 _ 6 , C4_ 6 , C 5 _ 6 , Ci_ 5 , C 2 _5, C 3 _5, C4_5, Ci_4, C 2 _4, C 3 _4, Ci_ 3 , C 2 _ 3 , and Ci_ 2 alkyl.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radical containing between one and thirty carbon atoms. In certain embodiments, the alkyl group contains 1-20 carbon atoms. Alkyl groups, unless otherwise specified, can optionally be substituted with one or more substituents. In certain embodiments, the alkyl group contains 1-10 carbon atoms. In certain embodiments,
  • the alkyl group contains 1-6 carbon atoms. In certain embodiments, the alkyl group contains 1-5 carbon atoms. In certain embodiments, the alkyl group contains 1—4 carbon atoms. In certain embodiments, the alkyl group contains 1-3 carbon atoms. In certain embodiments, the alkyl group contains 1-2 carbon atoms. In certain embodiments, the alkyl group contains 1 carbon atom. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, Attorney Docket No.
  • I2041-7000WO/3020PCT sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n- heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.
  • alkenyl denotes a straight- or branched-chain hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom, and containing between two and thirty carbon atoms.
  • Alkenyl groups can optionally be substituted with one or more substituents.
  • the alkenyl group contains 2-20 carbon atoms.
  • the alkenyl group contains 2-10 carbon atoms.
  • the alkenyl group contains 2-6 carbon atoms.
  • the alkenyl group contains 2-5 carbon atoms.
  • the alkenyl group contains 2-4 carbon atoms.
  • the alkenyl group contains 2-3 carbon atoms. In certain embodiments, the alkenyl group contains 2 carbon atoms.
  • Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l- yl, and the like.
  • alkynyl denotes a straight- or branched-chain hydrocarbon radical having at least one carbon-carbon triple bond by the removal of a single hydrogen atom, and containing between two and thirty carbon atoms. Alkynyl groups, unless otherwise specified, can optionally be substituted with one or more substituents. In certain embodiments, the alkynyl group contains 2-20 carbon atoms. In certain embodiments, the alkynyl group contains 2-10 carbon atoms. In certain embodiments, the alkynyl group contains 2-6 carbon atoms. In certain embodiments, the alkynyl group contains 2-5 carbon atoms. In certain embodiments, the alkynyl group contains 2-4 carbon atoms.
  • the alkynyl group contains 2-3 carbon atoms. In certain embodiments, the alkynyl group contains 2 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.
  • cycloalkyl used alone or as part of a larger moiety, refer to a saturated monocyclic or bicyclic hydrocarbon ring system having from 3-15 carbon ring members. Cycloalkyl groups, unless otherwise specified, can optionally be substituted with one or more substituents. In certain embodiments, cycloalkyl groups contain 3-10 carbon ring members. In certain embodiments, cycloalkyl groups contain 3-9 carbon Attorney Docket No. I2041-7000WO/3020PCT ring members. In certain embodiments, cycloalkyl groups contain 3-8 carbon ring members. In certain embodiments, cycloalkyl groups contain 3-7 carbon ring members. In certain embodiments, cycloalkyl groups contain 3-6 carbon ring members.
  • cycloalkyl groups contain 3-5 carbon ring members.
  • Cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the term "cycloalkyl” also includes saturated hydrocarbon ring systems that are fused to one or more aryl or heteroaryl rings, such as
  • aryl used alone or as part of a larger moiety (as in “aralkyl”), refers to an aromatic monocyclic and bicyclic hydrocarbon ring system having a total of 6-10 carbon ring members. Aryl groups, unless otherwise specified, can optionally be substituted with one or more substituents. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthrancyl and the like, which can bear one or more substituents.
  • aryl is a group in which an aryl ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl or tetrahydronaphthalyl, and the like, where the point of attachment is on the aryl ring.
  • aralkyl refers to an alkyl group, as defined herein, substituted by aryl group, as defined herein, wherein the point of attachment is on the alkyl group.
  • heteroatom refers to boron, phosphorus, selenium, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of abasic nitrogen.
  • heteroaryl used alone or as part of a larger moiety, e.g.,
  • hetero aralkyl refers to an aromatic monocyclic or bicyclic hydrocarbon ring system having 5-10 ring atoms wherein the ring atoms comprise, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups, unless otherwise specified, can optionally be substituted with one or more substituents. When used in reference to a ring atom of a heteroaryl group, the term “nitrogen” includes a substituted nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, Attorney Docket No. I2041-7000WO/3020PCT pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaryl ring is fused to one or more aryl, cycloalkyl or heterocycloalkyl rings, wherein the point of attachment is on the heteroaryl ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • heteroarylkyl refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl group.
  • heterocycloalkyl or “heterocyclyl” refer to a stable non-aromatic 5-7 membered monocyclic hydrocarbon or stable non-aromatic 7-10 membered bicyclic hydrocarbon that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more heteroatoms.
  • Heterocycloalkyl or heterocyclyl groups unless otherwise specified, can optionally be substituted with one or more substituents.
  • nitrogen includes a substituted nitrogen.
  • heterocycloalkyl groups include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • Heterocycloalkyl also include groups in which the heterocycloalkyl ring is fused to one or more aryl, heteroaryl or cycloalkyl rings, such as indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocycloalkyl ring.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups, such as aryl or heteroaryl moieties, as defined herein.
  • diradical refers to an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl groups, as described herein, wherein 2 hydrogen atoms are removed to form a divalent moiety. Diradicals are typically end with a suffix of "-ene”.
  • alkyl diradicals are referred to as alkylenes (for e and -(CR' 2 ) X - wherein R' is hydrogen or other substituent and x is 1 , 2, 3, 4, 5 or 6); alkenyl diradicals are referred to as “alkenylenes”; alkynyl diradicals are referred to as “alkynylenes”; aryl and aralkyl diradicals are referred to as “arylenes” and “aralkylenes”, respectively (for example: eroaryl and heteroaralkyl diradicals are referre
  • cycloalkyl diradicals are referred to as “cycloalkylenes”; heterocycloalkyl diradicals are referred to as “heterocycloalkylenes”; and the like.
  • halo refers to an atom selected from fluorine (fluoro, F), chlorine (chloro, CI), bromine (bromo, Br), and iodine (iodo, I).
  • haloalkyl refers to an alkyl group, as described herein, wherein one or more of the hydrogen atoms of the alkyl group is replaced with one or more halogen atoms.
  • the haloalkyl group is a perhaloalkyl group, that is, having all of the hydrogen atoms of the alkyl group replaced with halogens (e.g., such as the perfluoroalkyl group -CF 3 ).
  • azido refers to the group -N 3 .
  • nitrile refers to the group -CN.
  • nitro refers to the group -N0 2 .
  • hydroxyl or "hydroxy” refers to the group -OH.
  • thiol refers to the group -SH.
  • carboxylic acid refers to the group -C0 2 H.
  • aldehyde refers to the group -CHO.
  • alkoxy refers to the group -OR', wherein R' is an alkyl, alkenyl or alkynyl group, as defined herein.
  • aryloxy refers to the group -OR' , wherein each R' is an aryl or heteroaryl group, as defined herein.
  • alkthiooxy refers to the group -SR', wherein each R' is, independently, a carbon moiety, such as, for example, an alkyl, alkenyl, or alkynyl group, as defined herein.
  • arylthio refers to the group -SR', wherein each R' is an aryl or heteroaryl group, as defined herein.
  • amino refers to the group -NR' 2 , wherein each R' is, independently, hydrogen, a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein, or two R' groups together with the nitrogen atom to which they are bound form a 5-8 membered ring.
  • sulfonamido or “sulfonamide” refers to the group -N(R')S0 2 R' or - S0 2 N(R') 2 , wherein each R' is, independently, hydrogen or a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein, or two R' groups together with the nitrogen atom to which they are bound form a 5-8 membered ring.
  • R' is, independently, hydrogen or a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein, or two R' groups together with the nitrogen atom to which they are bound form a 5-8 membered ring.
  • sulfamido or “sulfamide” refers to the group -NR'S0 2 N(R') 2 , wherein each R' is, independently, hydrogen or a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein, or two R' groups together with the nitrogen atom to which they are bound form a 5-8 membered ring.
  • ilyl refers to the group -SiR' wherein R' is a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group.
  • the hedgehog inhibitor can contain one or more basic functional groups (e.g., such as an amino group), and thus is capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic acid addition salts. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately treating the compound in its free base form with a suitable acid.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts from inorganic acids include, but are not limited to, hydrochloric, hydrobromic, phosphoric, sulfuric, nitric and perchloric acid or from organic acids include, but are not limited to, acetic, adipic, alginic, ascorbic, aspartic, 2- acetoxybenzoic, benzenesulfonic, benzoic, bisulfonic, boric, butyric, camphoric, camphorsulfonic, citric, cyclopentanepropionic, digluconic, dodecylsulfonic,
  • the hedgehog inhibitor can contain one or more acidic functional groups, and thus is Attorney Docket No. I2041-7000WO/3020PCT capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts in these instances refers to the
  • suitable bases include, but are not limited to, metal hydroxides, metal
  • Suitable bases can also include ammonia or organic primary, secondary or tertiary amines.
  • Organic amines useful for the formation of base addition salts include, for example, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, e.g., Berge et ah, supra).
  • solvate refers to a compound of the present invention having either a stoichiometric or non-stoichiometric amount of a solvent associated with the compound.
  • the solvent can be water ⁇ i.e., a hydrate), and each molecule of inhibitor can be
  • the solvent can also be an alcohol ⁇ e.g., methanol, ethanol, propanol, isopropanol, etc.), a glycol ⁇ e.g., propylene glycol), an ether ⁇ e.g., diethyl ether), an ester ⁇ e.g., ethyl acetate), or any other suitable solvent.
  • the hedgehog inhibitor can also exist as a mixed solvate ⁇ i.e., associated with two or more different solvents).
  • sucrose refers to a natural or an unnatural
  • the sugar can be covalently bonded to the steroidal alkaloid of the
  • the saccharide moiety can be covalently bonded to a steroidal alkaloid of the present invention at an anomeric center of a saccharide ring.
  • Sugars can include, but are not limited to ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, glucose, and trehalose.
  • “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.
  • Figure 1 is a graph depicting the change in tumor volume over time for BxPC-3 pancreatic tumor xenografts treated with vehicle and IPI-926.
  • Figure 2A is a graph depicting human Gli- 1 levels in BxPC-3 pancreatic tumor xenografts treated with vehicle and IPI-926.
  • Figure 2B is a graph depicting murine Gli- 1 levels in BxPC-3 pancreatic tumor xenografts treated with vehicle and IPI-926.
  • Figure 3 is a graph depicting the change in tumor volume over time for BxPC-3 pancreatic tumor xenografts treated with vehicle, IPI-926, gemcitabine, and a
  • Figure 4 is a graph depicting the change in tumor volume over time for MiaPaCa pancreatic tumor xenografts treated with vehicle, IPI-926, gemcitabine, and a
  • Figure 5 is a graph depicting the change in tumor volume over time for LX22
  • Figure 6 is a graph depicting the change in tumor volume over time for LX22
  • Figure 7A is a graph depicting murine Indian hedgehog levels in LX22 small cell lung cancer tumor xenografts that were treated with etoposide/carboplatin followed by
  • Figure 7B is a graph depicting human Indian hedgehog levels in LX22 small cell lung cancer tumor xenografts that were treated with etoposide/carboplatin followed by vehicle or IPI-926.
  • Figure 8 A is a graph depicting murine Gli-1 expression levels in LX22 small cell lung cancer tumor xenografts that were treated with etoposide/carboplatin followed by vehicle or IPI-926.
  • Figure 8B is a graph depicting human Gli-1 expression levels in LX22 small cell lung cancer tumor xenografts that were treated with etoposide/carboplatin followed by vehicle or IPI-926.
  • Figure 9 A is a graph depicting the change in murine hedgehog ligand expression levels in UMUC-3 bladder cancer tumor xenografts treated with gemcitabine as compared to naive UMUC-3 bladder cancer tumor xenografts.
  • Figure 9B is a graph depicting the change in human hedgehog ligand expression levels in UMUC-3 bladder cancer tumor xenografts treated with gemcitabine as compared to naive UMUC-3 bladder cancer tumor xenografts.
  • Figure 10 is a graph depicting the change in human Sonic, Indian and Desert Hedgehog ligand expression in UMUC-3 bladder cancer tumor cells treated with doxorubicin as compared to naive UMUC-3 bladder cancer tumor cells.
  • Figure 11 is a graph depicting the change in human Sonic and Indian Hedgehog ligand expression in A2780 ovarian cancer tumor cells treated with carboplatin or docetaxel as compared to naive A2780 ovarian cancer tumor cells.
  • Figure 12 is a graph depicting the change in human Sonic and Indian Hedgehog ligand expression in IGROV- 1 ovarian cancer tumor cells treated with carboplatin or docetaxel as compared to naive IGROV- 1 ovarian cancer tumor cells.
  • Figure 13 is a graph depicting the change in human Sonic and Indian Hedgehog ligand expression in H82 small cell lung cancer tumor cells treated with carboplatin or docetaxel as compared to naive H82 small cell lung cancer tumor cells.
  • Figure 14 is a graph depicting the change in Sonic Hedgehog ligand expression in UMUC-3 bladder cancer tumor cells exposed to hypoxic conditions as compared to UMUC-3 bladder cancer tumor cells exposed to normoxic conditions.
  • Figures 15A- 15G are bar graphs depicting the detection of human Sonic
  • SHH Hedgehog
  • N/A spot missing/staining un-interpretable; -: negative; -/+: overall light staining; +: 5-25%; ++: 25-50%; +++: 50-75%; ++++: 75-100%.
  • Figures 16A- 16B are graphs depicting murine (A) or human (B) Gli- 1 mRNA levels in Bon-1 pancreatic neuroendocrine cancer (NET) xenografts treated with IPI-926 ( *p ⁇ 0.005).
  • Figures 16C- 16D are bar graphs depicting the mRNA levels of human Sonic Hedgehog (SHH) (A) or Indian Hedgehog (IHH) (B) in Bon-1 pancreatic neuroendocrine cancer (NET) xenografts treated with IPI-926.
  • SHH Sonic Hedgehog
  • IHH Indian Hedgehog
  • NET Bon-1 pancreatic neuroendocrine cancer
  • Figure 17 is an image (lOx Obj.) depicting the expression of human Sonic Hedgehog (SHH) in Bon- 1 pancreatic neuroendocrine cancer (NET) xenografts detected by immuno staining.
  • SHH Sonic Hedgehog
  • NET pancreatic neuroendocrine cancer
  • Figure 18 is a graph depicting the change in tumor volume over time for Bon- 1 pancreatic neuroendocrine cancer (NET) xenografts treated with vehicle, IPI-926, sunitinib, or a combination of IPI-926 and sunitinib.
  • NET pancreatic neuroendocrine cancer
  • Figure 19 is a summary of the cancers that can be treated with hedgehog inhibitors, e.g., IPI-926.
  • Figure 20 is a panel of photograps depicting the detection and histologic characterization of the rat chondrosarcoma model.
  • Panel (A) depicts an MRI image of tumor lobules at the graft site and in the surrounding muscles (arrows) 1 1 days after tumor transplantation.
  • Panel (B) shows the histology of the typical pattern of chondrosarcoma with lobules separated by fascia.
  • Panel (C) shows the presence of cartilage and mitotic cells classified in this model as grade II chondrosarcoma.
  • Figures 21A-21D is a panel of bar graphs showing the effects of IPI-926 in decreasing Hh signaling in tumor and stromal cells of osteosarcoma xenograft models.
  • Figures 21A-21B show a decrease in PTCHl and Glil mRNA expression in tumor cells from Xenograft A and B aninals treated with IPI-926 compared to controls. Similar decreases in PTCHl and Glil mRNA expression is detected in stromal cells treated with IPI-926 compared to controls ( Figures 21C-21D).
  • Figures 22A-22D is a panel of bar graphs showing the effects of IPI-926 in proliferation and apoptosis in osteosarcoma xenograft models.
  • Figures 22A and 22C show a decrease in proliferation of tumor cells detected by the percentage of cells showing Ki-67 staining in two different animals in response to IPI-926 compared to controls.
  • Figures 22B and 22D show an increase in apoptosis detected by Tunel Staning in response to IPI-926 compared to controls.
  • Figure 23 is a panel of bar graphs showing the inhibition of Hh pathway markers in tumor cells treated with IPI-926, compared to the vehicle control.
  • Figure 24 is a bar graph showing a comparison of IPI-926-treated primary chondrosarcoma xenografts to other chemotherapies.
  • Figure 25 is a bar graph summarizing the effects in human Glil modulation in primary chondrosarcoma xenograft models treated with multiple inhibitors.
  • Figure 26 depicts the change in tumor volume over time for L3.6pl pancreatic tumor xenografts treated with vehicle, ABRAXANE®, and a combination of
  • Figure 27A shows images of phospho histone 3 (PH3) staining on the L3.6pl tumor model comparing vehicle, ABRAXANE®, and a combination of IPI-926 and ABRAXANE® treated tumors.
  • Figure 27B quantitates the % PH3 positive neoplastic nuclei per stained tumor section in Figure 27A.
  • Figure 28 A shows the change in tumor growth over time for ASPC-1 tumor- bearing Ncr nude mice treated with vehicle, IPI-926, ABRAXANE®, and a combination of IPI-926 and ABRAXANE®.
  • Figure 28B shows the change in tumor growth over time for ASPC-1 tumor- bearing Ncr nude mice treated with vehicle, IPI926, paclitaxel, and a combination of IPI- 926 and paclitaxel.
  • Figure 29A shows the change in tumor volume over time for L3.6pl tumor bearing mice treated with Vehicle, IPI-926 alone, Abraxane +/- IPI-926, Gemzar® +/- IPI-926, ABRAXANE® + Gemzar® and ABRAXANE® + Gemzar® + IPI-926.
  • IPI-926 alone, Abraxane +/- IPI-926, Gemzar® +/- IPI-926, ABRAXANE® + Gemzar® and ABRAXANE® + Gemzar® + IPI-926.
  • Figure 29B shows the change in tumor volume over time for L3.6pl tumor bearing mice treated with Vehicle, IPI-926 alone, ABRAXANE® alone, and the combination of ABRAXANE® and IPI-926.
  • Figure 29C compares survival of L3.6pl tumor bearing mice being treated with Vehicle, IPI-926 alone, ABRAXANE® +/- IPI-926, Gemzar® +/- IPI-926,
  • ABRAXANE® + Gemzar® and ABRAXANE® + Gemzar + IPI-926.
  • Figure 29D compares survival of L3.6pl tumor bearing mice being treated with Vehicle, IPI-926 alone, Abraxane alone and the combination of ABRAXANE® and IPI- 926.
  • Figure 30A depicts contrast enhanced ultrasound images showing tumor perfusion in vehicle treated animals.
  • Figure 3 OB depicts contrast enhanced ultrasound images showing tumor perfusion in IPI-926 treated animals.
  • Figure 30C depicts quantitation of contrast enhanced ultrasound images showing tumor perfusion in vehicle treated animals.
  • Figure 30D depicts quantitation of contrast enhanced ultrasound images showing tumor perfusion in IPI-926 treated animals.
  • Figure 31 depicts the amount of Gli-1 inhibition in excised IPI-926 treated tumors of L3.6pl pancreatic cell lines and ASPC-1 pancreatic cell lines versus control.
  • Figure 32 is a graph depicting therapeutic testing of IPI-926 and cetuximab
  • Figure 33 is a graph depicting that IPI-926 delays re-growth in non-small cell cancer NCI-H1650 xenograft model post gefitinib therapy.
  • NCI-H1650 were grown subcutaneously in nude mice. Tumor bearing mice were administered gefitinib (40 Attorney Docket No. I2041-7000WO/3020PCT mg/kg, p.o) for 7 days then followed-by (fb) IPI-926 (40 mg/kg, p.o) every other day.
  • H1650 sensitivity (regression) to gefitinib in vivo was followed by a 65% inhibition (p ⁇ 0.02) of tumor re-growth with IPI-926 treatment.
  • Figure 34 is a graph depicting that IPI-926 delays tumor re-growth in non-small cell cancer HCC827 xenograft model post gefitinib therapy.
  • HCC827 cells were grown subcutaneously in nude mice.
  • Gefitinib was administered (10 mg/kg, p.o) for 3 days then followed-by (fb) IPI-926 (40 mg/kg, p.o) every other day.
  • Figure 35 is a graph showing that tumor human hedgehog ligands IHh and DHh are upregulated in the non-small cell cancer NCI-H1650 xenograft model post gefitinib treatment.
  • Figure 36 is a graph showing that IPI-926 inhibits the up-regulation of stromal cell Glil and Gli2 in the non-small cell cancer NCI-H1650 xenograft model post gefitinib treatment.
  • Murine Glil is up-regulated (p ⁇ 0.05) post therapy compared to vehicle treated tumor, and down modulated (p ⁇ 0.0001) with IPI-926 treatment.
  • Murine Gli2 is up- regulated (p ⁇ 0.01) post target therapy when compared to vehicle, and down modulated (p ⁇ 0.03) with IPI-926 treatment.
  • Figure 37 is a linear graph showing the effects of IPI-926, Avastin®, or the combination of IPI-926 and Avastin® in BXPC3 tumor bearing mice.
  • Hh Hedgehog
  • Malignant activation of the Hedgehog (Hh) pathway is associated with multiple tumor types and can promote the growth of certain cancers via at least three modes: Hh ligand-dependent signaling between tumor cells, Hh ligand-dependent signaling between tumor cells and their microenvironment, and ligand-independent signaling caused by mutations in the Hh receptors Patched or Smoothened.
  • Figure 19 provides a summary of the cancers that can be treated with hedgehog inhibitors, such as IPI-926.
  • hedgehog inhibitors can target the tumors directly.
  • Hh inhibitors can target the tumor microenvironment of ligand dependent cancers (e.g., desmoplastic tumors, such as pancreatic cancer and/or neurodendocrine tumors).
  • hedgehog inhibitors can decrease fibrosis, thus leading to improved drug delivery and/or Attorney Docket No. I2041-7000WO/3020PCT survival.
  • hedgehog inhibitors can target ligand-dependent residual disease.
  • hedgehog inhibitor can target ligand-independent cancers.
  • Hh ligands are believed to act via a paracrine role whereby cancer cells produce the Hh ligand that activates the Hh pathway in the surrounding stromal cell microenvironment.
  • Hh ligands can signal a tumor or cancer cell directly, as opposed to through the surrounding stromal tissue.
  • Exemplary tumors and cancer cells that are believed to be activated directly by Hh ligands include chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), multiple myeloma, small cell lung cancer, chondrosarcoma and osteosarcoma.
  • CML chronic myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphoblastic leukemia
  • multiple myeloma small cell lung cancer
  • chondrosarcoma chondrosarcoma
  • osteosarcoma include, but are not limited to, Gorlin's Syndrome, basal cell carcinoma (BCC) and
  • IPI-926 is a potent and selective Smoothened (Smo) inhibitor currently in clinical trials in solid tumors and metastatic pancreatic cancer. Smo is believed to play an important role in the malignant activation of the hedgehog pathway in both Hh ligand dependent and ligand independent cancers. Thus, IPI-926 is believed to disrupt the malignant activation of both Hh ligand dependent and ligand independent cancers. For example, IPI-926 is believed to inhibit pancreatic cancer by inhibiting Smo within the stroma. Inhibition of Smo within the tumor microenvironment is believed to deplete the desmoplastic stroma, increasing the vascularity of the tumor and rendering it more accessible to chemotherapy.
  • Smo smoothened
  • IPI-926 blocks Hh signaling in tumor-associated stromal cells -but not in the cancer cells- of several pancreatic xenograft models, resulting in reduced growth of the xenografts. This leads to a depletion of stromal tissue.
  • Studies in a Kras, p53 model of pancreatic cancer demonstrated that IPI- 926 decreased the desmoplastic stroma and enabled chemotherapy to access the tumor cells, leading to decreased incidence of tumor metastases and an increase in median survival. Improved survival of pancreatic cancer models is seen when IPI-926 is combined with gemcitabine.
  • Applicants show that administration of a hedgehog inhibitor, alone or in combination with a tyrosine kinase inhibitor (in this case, sunitinib), reduced pancreatic neuroendocrine cancer cell growth in vivo (Examples 14-15).
  • a tyrosine kinase inhibitor in this case, sunitinib
  • SHH Sonic Hedgehog
  • the hedgehog inhibitor reduced expression of Hh- dependent genes in the stroma surrounding neuroendocrine cancers, while no significant reduction of Hh dependent genes in the neuroendocrine tumor was detected, thus supporting a paracrine signaling mechanism between the hedgehog-secreting tumors and hedgehog signaling pathway in the surrounding stroma (Example 14).
  • the hedgehog inhibitor reduced the activity of a hedgehog receptor, e.g., Smoothened and/or Patched, in a tumor microenvironment, thereby causing one or more of: (i) depleting or reducing desmoplastic stroma; (ii) increasing the vascularity of the tumor; or (iii) rendering the tumor more accessible to chemotherapy.
  • compositions for treating or preventing a cancer ⁇ e.g., a neuroendocrine cancer
  • a hedgehog inhibitor alone or combination with a tyrosine kinase inhibitor ⁇ e.g., a receptor tyrosine kinase (RTK) inhibitor
  • a tyrosine kinase inhibitor e.g., a receptor tyrosine kinase (RTK) inhibitor
  • preclinical studies using inhibitors of hedgehog signaling in chondrosarcoma and osteosarcoma cell lines provided evidence for the potency of Hh- inhibitors as future agents for musculoskeletal sarcoma treatment (see Example 16).
  • Inhibiting Hh pathway is believed to have antitumor and anti-stromal activity, and can be used to limit or prevent sarcoma invasion (local and metastatic).
  • a hedgehog inhibitor alone or in combination with an mTOR inhibitor, is expected to reduce the growth and/or tumor progression of musculoskeletal or soft-tissue sarcomas, such as chondrosarcomas, synovial sarcoma, liposarcoma, and osteosarcomas.
  • administration of a hedgehog inhibitor in combination with paclitaxel or a paclitaxel agent reduces the growth and/or tumor progression of a Attorney Docket No. I2041-7000WO/3020PCT pancreatic cancer to a greater extent than administration of each agent alone (Examples 17-19).
  • This combination can additionally include gemcitabine and/or a VEF inhibitor (e.g., bevacizumab).
  • a VEF inhibitor e.g., bevacizumab
  • a hedgehog inhibitor in combination with a tyrosine kinase inhibitor reduces the growth and/or tumor progression of a hedgehog-associated cancer or tumor (e.g., a head and neck cancer and/or lung cancer (e.g., non-small cell lung cancer)) (Examples 22-25).
  • a hedgehog-associated cancer or tumor e.g., a head and neck cancer and/or lung cancer (e.g., non-small cell lung cancer)
  • the hedgehog inhibitor extends the relapse free survival of a subject who is undergoing, or has been previously treated with, an anti-cancer agent (e.g., a tyrosine kinase inhibitor).
  • the tyrosine kinase inhibitor is geftinib or cetuximab.
  • the hedgehog inhibitor reduces or inhibits tumor re-growth of a hedgehog-associated cancer after therapy with a tyrosine kinase inhibitor is less effective or ineffective (e.g., a subject having a relapse after therapy with a tyrosine kinase inhibitor).
  • the subject is a patient with lung cancer (e.g., non-small cell lung cancer) who relapses after geftinib therapy.
  • the subject is a patient with head and neck squamous cell carcinoma (FINSCC) who is undergoing or has undergone therapy with a tyrosine kinase inhibitor (e.g., an EGFR tyrosine kinase inhibitor such as cetuximab).
  • a tyrosine kinase inhibitor e.g., an EGFR tyrosine kinase inhibitor such as cetuximab.
  • a hedgehog-associated cancer e.g., a hedgehog ligand-dependent cancer cell growth chosen from a neuroendocrine cancer, a sarcoma (e.g., a musculoskeletal sarcoma, such as
  • a head and neck cancer or a lung cancer by administering to a subject a hedgehog inhibitor, alone or combination with another anticancer agent (e.g., paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor (e.g., receptor tyrosine kinase (RTK) inhibitor) or an mTOR inhibitor) are disclosed.
  • a hedgehog inhibitor alone or combination with another anticancer agent
  • another anticancer agent e.g., paclitaxel or a paclitaxel agent, a tyrosine kinase inhibitor (e.g., receptor tyrosine kinase (RTK) inhibitor) or an mTOR inhibitor
  • Suitable hedgehog inhibitors include, for example, those described and disclosed in U.S. Patent 7,230,004, U.S. Patent Application Publication No. 2008/0293754, U.S. Patent Application Publication No. 2008/0287420, and U.S. Patent Application
  • Suitable hedgehog inhibitors include those described in U.S. Patent Application Publication Nos. US 2002/0006931 , US 2007/0021493 and US 2007/0060546, and International Application Pubhcation Nos. WO 2001/19800, WO 2001/26644, WO 2001/27135, WO 2001/49279, WO 2001/74344, WO 2003/011219, WO 2003/088970, WO 2004/020599, WO 2005/013800, WO 2005/033288, WO
  • Hh inhibitors are described in Yauch, R. L. et al. (2009)
  • the hedgehog inhibitor can be a compound having the following structure:
  • R 1 is H, alkyl, -OR, amino, sulfonamido, sulfamido, -OC(0)R 5 , - N(R 5 )C(0)R 5 or a sugar;
  • R 3 is H, alkyl, alkenyl, or alkynyl
  • R 4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -
  • each W is independently for each occurrence a diradical
  • each q is independently for each occurrence 1 , 2, 3, 4, 5, or 6;
  • X " is a halide
  • each R 5 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or -[C(R) 2 ] P -R 6 ;
  • R 5 on the same substituent can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from , O, S, and P;
  • p 0-6;
  • each R 6 is independently hydroxyl, -N(R)COR, -N(R)C(0)OR, -N(R)S0 2 (R), -C(0)N(R) 2 , -OC(0)N(R)(R), -S0 2 N(R)(R), -N(R)(R), -COOR, -C(0)N(OH)(R), -OS(0) 2 OR, -S(0) 2 OR, -OP(0)(OR)(OR), -NP(0)(OR)(OR), or -P(0)(OR)(OR);
  • R 1 can not be hydroxyl; provided that when R 2 , R 3 are H and R 4 is hydroxyl; R 1 can not be hydroxyl; provided that when R 2 , R 3 , and R 4 are H ; R 1 can not be hydroxyl; and
  • R 1 can not be sugar.
  • Examples of compounds include:
  • a pharmaceutically acceptable salt thereof is a hydrochloride salt of the compound of formula I (also referred to herein as "Compound 42" or "IPI-926").
  • IPI-926 is believed to disrupt malignant activation of the hedgehog pathway in both Hh ligand dependent and Hh ligand independent cancers.
  • IPI-926 shows an EC50 of 7-15 nM in C3H10 cells, and inhibits Smo binding with an IC 50 of 1-2 nM.
  • IPI-926 can be administered orally either once a day or continuously; it has a half-life of 20-40 hours after a single dose.
  • Hedgehog inhibitors useful in the current invention can contain a basic functional group, such as amino or alkylamino, and are thus capable of forming pharmaceutically- acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically - acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately treating the compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, besylate,
  • the pharmaceutically acceptable salts of the present invention include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention can contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately treating the compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et ah, supra).
  • the hedgehog inhibitor and/or the chemotherapeutic agent can be delivered in the form of pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more hedgehog inhibitors and/or one or more chemotherapeutic formulated together with one or more pharmaceutically acceptable excipients.
  • the hedgehog inhibitor and the chemotherapeutic agent are administered in separate pharmaceutical compositions and can ⁇ e.g., because of different physical and/or chemical characteristics) be administered by different routes (e.g., one therapeutic is administered orally, while the other is administered intravenously).
  • the hedgehog inhibitor and the chemotherapeutic can be administered separately, but via the same route (e.g., both orally or both intravenously).
  • the hedgehog inhibitor and the chemotherapeutic can be administered in the same pharmaceutical composition.
  • compositions can be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those Attorney Docket No. I2041-7000WO/3020PCT targeted for buccal, sublingual, and systemic absorption), capsules, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin;
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those Attorney Docket No. I2041-7000WO/3020PCT targeted for buccal, sublingual, and systemic absorption), capsule
  • intravaginally or intrarectally for example, as a pessary, cream or foam; sublingually; ocularly; transdermally; pulmonarily; or nasally.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants.
  • adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants.
  • Prevention of the action of microorganisms upon the compounds of the present invention can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the
  • compositions comprising compositions.
  • prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Methods of preparing these formulations or compositions include the step of bringing into association the hedgehog inhibitor and/or the chemotherapeutic with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • hedgehog inhibitors and the chemotherapeutics of the present invention can be given per se or as a pharmaceutical composition containing, for example, about 0.1 to Attorney Docket No. I2041-7000WO/3020PCT
  • compositions of the present invention can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including, for example, the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • chemotherapeutic will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • oral, intravenous and subcutaneous doses of the compounds of the present invention for a patient when used for the indicated effects, will range from about 0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg per day, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about 100 mg per day, or about 0.0001 mg to about 500 mg per day, or about 0.001 mg to about 500 mg per day, or about 0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg per day.
  • the subject receiving this treatment is any animal in need, including primates, in particular humans, equines, cattle, swine, sheep, poultry, dogs, cats, mice and rats.
  • the compounds can be administered daily, every other day, three times a week, twice a week, weekly, or bi-weekly.
  • the dosing schedule can include a "drug holiday," i.e., the drug can be administered for two weeks on, one week off, or three weeks on, one week off, or four weeks on, one week off, etc., or continuously, without a drug holiday.
  • the compounds can be administered orally, intravenously, intraperitoneally, topically, Attorney Docket No. I2041-7000WO/3020PCT transdermally, intramuscularly, subcutaneously, intranasally, sublingually, or by any other route.
  • the doses of each agent or therapy can be lower than the corresponding dose for single-agent therapy.
  • the dose for single-agent therapy can range from, for example, about 0.0001 to about 200 mg, or about 0.001 to about 100 mg, or about 0.01 to about 100 mg, or about 0.1 to about 100 mg, or about 1 to about 50 mg per kilogram of body weight per day. The determination of the mode of administration and the correct dosage is well within the knowledge of the skilled clinician.
  • the invention relates to a method of treating cancer by
  • a hedgehog inhibitor alone or in combination with a second therapeutic agent, e.g., an anti-cancer agent ⁇ e.g., a receptor tyrosine kinase inhibitor, paclitaxel or a paclitaxel agent, an mTOR inhibitor, and/or an IGF-1R antagonist).
  • a second therapeutic agent e.g., an anti-cancer agent ⁇ e.g., a receptor tyrosine kinase inhibitor, paclitaxel or a paclitaxel agent, an mTOR inhibitor, and/or an IGF-1R antagonist.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a patient is suffering from cancer, which reduces the severity of the cancer, or retards or slows the progression of the cancer.
  • the terms “prevent,” “preventing” and “prevention” contemplate an action that occurs before a patient begins to suffer from the regrowth of the cancer and/or which inhibits or reduces the severity of the cancer.
  • the terms “manage,” “managing” and “management” encompass preventing the recurrence of the cancer in a patient who has already suffered from the cancer, and/or lengthening the time that a patient who has suffered from the cancer remains in remission.
  • the terms encompass modulating the threshold, development and/or duration of the cancer, or changing the way that a patient responds to the cancer.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the Attorney Docket No. I2041-7000WO/3020PCT treatment or management of the cancer, or to delay or minimize one or more symptoms associated with the cancer.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapeutic agents, which provides a therapeutic benefit in the treatment or management of the cancer.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the cancer, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “prophylactically effective amount" of a compound is an amount sufficient to prevent regrowth of the cancer, or one or more symptoms associated with the cancer, or prevent its recurrence.
  • prophylactically effective amount of a compound means an amount of the compound, alone or in combination with other therapeutic agents, which provides a prophylactic benefit in the prevention of the cancer.
  • prophylactically effective amount can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • cancer and “tumor” are synonymous terms.
  • cancer therapy and “cancer treatment” are synonymous terms.
  • chemotherapy and “chemotherapeutic” and “chemotherapeutic agent” are synonymous terms.
  • the term "patient” or “subject” refers to an animal, typically a human (i.e., a male or female of any age group, e.g., a pediatric patient (e.g, infant, child, adolescent) or adult patient (e.g., young adult, middle-aged adult or senior adult) or other mammal, such as a primate (e.g., cynomolgus monkey, rhesus monkey); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, and/or turkeys, that will be or has been the object of treatment, observation, and/or experiment.
  • a human i.e., a male or female of any age group, e.g., a pediatric patient (e.g, infant, child, adolescent) or adult patient (e.g., young adult, middle-aged adult or
  • the hedgehog inhibitor is a first line treatment for the cancer, i.e., it is used in a subject who has not been previously administered another drug intended to treat the cancer.
  • the hedgehog inhibitor is a second line treatment for the cancer, i.e., it is used in a subject who has been previously administered another drug intended to treat the cancer.
  • the hedgehog inhibitor is a third or fourth line treatment for the cancer, i.e., it is used in a subject who has been previously administered two or three other drugs intended to treat the cancer.
  • a hedgehog inhibitor is administered to a subject following surgical excision/removal of the cancer.
  • a hedgehog inhibitor is administered to a subject before, during, and/or after radiation treatment of the cancer.
  • the hedgehog inhibitor is administered as neoadjuvant therapy, i.e., prior to another treatment.
  • the hedgehog inhibitor is administered as adjuvant therapy, i.e., a treatment in addition to primary therapy.
  • the methods include administration of a first therapeutic agent and a second therapeutic agent, wherein the second therapeutic agent is a hedgehog inhibitor.
  • the two agents can be administered concurrently (i.e., essentially at the same time, or within the same treatment) or sequentially (i.e., one immediately following the other, or alternatively, with a gap in between administration of the two).
  • the hedgehog inhibitor is administered sequentially (i.e., after the first therapeutic).
  • the first therapeutic agent can be a chemo therapeutic agent, or multiple chemotherapeutic agents administered sequentially or in combination.
  • the invention in another aspect, relates to a method of treating cancer including the steps of administering to a patient a first therapeutic agent, then administering the first therapeutic agent in combination with a second therapeutic agent, wherein the second therapeutic agent is a hedgehog inhibitor.
  • the invention in another aspect, relates to a method of treating a condition mediated by the hedgehog pathway by administering to a patient a first therapeutic agent Attorney Docket No. I2041-7000WO/3020PCT and a second therapeutic agent, wherein the second therapeutic agent is a hedgehog inhibitor.
  • the two agents can be administered concurrently (i.e., essentially at the same time, or within the same treatment) or sequentially (i.e., one immediately following the other, or alternatively, with a gap in between administration of the two).
  • the hedgehog inhibitor is administered sequentially (i.e., after the first therapeutic).
  • the first therapeutic agent can be a chemo therapeutic agent.
  • the invention in another aspect, relates to a method of treating a condition mediated by the hedgehog pathway including the steps of administering to a patient a first therapeutic agent, then administering the first therapeutic agent in combination with a second therapeutic agent, wherein the second therapeutic agent is a hedgehog inhibitor.
  • the invention also relates to methods of extending relapse free survival in a cancer patient who is undergoing or has undergone cancer therapy (for example, treatment with a chemotherapeutic (including small molecules and biotherapeutics, e.g., antibodies), radiation therapy, surgery, R Ai therapy and/or antisense therapy) by administering a therapeutically effective amount of a hedgehog inhibitor to the patient.
  • a chemotherapeutic including small molecules and biotherapeutics, e.g., antibodies
  • radiation therapy for example, treatment with a chemotherapeutic (including small molecules and biotherapeutics, e.g., antibodies), radiation therapy, surgery, R Ai therapy and/or antisense therapy
  • Relapse free survival is the length of time following a specific point of cancer treatment during which there is no clinically-defined relapse in the cancer.
  • the hedgehog inhibitor is administered concurrently with the cancer therapy. In instances of concurrent administration, the hedgehog inhibitor can continue to be administered after the cancer therapy has ceased.
  • the hedgehog inhibitor is administered after cancer therapy has ceased (i.e., with no period of overlap with the cancer treatment).
  • the hedgehog inhibitor can be administered immediately after cancer therapy has ceased, or there can be a gap in time (e.g., up to about a day, a week, a month, six months, or a year) between the end of cancer therapy and the administration of the hedgehog inhibitor.
  • Treatment with the hedgehog inhibitor can continue for as long as relapse-free survival is maintained (e.g., up to about a day, a week, a month, six months, a year, two years, three years, four years, five years, or longer).
  • the invention relates to a method of extending relapse free survival in a cancer patient who had previously undergone cancer therapy (for example, treatment with a chemotherapeutic (including small molecules and biotherapeutics, e.g., antibodies), Attorney Docket No. I2041-7000WO/3020PCT radiation therapy, surgery, R Ai therapy and/or antisense therapy) by administering a therapeutically effective amount of a hedgehog inhibitor to the patient after the cancer therapy has ceased.
  • the hedgehog inhibitor can be administered immediately after cancer therapy has ceased, or there can be a gap in time (e.g., up to about a day, a week, a month, six months, or a year) between the end of cancer therapy and the administration of the hedgehog inhibitor.
  • Hedgehog inhibitors e.g., IPI-926, described in PCT publications WO
  • 2008083252 and WO 2008083248 both of which are incorporated herein by reference, have been shown to inhibit in vitro growth of human cell lines derived from patients with pancreatic cancer, medulloblastoma, lung cancer, multiple myeloma, acute lymphocytic leukemia, myelodysplatic syndrome, non-Hodgkin's type lymphoma, Hodgkin's disease and lymphocygtic leukemia.
  • Hedgehog inhibitors e.g., IPI-926
  • IPI-926 have also shown tumor growth inhibition in a number of preclinical in vivo models, such as medulloblastoma (Pink et ah, American Association for Cancer Research, 1588, 2008; Villavicencia et al. American Association or Cancer Research, 2009); small cell lung cancer (Travaglione et ah, American Association for Cancer Research, 4611 , 2008; Peacock et ah, American Association for Cancer Research, 2009); and ovarian cancer (Growdon et al, Society of Gynecologic Oncologists Annual Meeting on Women's Cancer, 2009).
  • hedgehog inhibitors e.g., IPI-926
  • IPI-926 have demonstrated rapid and sustained Hedgehog pathway inhibition in stromal cells, a downstream mediator of Hedgehog signaling, after single administration in a model of human pancreatic cancer (Traviglione et ah, EORTC-NCI-AACR Symposium on "Molecular Targets and Cancer Therapeutics” 2008).
  • Inhibition of the hedgehog pathway has also been shown to reduce or inhibit the growth of a variety of cancers, such as acute lymphocytic leukemia (ALL) (Ji et ah, Journal of Biological Chemistry (2007) 282:37370-37377); basal cell carcinoma (Xie et ah, Nature (1998) 391 :90-92; Williams et ah, PNAS (2003) 100:4616-4621 ; Bale and Yu (2001) Human Molecular Genetics (2001) 10:757-762); biliary cancer (Berman et ah, Nature (2003) 425:846-851 ; WO 2005/013800); brain cancer and glioma (Clement et ah, Current Biology (2007) 17: 1-8; Ehtesham et ah, Ongogene (2007) 1-10); bladder cancer; Attorney Docket No. I2041-7000WO/3020PCT breast cancer (Kubo et ah, Cancer Research
  • GIST gastrointestinal stromal tumor
  • pancreatic cancer (Thayer et ah, Nature (2003) 425:851-856; Berman et ah, Nature (2003) 425:846-851; WO 2005/013800); prostate cancer (Karhadkar et ah, Nature (2004) 431 :707-712; Sheng et ah, Molecular Cancer (2004) 3:29-42; Fan et ah, Endocrinology (2004) 145:3961-3970); and testicular cancer (Dormeyer et ah, J. Proteome Res. (2008) 7:2936-2951).
  • lung cancer e.g., small cell lung cancer or non-small cell lung cancer
  • pancreatic cancer bladder cancer
  • ovarian cancer breast cancer
  • colon cancer multiple myeloma
  • acute myelogenous leukemia Attorney Docket No. I2041-7000WO/3020PCT
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • neuroendocrine cancer and a sarcoma (e.g., a musculoskeletal sarcoma, such as chondrosarcoma and osteosarcoma).
  • a sarcoma e.g., a musculoskeletal sarcoma, such as chondrosarcoma and osteosarcoma.
  • lung cancer including small cell lung cancer and non small cell lung cancer
  • other cancers of the pulmonary system including small cell lung cancer and non small cell lung cancer
  • pancreatic cancer basal cell carcinoma, breast cancer, prostate cancer and other genitourinary cancers
  • gastrointestinal stromal tumor GIST
  • other cancers of the gastrointestinal tract colon cancer
  • colorectal cancer ovarian cancer
  • cancers of the hematopoietic system including multiple myeloma, acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and myelodysplastic syndrome
  • polycythemia Vera Waldenstrom's macroglobulinemia, heavy chain disease, soft-tissue sarcomas, such as fibro
  • the cancer is selected from bladder cancer, brain cancer, breast cancer, colorectal cancer, esophageal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymphoma, leukemia, meduloblastoma, melanoma, multiple myeloma, neuroendocrine cancer, osteosarcoma, ovarian cancer, pancreatic cancer and prostate cancer.
  • the cancer is lung cancer.
  • the lung cancer is small cell lung cancer (SCLC).
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the cancer is colorectal cancer.
  • the cancer is neuroendocrine cancer.
  • Neuroendocrine cancers are cancers derived from cells at the interface between the endocrine (hormonal) system and the nervous system.
  • the majority of neuroendocrine cancers fall into two categories: carcinoids and pancreatic endocrine tumors (also known as endocrine pancreatic tumors or islet cell tumors).
  • carcinoids also known as endocrine pancreatic tumors or islet cell tumors.
  • pancreatic endocrine tumors also known as endocrine pancreatic tumors or islet cell tumors.
  • other forms of neuroendocrine cancers exist, including neuroendocrine lung tumors, which arise from the respiratory rather than the gastro-entero-pancreatic system.
  • Neuroendocrine cancers can originate from endocrine glands such as the adrenal medulla, the pituitary, and the parathyroids, as well as endocrine islets within the thyroid or the pancreas, and dispersed endocrine cells in the respiratory and gastrointestinal tract.
  • endocrine glands such as the adrenal medulla, the pituitary, and the parathyroids
  • endocrine islets within the thyroid or the pancreas
  • dispersed endocrine cells in the respiratory and gastrointestinal tract The total incidence of neuroendocrine cancers in the United States is about 9,000 new cases per year.
  • the cancer treated can be a neuroendocrine cancer chosen from one or more of, e.g., a neuroendocrine cancer of the pancreas, lung, appendix, duodenum, ileum, rectum or small intestine.
  • the neuroendocrine cancer is chosen from one or more of: a pancreatic endocrine tumor; a neuroendocrine lung tumor; or a neuroendocrine cancer from the adrenal medulla, the pituitary, the parathyroids, thyroid endocrine islets, pancreatic endocrine islets, or dispersed endocrine cells in the respiratory or gastrointestinal tract.
  • Pancreatic endocrine tumors can secrete biologically active peptides (e.g., hormones) that can cause various symptoms in a subject. Such tumors are referred to Attorney Docket No. I2041-7000WO/3020PCT functional or secretory tumors. Functional tumors can be classified by the hormone most strongly secreted.
  • biologically active peptides e.g., hormones
  • pancreatic endocrine tumors examples include gastrinoma (producing excessive gastrin and causing Zollinger-Ellison Syndrome), insulinoma (producing excessive insulin), glucagonoma (producing excessive glucagon), vasoactive intestinal peptideoma (VIPoma, producing excessive vasoactive intestinal peptide), PPoma (producing excessive pancreatic polypeptide), somatostatinoma
  • pancreatic endocrine tumors can arise in subjects who have multiple endocrine neoplasia type 1 (ME 1); such tumors often occur in the pituitary gland or pancreatic islet cells.
  • Pancreatic endocrine tumors that do not secrete peptides are called nonfunctional (or nonsecretory or nonfunctional) tumors.
  • the cancer treated is a pancreatic ductal adenocarcinoma.
  • the cancer treated is a carcinoid tumor, e.g., a carcinoid neuroendocrine cancer.
  • Carcinoid tumors tend to grow more slowly than pancreatic endocrine tumors.
  • a carcinoid tumor can produce biologically active molecules such as serotonin, a biogenic molecule that causes a specific set of symptoms called carcinoid syndrome.
  • Carcinoid tumors that produce biologically active molecules are often referred to as functional carcinoid tumors, while those that do not are referred to as nonfunctional carcinoid tumors.
  • the neuroendocrine cancer is a functional carcinoid tumor (e.g., a carcinoid tumor that can produce biologically active molecules such as serotonin).
  • the neuroendocrine cancer is a nonfunctional carcinoid tumor.
  • the carcinoid tumor is a tumor from the thymus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, colon), rectal, pancreatic, appendix, ovarian or testicular carcinoid.
  • Attorney Docket No. I2041-7000WO/3020PCT is a tumor from the thymus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, colon), rectal, pancreatic, appendix, ovarian or testicular carcinoid.
  • Carcinoid tumors can be further classified depending on the point of origin, such as lung, thymus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, colon), rectum, pancreas, appendix, ovaries and testes.
  • point of origin such as lung, thymus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, colon), rectum, pancreas, appendix, ovaries and testes.
  • the neuroendocrine cancer is a carcinoid tumor. In other embodiments, the neuroendocrine cancer is a pancreatic endocrine tumor. In still other embodiments, the neuroendocrine cancer is a neuroendocrine lung tumor. In certain embodiments, the neuroendocrine cancers originate from the adrenal medulla, the pituitary, the parathyroids, thyroid endocrine islets, pancreatic endocrine islets, or dispersed endocrine cells in the respiratory or gastrointestinal tract.
  • neuroendocrine cancers that can be treated include, but are not limited to, medullary carcinoma of the thyroid, Merkel cell cancer (trabecular cancer), small-cell lung cancer (SCLC), large-cell neuroendocrine carcinoma (of the lung), extrapulmonary small cell carcinomas (ESCC or EPSCC), neuroendocrine carcinoma of the cervix, Multiple Endocrine Neoplasia type 1 (MEN-1 or ME 1), Multiple Endocrine Neoplasia type 2 (MEN-2 or MEN2), neurofibromatosis type 1 , tuberous sclerosis, von Hippel-Lindau (VHL) disease, neuroblastoma,
  • MEN-1 or ME 1 Multiple Endocrine Neoplasia type 1
  • MEN-2 or MEN2 Multiple Endocrine Neoplasia type 2
  • VHL von Hippel-Lindau
  • pheochromocytoma (phaeochromocytoma), paraganglioma, neuroendocrine cancer of the anterior pituitary, and/or Carney's complex.
  • the cancer or tumor treated is a sarcoma, e.g., a musculoskeletal sarcoma (e.g., bone and cartilage sarcoma).
  • a musculoskeletal sarcoma e.g., bone and cartilage sarcoma
  • exemplary musculoskeletal sarcomas include but are not limited to, osteosarcoma (e.g., conventional osteogenic sarcoma), chondrosarcoma (e.g., conventional chondrosarcoma), Ewing sarcoma, dedifferentiated chondrosarcoma, parosteal osteogenic sarcoma, periosteal osteogenic sarcoma, mesenchymal chondrosarcoma, giant cell tumor of bone, adamantinoma, chordoma and other sarcomas that typically occur in soft tissue in adults that can also occur in bone, such as malignant fibrous histiocytoma (MF
  • osteosarcoma e.g., conventional osteogenic sarcoma
  • chondrosarcoma Attorney Docket No. I2041-7000WO/3020PCT
  • Osteogenic sarcoma (also called osteosarcoma) is the most common tumor of bone. Approximately 800- 1000 cases of osteogenic sarcoma are seen in the United States each year. A second peak of incidence of osteosarcoma occurs in the 8th decade of life, typically associated with Paget disease of bone. Osteosarcoma typically affects adolescents, and generally affects bones around the knee joint, though any bone of the body can be affected. Treatment typically involves chemotherapy and surgery to try to achieve the best cure rate. Standard drugs that are used include doxorubicin and cisp latin in adults, and the same two drugs with high-dose methotrexate in children, adolescents, or young adults. The use of ifosfamide remains controversial. Recurrences typically occur in the lungs.
  • osteosarcoma This is one situation where surgery can be curative; resection of lung metastases from a primary osteosarcoma is a standard of care when there is a small number of lung nodules that can be removed safely, and can be associated with a 30-35% cure rate.
  • Osteosarcomas occur commonly in familial syndromes associated with sarcoma, such as Li-Fraumeni syndrome (involving a mutation in the p53 gene), retinoblastoma (involving a mutation in the Rb gene), and Rothmund-Thomson syndrome.
  • chondrosarcoma can be a difficult tumor to treat. It often arises in older patients, and often in the pelvis. As a result, people with multiple medical diagnoses are put in the position of requiring a very large operation with a high risk of postoperative complications, with subsequent loss of function. For chondrosarcomas that arise in other sites, surgery can be less morbid and represents the standard of care. People with metastatic disease often times do not respond well to chemotherapy. Grade 1 chondrosarcomas nearly never metastasize, Grade 2 chondrosarcomas have only a 10- 15% risk of metastasis, and grade 3 chondrosarcomas have a two-thirds or higher risk of metastasis. As a result, some people with grade 3 chondrosarcomas will be given adjuvant chemotherapy. A version of chondrosarcoma called clear cell chondrosarcoma has an intermediate risk of metastasis, but treatment is typically surgery alone.
  • Ewing sarcoma is the third most common sarcoma of bone, and second most common in children. The same tumor occurs in the soft tissue of adults more than it occurs in bone. We estimate there are fewer than 500 cases a year in the United States. Attorney Docket No. I2041-7000WO/3020PCT
  • Dedifferentiated chondrosarcoma is a more aggressive version of chondrosarcoma, typically occurring in adolescence and in people over age 60. It shows features of both chondrosarcoma and of elements of a less differentiated tumor, such as MFH (malignant fibrous histiocytoma), which does not show even a hint of relatedness to the
  • chondrosarcoma This version of chondrosarcoma has a high risk of recurrence, even greater than that of grade 3 conventional chondrosarcoma (described above).
  • ⁇ osteogenic sarcoma parosteal osteogenic sarcoma
  • periosteal osteogenic sarcoma mesenchymal chondrosarcoma
  • giant cell tumor of bone adamantinoma
  • chordoma mesenchymal chondrosarcoma
  • Parosteal osteosarcoma is a low grade osteosarcoma of bone that grows from the surface of the bone without lifting off the surface connective tissue of bone, called periosteum. It occurs by far most commonly along the posterior, distal femur in the 3rd decade of life. Treatment for this rare form of osteosarcoma is usually surgery alone, although if there are aggressive features such as dedifferentiation or a high grade component seen, chemotherapy is also often given.
  • Periosteal osteosarcoma is a low grade osteosarcoma of bone that grows from the surface of the bone and lifts off the surface connective tissue of bone, called periosteum, and is also associated with new bone formation in the area of the lifted periosteum. It typically occurs between ages of 10 and 30. Treatment for this rare form of osteosarcoma is usually surgery alone. It is not clear if chemotherapy is helpful for this type of osteosarcoma, though it is often given if the tumor appears more aggressive than usual.
  • Mesenchymal chondrosarcoma is a rare bone tumor which shows a mixture of aggressive small round blue cells mixed with more typical lower grande chondrosarcoma. They usually affect people between ages of 15 and 30, and have a high risk of recurrence. The benefit of chemotherapy is not known, though chemotherapy is often used.
  • the Attorney Docket No. I2041-7000WO/3020PCT typical chemotherapy drugs that are used in the adjuvant setting (or metastatic setting, for that matter) are the drugs used for Ewing sarcoma and similar sarcomas.
  • Giant cell tumor of bone is a tumor of bone that typically occurs between ages 20 and 40, and has a unique appearance under the microscope. It occurs in the area of the knee and lower spine, typically. It is treated by scraping out the tumor and treating the tumor cavity with cement (which heats up and also destroys tumor as a result) or with liquid nitrogen (freezing and thawing the tumor in place, often killing remaining cells).
  • a bone graft is often used to try to reconstruct the area as well. In some cases, the tumor can be removed as one piece without damaging other tissues, and in these cases a bone graft can be performed as well.
  • Conventional giant cell tumors have a risk of recurrence where they start, and have a low but real chance of metastasis to the lungs. Giant cell tumors must be differentiated from aneurysmal bone cysts,
  • Adamantinoma is a very rare tumor of cells that are associated with bone formation that are can be similar to the cells responsible for forming teeth.
  • the latter cells can form cancers of the lower jaw more than the upper jaw, termed ameloblastoma.
  • Adamantinoma nearly always affects the tibia, and is treated with surgery. Rare cases can travel elsewhere in the body, at which point chemotherapy is used to try and increase lifespan.
  • Chordoma is a tumor that appears very similar to the cells that fetal cells that formed the spine during development, the notochord.
  • the relationship to development of the bone while the fetus is growing in the uterus is hard to understand, since tumors of this sort typically only arise in people over age 50. It typically occurs at the base of the skull, or in the sacrum (the very base of the spine in the pelvis). Given these locations, surgical removal is often times not possible.
  • This is one tumor that can respond to radiation, with an intent to cure even tumors that are not surgically removable, and is an ideal type of tumor with which to try proton beam radiation.
  • imatinib can be of some use, and only infrequently are responses seen to other chemotherapy drugs.
  • sarcomas that typically occur in soft tissue in adults that can also occur in bone. These include malignant fibrous histiocytoma (MFH [also termed high grade Attorney Docket No. I2041-7000WO/3020PCT undifferentiated pleomorphic sarcoma or HGUPS]), fibrosarcoma, leiomyosarcoma, and angiosarcoma, among others.
  • MSH malignant fibrous histiocytoma
  • fibrosarcoma also termed high grade Attorney Docket No. I2041-7000WO/3020PCT undifferentiated pleomorphic sarcoma or HGUPS
  • fibrosarcoma fibrosarcoma
  • leiomyosarcoma and angiosarcoma
  • Certain methods of the current invention can be especially effective in treating cancers that respond well to existing chemotherapies, but suffer from a high relapse rate.
  • treatment with the hedgehog inhibitor can increase the relapse-free survival time or rate of the patient.
  • cancers include lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), bladder cancer, ovarian cancer, breast cancer, colon cancer, multiple myeloma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), neuroendocrine cancer, and sarcomas.
  • the invention also encompasses the use of a chemotherapeutic agent and a hedgehog inhibitor for preparation of one or more medicaments for use in a method of extending relapse free survival in a cancer patient.
  • the invention also relates to the use of a hedgehog inhibitor in the preparation of a medicament for use in a method of extending relapse free survival in a cancer patient who had previously been treated with a chemotherapeutic.
  • the invention also encompasses the use of a hedgehog inhibitor in the preparation of a medicament for use in a method of treating pancreatic cancer patient.
  • Hh ligands post chemotherapy exhibit up-regulation of Hh ligands post chemotherapy (see Examples 11 and 12 herein) and in response to other stress, such as hypoxia (see Example 12).
  • the type of Hh ligand that is up-regulated i.e., Sonic, Indian and/or Desert
  • the degree of up-regulation vary depending upon the tumor type and the chemotherapeutic agent.
  • stress including chemotherapy
  • up-regulation of tumor-derived Hh ligand post-chemotherapy can confer upon the surviving cell population a dependency upon the Hh pathway that is important for tumor recurrence, and thus can be susceptible to Hh pathway inhibition.
  • an aspect of the invention is a method of treating cancer by determining whether expression of one or more hedgehog ligands has increased during or after chemotherapy, then administering a hedgehog inhibitor.
  • Ligand expression can be measured by detection of a soluble form of the ligand in peripheral blood and/or urine (e.g., by an ELISA assay or radioimmunoassay), in circulating tumor cells (e.g., by a Attorney Docket No.
  • FACS fluorescence-activated cell sorting
  • RT-PCR reverse transcription polymerase chain reaction
  • Detection of hedgehog ligand in a given patient tumor could also be assessed in vivo, by systemic administration of a labeled form of an antibody to a hedgehog ligand followed by imaging, similar to detection of PSMA in prostate cancer patients (Bander, NH Nat Clin Pract Urol 2006; 3:216-225).
  • Expression levels in a patient can be measured at least at two time-points to determine of ligand induction has occurred.
  • hedgehog ligand expression can be measured pre- and post- chemotherapy, pre-chemo therapy and at one or more time-points while chemotherapy is ongoing, or at two or more different time -points while chemotherapy is ongoing. If a hedgehog ligand is found to be up-regulated, a hedgehog inhibitor can be administered. Thus, measurement of hedgehog ligand induction in the patient can determine whether the patient receives a hedgehog pathway inhibitor in combination with or following other chemotherapy.
  • Another aspect of the invention relates to a method of treating cancer in a patient by identifying one or more chemotherapeutics that elevate hedgehog ligand expression in the cancer tumor, and administering one or more of the chemotherapeutics that elevate hedgehog ligand expression and a hedgehog inhibitor. To determine which
  • chemotherapeutics elevate hedgehog expression
  • tumor cells can be removed from a patient prior to therapy and exposed to a panel of chemotherapeutics ex vivo and assayed to measure changes in hedgehog ligand expression (see, e.g., Am. J. Obstet. Gynecol. Nov. 2003, 189(5): 1301-7; J. NeurooncoL, Feb. 2004, 66(3):365-75).
  • chemotherapeutic that causes an increase in one or more hedgehog ligands is then administered to the patient.
  • a chemotherapeutic that causes an increase in one or more hedgehog ligands can be administered alone or in combination with one or more different chemotherapeutics that can or can not cause an increase in one or more hedgehog ligands.
  • the hedgehog inhibitor and chemotherapeutic can be administered concurrently (i.e., essentially at the same time, or within the same treatment) or sequentially (i.e., one immediately following the other, or alternatively, with a gap in between administration of the two).
  • Treatment with the hedgehog inhibitor can continue after treatment with the Attorney Docket No. I2041-7000WO/3020PCT chemotherapeutic ceases.
  • the chemotherapeutic is chosen based upon its ability to up-regulate hedgehog ligand expression (which, in turn, renders the tumors dependent upon the hedgehog pathway), which can make the tumor susceptible to treatment with a hedgehog inhibitor.
  • Another aspect of the invention relates to a method of treating cancer in a patient by identifying an alteration in an EGFR gene or gene product.
  • the alteration of the EGFR gene or gene product includes, but is not limited to, cytogenetic abnormalities, non-reciprocal translocations, rearrangements, intra-chromosomal inversions, mutations, point mutations, deletions, changes in gene copy number, mutations in a transcript, and changes in expression of a gene or gene product.
  • the mutation in a transcript is an mRNA mutation, rR A mutation or tR A mutation.
  • the expression level, structure (e.g., post-translational modifications, such as phosphorylation) and/or activity of one or more oncogenic polypeptides is evaluated.
  • the expression level, structure, and/or activity of one or more mutant oncogenic isoforms, e.g., isoforms arising from one or more of alternative splicing, frameshifting, translational and/or post-translational events, of various proto- oncogene expression products in a cell, e.g., a hyperproliferative cell (e.g., a cancerous or tumor cell) are detected.
  • EGFR mutations are described in e.g., Couzin J., (2004) Science 305: 1222-1223; Fukuoka, M. et al, (2003) J. Clin. Oncol. 21 :2237-46; Lynch et al,
  • exemplary alterations in an EGFR gene or gene product include but are not limited to, an EGFR exon deletion ⁇ e.g., EGFR exon 19 Deletion), and/or exon mutation ⁇ e.g., an L858R T790M EGFR mutation).
  • Other exemplary alterations include, but are not limited to, EGFR_ D770_N771>AGG;
  • EGFR E709A EGFR E709G; EGFR 709H; EGFR E709K; EGFR E709V;
  • EGFR_E746_A750del EGFR_E746_A750del
  • EGFR_E746_A750del T751A
  • EGFR_E746_A750del V ins
  • EGFR_E746_T751del I ins; EGFR_E746_T751del, S752A; EGFR_E746_T751del, S752D; EGFR_E746_T751 del, V ins; EGFR G719A; EGFR G719C; EGFR G719S:
  • EGFR_L747_S752del EGFR_L747_S752del
  • EGFR_L747_S752del P753S
  • EGFR_L747_S752del Q ins
  • EGFR_L747_T750del P ins; EGFR_L747_T751del; EGFR L858R; EGFR L861Q; EGFR_M766_A767insAI; EGFR_P772_H773insV; EGFR S752_1759del; EGFR S768I;
  • the alteration can be detected by any method of detection available in the art, including but not limited to, one or more of nucleic acid hybridization assay,
  • amplification-based assays ⁇ e.g., polymerase chain reaction (PCR)), PCR-RFLP assay, real-time PCR, sequencing, screening analysis (including metaphase cytogenetic analysis by standard karyotype methods, FISH, spectral karyotyping or MFISH, comparative genomic hybridization), in situ hybridization, SSP, HPLC or mass-spectrometric genotyping.
  • PCR polymerase chain reaction
  • PCR-RFLP assay real-time PCR
  • sequencing screening analysis (including metaphase cytogenetic analysis by standard karyotype methods, FISH, spectral karyotyping or MFISH, comparative genomic hybridization), in situ hybridization, SSP, HPLC or mass-spectrometric genotyping.
  • screening analysis including metaphase cytogenetic analysis by standard karyotype methods, FISH, spectral karyotyping or MFISH, comparative genomic hybridization
  • in situ hybridization SSP, HPLC or mass-spectrometric genotyping.
  • the hedgehog inhibitor as described above and herein, can be administered in combination with one or more additional therapies, e.g., such as radiation therapy, surgery and/or in combination with one or more therapeutic agents, to treat the cancers described herein.
  • additional therapies e.g., such as radiation therapy, surgery and/or in combination with one or more therapeutic agents, to treat the cancers described herein.
  • compositions can be administered concurrently with, prior to, or subsequent to, one or more other additional therapies or therapeutic agents.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutic agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive pharmaceutical composition with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • the cancer treated by the methods described herein can be selected from, for example, medulloblastoma; a sarcoma ⁇ e.g., bone or soft-tissue sacoma (e.g., synovial sarcoma, liposarcoma), musculoskeletal sarcoma such as bone and cartilage sarcoma, osteosarcoma, and chondrosarcoma; pancreatic cancer; lung cancer (e.g., small cell lung cancer (SCLC) or non-small cell lung cancer ( SCLC)); colorectal cancer; ovarian cancer; head and neck squamous cell carcinoma (HNSCC); chronic myelogenous leukemia (CML); chronic lymphocytic leukemia (CLL); acute
  • ALL lymphoblastic leukemia
  • AML acute myeloid leukemia
  • multiple myeloma and prostate cancer.
  • Suitable therapeutics for use in combination with the hedgehog inhibitors for treatment of small cell lung cancer includes, but is not limited to, a Attorney Docket No. I2041-7000WO/3020PCT chemo therapeutic agent, e.g., etoposide, carboplatin, cisp latin, irinotecan, topotecan, gemcitabine, liposomal SN-38, bendamustine, temozolomide, belotecan, NK012,
  • a Attorney Docket No. I2041-7000WO/3020PCT chemo therapeutic agent e.g., etoposide, carboplatin, cisp latin, irinotecan, topotecan, gemcitabine, liposomal SN-38, bendamustine, temozolomide, belotecan, NK012,
  • tyrosine kinase inhibitor e.g., EGFR inhibitor (e.g., erlotinib, gefitinib, cetuximab, panitumumab); multikinase inhibitor (e.g., sorafenib, sunitinib); VEGF inhibitor (e.g., bevacizumab, vandetanib); cancer vaccine (e.g., GVAX); Bcl-2 inhibitor (e.g., oblimersen sodium, ABT-263); proteasome inhibitor (e.g., bortezomib (Velcade), NPI-0052), paclitaxel or a paclitaxel agent; docetaxel; IGF- 1 receptor inhibitor (e.g., AMG 479); HGF/SF inhibitor (e.g., AMG 102, MK-0646); chloroquine; Aurora kinase inhibitor (e.g.,
  • HDAC inhibitor e.g., belinostat
  • SMO antagonist e.g., BMS 833923
  • amrubicin e.g., amrubicin, peptide cancer vaccine, and radiation therapy (e.g., intensity-modulated radiation therapy (IMRT), hypofractionated radiotherapy, hypoxia-guided radiotherapy), surgery, and combinations thereof.
  • IMRT intensity-modulated radiation therapy
  • a chemo therapeutic agent e.g., vinorelbine, cisplatin, docetaxel, pemetrexed disodium, etoposide, gemcitabine, carboplatin, liposomal SN-38, TLK286, temozolomide, topotecan, pemetrexed disodium, azacitidine, irinotecan, tegafur-gimeracil-oteracil potassium, sapacitabine); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib, gefitinib, cetuximab, panitumumab, necitumumab, PF-00299804, nimotuzumab,
  • EGFR inhibitor e.g., erlotinib, gefitinib, cetuximab, panitumumab, necitumumab, PF-00299804, ni
  • RO5083945) MET inhibitor (e.g., PF-02341066, ARQ 197), PI3K kinase inhibitor (e.g., XL147, GDC-0941), Raf/MEK dual kinase inhibitor (e.g., R05126766), PI3K/mTOR dual kinase inhibitor (e.g., XL765), SRC inhibitor (e.g., dasatinib), dual inhibitor (e.g., BIBW 2992, GSK1363089, ZD6474, AZD0530, AG-013736, lapatinib, MEHD7945A, linifanib), multikinase inhibitor (e.g., sorafenib, sunitinib, pazopanib, AMG 706, XL184, MGCD265, BMS-690514, R935788), VEGF inhibitor (e.g., endostar, endostatin, bevaci
  • GSK1572932A melatonin, talactoferrin, dimesna, topoisomerase inhibitor (e.g., amrubicin, etoposide, karenitecin), nelfinavir, cilengitide, ErbB3 inhibitor (e.g., MM- 121 , U3-1287), survivin inhibitor (e.g., YM155, LY2181308), eribulin mesylate, COX-2 inhibitor (e.g., celecoxib), pegfilgrastim, Polo-like kinase 1 inhibitor (e.g., BI 6727), TRAIL receptor 2 (TR-2) agonist (e.g., CS-1008), CNGRC peptide-TNF alpha conjugate, dichloroacetate (DCA), HGF inhibitor (e.g., SCH 900105), SAR240550, PPAR-gamma agonist (e.g., CS-7017),
  • Suitable therapeutics for use in combination with the hedgehog inhibitors for treatment of colorectal cancer includes, but is not limited to, 5-Fluorouracil (5FU-TS inhibitor); Irinotecan (Topo I poison); Oxaliplatin (DNA adducts), monoclonal antibodies against EGFR, e.g., Erbitux® and Vectabix, FOLFOX: 5-Fluorouracil + Leucovorin +Oxaliplatin; FOLFIRI: 5-Fluorouracil + Leucovorin +Irinotecan, VEGF Attorney Docket No. I2041-7000WO/3020PCT inhibitor (e.g., anti-VEGF antibody) alone or in combination with 5FU, and a combination thereof.
  • 5-Fluorouracil 5FU-TS inhibitor
  • Irinotecan Topic I poison
  • Oxaliplatin DNA adducts
  • FOLFOX 5-Fluorouracil + Leucovorin +Oxalip
  • Suitable therapeutics for use in combination with the hedgehog inhibitors for treatment of medulloblastoma includes, but is not limited to, a
  • chemotherapeutic agent e.g., lomustine, cisplatin, carboplatin, vincristine, and cyclophosphamide
  • radiation therapy surgery, and a combination thereof.
  • Suitable therapeutics for use in combination with the hedgehog inhibitors for treatment of chondrosarcoma includes, but is not limited to, a
  • chemotherapeutic agent e.g., one or more of: doxorubicin, cisplatin, ifosfamide, or methotrexate (e.g., high dose methotrexate), trabectedin, triparanol, or DAPT), mTOR inhibitors, NOTCH inhibitors (e.g., gamma secretase inhibitors (e.g., RO499097), radiation therapy (e.g., proton therapy), surgery, and a combination thereof.
  • Additional agents that can be used in combination with the hedgehog inhibitors include other anticancer agents used for sarcoma treatment.
  • Suitable therapeutics for use in combination with the hedgehog inhibitors for treatment of osteosarcoma includes, but is not limited to, a
  • chemotherapeutic agent e.g., one or more of: doxorubicin, cisplatin, methotrexate (e.g., high dose methotrexate) (e.g., alone or in combination with leucovorin rescue), gemcitabine, docetaxel, adriamycin, ifosfamide (e.g., alone or in combination with mesna), BCG (Bacillus Calmette-Guerin), etoposide, muramyl tri-peptite (MTP)), radiation therapy, surgery, and a combination thereof.
  • the hedgehog inhibitor is used I combination with gemcitabine and docetaxel. Additional agents that can be used in combination with the hedgehog inhibitors include other anti-cancer agents used for sarcoma treatment.
  • Suitable therapeutics for use in combination with the hedgehog inhibitors for treatment of pancreatic cancer includes, but is not limited to, a
  • chemotherapeutic agent e.g., paclitaxel or a paclitaxel agent (e.g., a paclitaxel formulation such as TAXOL®), an albumin-stabilized nanoparticle paclitaxel formulation (e.g., ABRAXANE®) or a liposomal paclitaxel formulation); gemcitabine (e.g., gemcitabine alone or in combination with AXP107-1 1); other chemotherapeutic agents such as oxaliplatin, 5-fluorouracil, capecitabine, rubitecan, epirubicin Attorney Docket No.
  • trastuzumab dual kinase inhibitor ⁇ e.g., bosutinib, saracatinib, lapatinib, vandetanib); multikinase inhibitor ⁇ e.g., sorafenib, sunitinib, XL184, pazopanib); VEGF inhibitor ⁇ e.g., bevacizumab, AV-951 , brivanib); radioimmunotherapy ⁇ e.g., XR303); cancer vaccine ⁇ e.g., GVAX, survivin peptide); COX-2 inhibitor ⁇ e.g., celecoxib); IGF-1 receptor inhibitor ⁇ e.g., AMG 479, MK-0646); mTOR inhibitor ⁇ e.g., everolimus, temsirolimus); IL-6 inhibitor ⁇ e.g., CNTO 328); cyclin- dependent kinase inhibitor ⁇ e.g., P276-0
  • metformin hydrochloride gamma-secretase inhibitor (e.g., RO4929097); ribonucleotide reductase inhibitor ⁇ e.g., 3-AP); immunotoxin ⁇ e.g., HuC242-DM4); PARP inhibitor (e.g., KU-0059436, veliparib); CTLA-4 inhbitor (e.g., CP-675,206, ipilimumab); AdV-tk therapy; proteasome inhibitor ⁇ e.g., bortezomib (Velcade), NPI-0052); thiazolidinedione ⁇ e.g., pioglitazone); NPC-1C; Aurora kinase inhibitor ⁇ e.g., R763/AS703569), CTGF inhibitor ⁇ e.g., FG-3019); siG12D LODER; and radiation therapy (e.g., tomotherapy, stereotactic radiation, proton therapy
  • a combination of paclitaxel or a paclitaxel agent, and gemcitabine can be used with the hedgehog inhibitors.
  • the hedgehog inhibitor is used in combination with folfirinox to treat pancreatic cancer.
  • Folfirinox comprises oxaliplatin 85 mg/m2 and irinotecan 180 mg/m2 plus leucovorin 400 mg/m2 followed by bolus fiuorouracil (5-FU) 400 mg/m2 on day 1 , then 5-FU 2,400 mg/m2 as a 46-hour continuous infusion.
  • 5-FU bolus fiuorouracil
  • Suitable therapeutics for use in combination with the hedgehog inhibitors for treatment of ovarian cancer includes, but is not limited to, a
  • chemotherapeutic agent e.g., paclitaxel or a paclitaxel agent; docetaxel; carboplatin; gemcitabine; doxorubicin; topotecan; cisplatin; irinotecan, TLK286, ifosfamide, olaparib, oxaliplatin, melphalan, pemetrexed disodium, SJG- 136, cyclophosphamide, etoposide, decitabine); ghrelin antagonist (e.g., AEZS-130), immunotherapy (e.g., APC8024, oregovomab, OPT-821), tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib), dual inhibitor (e.g., E7080), multikinase inhibitor (e.g., AZD0530, JI- 101 , sorafenib, sunitin
  • angiogenesis inhibitor e.g., lenalidomide
  • DHFR inhibitor e.g., pralatrexate
  • radio immuno therapeutic agnet e.g., Hu3S 193
  • statin e.g., lovastatin
  • topoisomerase 1 inhibitor e.g., NKTR-102
  • cancer vaccine e.g., p53 synthetic long peptides vaccine, autologous OC-DC vaccine
  • mTOR inhibitor e.g., temsirolimus, everolimus
  • BCR/ABL inhibitor e.g., imatinib
  • ET-A receptor antagonist e.g., ZD4054
  • TR-2 TRAIL receptor 2
  • HGF/SF inhibitor e.g., AMG 102
  • EGEN- 001 Polo-like kinase 1 inhibitor (e.g., BI 6727), gamma-secretase inhibitor (e.g., RO4929097), Wee-1 inhibitor (e.g., MK-1775), antitubulin agent (e.g., vinorelbine, E7389), immunotoxin (e.g., denileukin diftitox), SB-485232, vascular-disrupting agent (e.g., AVE8062), integrin inhibitor (e.g., EMD 525797), kinesin-spindle inhibitor (e.g., 4SC-205), revlimid, HER2 inhibitor (e.g.
  • chemotherapeutic e.g., cytarabine
  • tyrosine kinase inhibitor e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), ON 01910.Na, dual inhibitor (e.g., dasatinib, bosutinib), multikinase inhibitor (e.g., DCC- 2036, ponatinib, sorafenib, sunitinib, RGB-286638)), interferon alfa, steroids, apoptotic agent (e.g., omacetaxine mepesuccinat), immunotherapy (e.g.
  • apoptotic agent e.g., omacetaxine mepesuccinat
  • immunotherapy e.g.
  • Hydroxychloroquine retinoid (e.g., fenretinide), cyclin-dependent kinase inhibitor (e.g., UCN-01), HDAC inhibitor (e.g., belinostat, vorinostat, JNJ-26481585), PARP inhibitor (e.g., veliparib), MDM2 antagonist (e.g., RO5045337), Aurora B kinase inhibitor (e.g., TAK-901), radioimmunotherapy (e.g., actinium-225 -labeled anti-CD33 antibody
  • HuM195 Hedgehog inhibitor
  • Hedgehog inhibitor e.g., PF-04449913
  • STAT3 inhibitor e.g., OPB-31 121
  • KB004 cancer vaccine
  • bone marrow transplantation stem cell
  • a chemotherapeutic agent e.g., fludarabine, cyclophosphamide, doxorubicin, vincristine, chlorambucil, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, 5-azacytidine, pemetrexed disodium
  • tyrosine kinase inhibitor e.g., EGFR inhibitor (e.g., erlotinib)
  • BTK inhibitor e.g., PCI-32765
  • multikinase inhibitor e.g., MGCD265, RGB-286638
  • CD-20 targeting agent e.g., rituximab, ofatumumab, RO5072759, LFB-R603
  • CD52 targeting agent e.g.
  • immunotherapy e.g., allogeneic CD4+ memory Thl -like T cells/microparticle-bound anti-CD3/anti-CD28, autologous cytokine induced killer cells (CIK)
  • HDAC inhibitor e.g., vorinostat, valproic acid, LBH589, JNJ-26481585, AR-42
  • XIAP inhibitor e.g., AEG35156
  • CD-74 targeting agent e.g., milatuzumab
  • mTOR inhibitor e.g., everolimus
  • AT-101 e.g., immunotoxin (e.g., CAT-8015, anti-Tac(Fv)-PE38 (LMB-2)), Attorney Docket No. I2041-7000WO/3020PCT
  • CD37 targeting agent e.g., TRU-016
  • radio immunotherapy e.g., 131-tositumomab
  • hydroxychloroquine e.g., perifosine
  • SRC inhibitor e.g., dasatinib
  • thalidomide e.g., thalidomide
  • PI3K delta inhibitor e.g., CAL-101
  • retinoid e.g., fenretinide
  • MDM2 antagonist e.g.,
  • RO5045337) plerixafor, Aurora kinase inhibitor (e.g., MLN8237, TAK-901), proteasome inhibitor (e.g., bortezomib), CD- 19 targeting agent (e.g., MEDI-551 , MOR208), MEK inhibitor (e.g., ABT-348), JAK-2 inhibitor (e.g., INCB018424), hypoxia-activated prodrug (e.g., TH-302), paclitaxel or a paclitaxel agent, hedgehog inhibitor, AKT inhibitor (e.g., MK2206), HMG-CoA inhibitor (e.g., simvastatin), GNKG186, radiation therapy, bone marrow transplantation, stem cell transplantation, and a combination thereof.
  • Aurora kinase inhibitor e.g., MLN8237, TAK-901
  • proteasome inhibitor e.g., bortezomib
  • CD- 19 targeting agent
  • chemotherapeutic agent e.g., prednisolone, dexamethasone, vincristine, asparaginase, daunorubicin, cyclophosphamide, cytarabine, etoposide, thioguanine, mercaptopurine, clofarabine, liposomal annamycin, busulfan, etoposide, capecitabine, decitabine, azacitidine, topotecan, temozolomide), tyrosine kinase inhibitor (e.g., BCR ABL inhibitor (e.g., imatinib, nilotinib), ON 01910.Na, multikinase inhibitor (e.g., sorafenib)), CD-20 targeting agent (e.g., ritux
  • a chemotherapeutic agent e.g., cytarabine, daunorubicin, idarubicin, clofarabine, Attorney Docket No.
  • I2041-7000WO/3020PCT decitabine vosaroxin, azacitidine, clofarabine, ribavirin, CPX-351 , treosulfan, elacytarabine, azacitidine), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), ON 01910.Na, multikinase inhibitor (e.g., midostaurin, SU 1 1248, quizartinib, sorafinib)), immunotoxin (e.g., gemtuzumab ozogamicin), DT388IL3 fusion protein, HDAC inhibitor (e.g., vorinostat, LBH589), plerixafor, mTOR inhibitor (e.g., everolimus), SRC inhibitor (e.g., dasatinib), hedgehog inhbitor (e.g., STA-90
  • MLN4924 lenalidomide
  • immunotherapy e.g., AHN-12
  • histamine dihydrochloride e.g., radiation therapy, bone marrow transplantation, stem cell transplantation, and a combination thereof.
  • a chemotherapeutic agent e.g., melphalan, amifostine, cyclophosphamide, doxorubicin, clofarabine, bendamustine, fludarabine, adriamycin, SyB L-0501
  • thalidomide lenalidomide
  • dexamethasone prednisone
  • pomalidomide proteasome inhibitor
  • cancer vaccine e.g., GVAX
  • CD-40 targeting agent e.g., SGN-40, CHIR-12.12
  • perifosine zoledronic acid
  • Immunotherapy e.g., MAGE -A3, NY-ESO-1 , HuMax-CD38
  • HDAC inhibitor e.g.
  • a chemotherapeutic e.g., paclitaxel or a paclitaxel agent, carboplatin, docetaxel, amifostine, cisplantin, oxaliplatin, docetaxel
  • tyrosine kinase inhibitors e.g., EGFR inhibitor (e.g., erlotinib, gefitinib, icotinib, cetuximab, panitumumab, zalutumumab, nimotuzumab, necitumumab, matuzumab, cetuximab), dual inhibitor (e.g., lapatinib, neratinib, vandetanib, BIBW 2992, multikinase inhibitor (e.g., XL-647)), VEGF inhibitor (e.g., be
  • Suitable therapeutics for use in combination with the hedgehog inhibitors for treatment of prostate cancer includes, but is not limited to, a
  • chemotherapeutic agent e.g., docetaxel, carboplatin, fludarabine
  • hormonal therapy e.g., flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole,
  • tyrosine kinase inhibitor e.g., dual kinase inhibitor (e.g., lapatanib), multikinase inhibitor (e.g., sorafenib, sunitinib)
  • VEGF inhibitor e.g., bevacizumab
  • TAK-700 cancer vaccine (e.g., BPX-101 , PEP223), lenalidomide, TOK-001 , IGF-1 receptor inhibitor (e.g., cixutumumab), TRC105, Aurora A kinase inhibitor (e.g., MLN8237), proteasome inhibitor (e.g., bortezomib), OGX-01 1, radioimmunotherapy (e.g., HuJ591-GS), HDAC inhibitor (e.g., valproic
  • the hedgehog inhibitor is used in combination with an mTOR inhibitor.
  • mTOR inhibitor refers to an agent that directly or indirectly target, decreases or inhibits the activity/function of an mTOR kinase
  • mTOR inhibitors suitable for use in Attorney Docket No. I2041-7000WO/3020PCT the invention are described in numerous references, including but not limited to: WO 94/02136 (16-O-substituted derivatives); U.S. Pat. No. 5,258,389 (40-O-substituted derivatives); WO 94/9010 (O-aryl and O-alkyl derivatives); WO 92/05179 (carboxylic acid esters); U.S. Pat. Nos. 5,1 18,677 and 5,118,678 (amide esters); U.S. Pat. No.
  • Exemplary mTOR inhibitors include, but are not limited to, rapamycin, temsirolimus (TORISEL®), everolimus (RADOOl, AFINITOR®), ridaforolimus, AP23573, AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794, WYE-354, INK128, temsirolimus (CCI-779), Palomid 529 (P529), PF- 04691502, or PKI-587.
  • the mTOR inhibitor inhibits TORC1 and TORC2.
  • Examples of TORC1 and TORC2 dual inhibitors include, e.g., OSI-027, XL765, Palomid 529, and INK128.
  • the hedgehog inhibitor is used in combination with an inhibitor of insulin-like growth factor receptor (IGF-1R).
  • IGF-1R also known as EC 2.7.112, CD 221 antigen
  • IGF-1R belongs to the family of transmembrane protein tyrosine kinases (Ullrich et al, Cell, 61 : 203-212, (1990), LeRoith et al, Endocrin. Rev., 16: 143- 163 (1995); Traxler, Exp. Opin. Ther. Patents, 7: 571-588 (1997); Adams et al, Cell. Mol. Life. Sci., 57: 1050-1063 (2000)), and is involved in childhood growth ((Liu et al, Attorney Docket No. I2041-7000WO/3020PCT
  • Inhibitory peptides targeting IGF-IR have been generated that possess antiproliferative activity in vitro and in vivo (Pietrzkowski et al., Cancer Res., 52:6447-6451 (1992); Haylor et al, J. Am. Soc. Nephrol, 1 1 :2027-2035 (2000)). Growth can also be inhibited using peptide analogues of IGF-I (Pietrzkowski et al., Cell Growth &Diff., 3: 199-205 (1992); Pietrzkowski et al, Mol. Cell. Biol, 12: 3883-3889 (1992)). In addition, dominant-negative mutants of IGF-IR (Li et al, J.
  • IGF-IR antagonists or inhibitors of IGF-IR that can be used in combination with the therapies disclosed herein include, but are not limited to, small molecule IGF-IR Attorney Docket No. I2041-7000WO/3020PCT antagonists (e.g., GSK1904529A), antibody antagonists, IGF-IR peptide antagonists, or anti-sense or other nucleic acid antagonists.
  • IGF-IR inhibitors include, but are not limited to, BMS-536924, GSK1904529A, AMG 479, MK-0646, cixutumumab, OSI 906, figitumumab (CP-751 ,871), and BIIB022.
  • the IGF-IR antagonist is GSK1904529A described in, e.g.,
  • Exemplary peptides that antagonize IGF-IR or treat cancer involving IGF-I include those described by U.S. Pat. No. 6,084,085; U.S. Pat. No. 5,942,489; WO
  • anti-sense and nucleic acids that antagonize IGF-IR are described, e.g., in Wraight et al, Nat. Biotech., 18: 521-526 (2000); U.S. Pat. No. 5,643,788; U.S. Pat. Attorney Docket No. I2041-7000WO/3020PCT
  • the hedgehog inhibitor is used in combination with a tyrosine kinase inhibitor (e.g., a receptor tyrosine kinase (RTK) inhibitor).
  • a tyrosine kinase inhibitor include, but are not limited to, an epidermal growth factor (EGF) pathway inhibitor (e.g., an epidermal growth factor receptor (EGFR) inhibitor), a vascular endothelial growth factor (VEGF) pathway inhibitor (e.g., a vascular endothelial growth factor receptor (VEGFR) inhibitor (e.g., a VEGFR-1 inhibitor, a VEGFR-2 inhibitor, a VEGFR-3 inhibitor)), a platelet derived growth factor (PDGF) pathway inhibitor (e.g., a platelet derived growth factor receptor (PDGFR) inhibitor (e.g., a platelet derived growth factor receptor (PDGFR) inhibitor (e.g., a PDGFR) inhibitor (e.g., a vascular endo
  • the anti-cancer agent used in combination with the hedgehog inhibitor is selected from the group consisting of: axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU1 1248), tocerani
  • axitinib AG013736
  • bosutinib SKI-606
  • cediranib
  • Selected tyrosine kinase inhibitors are chosen from sunitinib, erlotinib, gefitinib, or sorafenib. In one embodiment, the tyrosine kinase inhibitor is sunitinib.
  • the hedgehog inhibitor is used in combination with folfirinox to treat the cancers and metastatic growths described herein, e.g., pancreatic cancer.
  • Folfirinox comprises oxaliplatin 85 mg/m2 and irinotecan 180 mg/m2 plus leucovorin 400 mg/m2 followed by bolus fluorouracil (5-FU) 400 mg/m2 on day 1 , then 5-FU 2,400 mg/m2 as a 46-hour continuous infusion.
  • the hedgehog inhibitor is used in combination with a PI3K inhibitor.
  • the PI3K inhibitor is an inhibitor of delta and gamma isoforms of PI3K.
  • the hedgehog is used in combination with a dual PI3K/mTOR inhibitor.
  • Exemplary PI3K inhibitors that can be used in combination are described in, e.g., WO 2010/036380; WO 2010/006086, WO 09/1 14870, WO 05/1 13556.
  • PI3K inhibitors that can be used in combination with the pharmaceutical compositions, include but are not limited to, GSK 2126458, GDC-0980, GDC-0941 , Sanofi XL147, XL756, XL147, PF-46915032, BKM 120, CAL- 101 , CAL 263, SF1 126, PX-886, and a dual PI3K inhibitor (e.g., Novartis BEZ235).
  • the PI3K inhibitor is an isoquinolinone.
  • the PI3K inhibitor is INKl 197 or a derivative thereof.
  • the PI3K inhibitor is INKl 1 17 or a derivative thereof.
  • the hedgehog inhibitor is administered in combination with a BRAF inhibitor, e.g., GSK21 18436, RG7204, PLX4032, GDC-0879, PLX4720, and sorafenib tosylate (Bay 43-9006), and/or other anti-cancer agents.
  • a BRAF inhibitor e.g., GSK21 18436, RG7204, PLX4032, GDC-0879, PLX4720, and sorafenib tosylate (Bay 43-9006), and/or other anti-cancer agents.
  • the hedgehog inhibitor is administered in combination with a MEK inhibitor, e.g., ARRY-142886, GSKl 120212, RDEA436, RDEAl 19/BAY 869766, AS703026, AZD6244 (selumetinib), BIX 02188, BIX 02189, CI-1040
  • a MEK inhibitor e.g., ARRY-142886, GSKl 120212, RDEA436, RDEAl 19/BAY 869766, AS703026, AZD6244 (selumetinib), BIX 02188, BIX 02189, CI-1040
  • PD184352 PD0325901 , PD98059, and U0126, and/or other anti-cancer agents.
  • the hedgehog inhibitor is administered in combination with a JAK2 inhibitor, e.g., CEP-701, INCB18424, CP-690550 (tasocitinib).
  • a JAK2 inhibitor e.g., CEP-701, INCB18424, CP-690550 (tasocitinib).
  • one or more of the following agents are used in combination with the hedgehog inhibitors described herein: inhibitors of B-Raf (e.g., Sorafenib, PLX4032), Mek (e.g., PD 032901), Erk (e.g., PD98059), Cdk4/6 (e.g., PD 0332991), and EGFR (e.g., Tarceva®)).
  • B-Raf e.g., Sorafenib, PLX4032
  • Mek e.g., PD 032901
  • Erk e.g., PD98059
  • Cdk4/6 e.g., PD 0332991
  • EGFR e.g., Tarceva®
  • the hedgehog inhibitor is administered in combination with paclitaxel or a paclitaxel agent, e.g., TAXOL®, protein-bound paclitaxel (e.g., ABRAXANE®), and/or other anti-cancer agents.
  • a paclitaxel agent e.g., TAXOL®, protein-bound paclitaxel (e.g., ABRAXANE®), and/or other anti-cancer agents.
  • Paclitaxel marketed as TAXOL is formulated in the nonionic surfactant Cremophor EL (polyoxyethylated castor oil) and ethanol to enhance drug solubility (Dorr et al, Ann. Pharmacother., (1994) 28: S 1 1— S 14). Cremophor EL can add to paclitaxel's toxic effects by producing or contributing to the well-described hypersensitivity reactions that commonly occur during infusion, affecting 25-30% of treated patients (Weiss et al., J. Clin. Oncol. (1990) 8: 1263-1268 and Rowinsky et al, N. Eng. J. Med.
  • paclitaxel marketed as TAXOL must be prepared and administered in either glass bottles or non-PVC infusion systems and with in-line filtration. These problematic issues have spurred interest in the development of new formulations of paclitaxel with improved solubility in aqueous solutions.
  • paclitaxel agent refers to a formulation of paclitaxel ⁇ e.g., for example, TAXOL®) or a paclitaxel equivalent ⁇ e.g., for example, a prodrug of paclitaxel).
  • Exemplary paclitaxel equivalents include, but are not limited to, nanoparticle albumin-bound paclitaxel (ABRAXANE®, marketed by Abraxis Bioscience), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin, marketed by Protarga), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT- 2103, XYOTAX, marketed by Cell Therapeutic), the tumor-activated prodrug (TAP),
  • ABRAXANE® nanoparticle albumin-bound paclitaxel
  • DHA-paclitaxel docosahexaenoic acid bound-paclitaxel
  • Taxoprexin marketed by Protarga
  • PG-paclitaxel polyglutamate bound-paclitaxel
  • paclitaxel poliglumex CT- 2103
  • XYOTAX XYOTAX
  • ANG105 Angiopep-2 bound to three molecules of paclitaxel, marketed by ImmunoGen
  • paclitaxel-EC- 1 paclitaxel bound to the erbB2-recognizing peptide EC-1; see Li et ah, Biopolymers (2007) 87:225-230
  • glucose-conjugated paclitaxel ⁇ e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate see Liu et ah, Bioorganic & Medicinal Chemistry Letters (2007) 17:617-620.
  • the paclitaxel agent is a paclitaxel equivalent.
  • the paclitaxel equivalent is ABRAXANE®.
  • the hedgehog inhibitor and the additional anti-cancer agent are administered concurrently ⁇ i.e., administration of the two agents at the same time or day, or within the same treatment regimen) or sequentially ⁇ i.e., administration of one agent over a period of time followed by administration of the other agent for a second period of time, or within different treatment regimens).
  • the hedgehog inhibitor and the additional anti-cancer agent are administered concurrently.
  • the hedgehog inhibitor and the additional anti-cancer agent are administered at the same time.
  • the hedgehog inhibitor and the additional anti-cancer agent are administered on the same day.
  • the hedgehog inhibitor is administered after the additional anti-cancer agent on the same day or within the same treatment regimen.
  • the hedgehog inhibitor is administered before the additional anti-cancer agent on the same day or within the same treatment regimen.
  • a hedgehog inhibitor is concurrently administered with additional anti-cancer agent for a period of time, after which point treatment with the additional anti-cancer agent is stopped and treatment with the hedgehog inhibitor continues.
  • a hedgehog inhibitor is concurrently with the additional anti-cancer agent for a period of time, after which point treatment with the hedgehog inhibitor is stopped and treatment with the additional anti-cancer agent continues.
  • the hedgehog inhibitor and the additional anti-cancer agent are administered sequentially.
  • the hedgehog inhibitor is administered after the treatment regimen of the additional anti-cancer agent has ceased.
  • the additional anti-cancer agent is administered after the treatment regimen of the hedgehog inhibitor has ceased.
  • two- or three-way combination therapies are provided below based on the combination of a second agent (e.g., the paclitaxel agent) and a hedgehog inhibitor. These are intended to be illustrative of combination treatments that can be modified and/or applied to other combination therapies disclosed herein.
  • a second agent e.g., the paclitaxel agent
  • a hedgehog inhibitor e.g., the paclitaxel agent
  • the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor are administered concurrently.
  • the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor are concurrently administered on the same day to the patient.
  • the second agent (e.g., the paclitaxel agent) is administered first, provided that the hedgehog inhibitor is also administered on the same day to the patient.
  • the hedgehog inhibitor is Attorney Docket No. I2041-7000WO/3020PCT administered first, provided that the second agent (e.g., the paclitaxel agent) is also administered on the same day to the patient.
  • the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor are administered simultaneously (i.e., at the same time) on the same day to the patient.
  • the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor are administered on different days and/or on different schedules (e.g., one administered daily while the other is administered weekly), provided that this treatment regimen for both begin and end on the same day.
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor is administered after administration of the second agent (e.g., the paclitaxel agent) has ceased.
  • the hedgehog inhibitor is administered immediately after administration of the second agent (e.g., the paclitaxel agent) has ceased (i.e., on the same day as treatment with the second agent (e.g., the paclitaxel agent) has ceased), or, in certain embodiments, there is a period of time (e.g., one day, two days, one week, two weeks, one month, two months, six months, one year, etc.) between the end of the second agent (e.g., the paclitaxel agent) administration and the beginning of the hedgehog inhibitor administration.
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor is administered after administration of the hedgehog inhibitor has ceased.
  • the second agent e.g., the paclitaxel agent
  • the second agent is administered immediately after administration of the hedgehog inhibitor has ceased (i.e., on the same day as treatment with the hedgehog inhibitor has ceased), or, in certain embodiments, there is a period of time (e.g., one day, two days, one week, two weeks, one month, two months, six months, one year, etc.) between the end of the hedgehog inhibitor administration and the beginning of the second agent (e.g., the paclitaxel agent) administration.
  • a period of time e.g., one day, two days, one week, two weeks, one month, two months, six months, one year, etc.
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor are administered concurrently for a first period of time, followed by administration of the hedgehog inhibitor for a second period of time (i.e., with administration of second agent (e.g., the paclitaxel agent) ceased).
  • second agent e.g., the paclitaxel agent
  • administration of the hedgehog inhibitor continues immediately after (i.e., Attorney Docket No. I2041-7000WO/3020PCT on the same day as) concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor ceases.
  • the second agent e.g., the paclitaxel agent
  • treatment with the hedgehog inhibitor begins after a period of time (e.g., one day, two days, one week, two weeks, one month, two months, six months, one year, etc.) after concurrent administration of the second agent and the hedgehog inhibitor ceases.
  • the hedgehog treatment regimen during the second period of time can be the same as the treatment regimen when the hedgehog inhibitor is concurrently administered with the second agent (e.g., the paclitaxel agent) during the first period of time, or the hedgehog treatment regimen during the second period of time can be different than the treatment regimen when the hedgehog inhibitor is concurrently administered with the second agent (e.g., the paclitaxel agent) during the first period of time.
  • the second agent e.g., the paclitaxel agent
  • the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor are administered concurrently for a first period of time, followed by administration of the second agent (e.g., the paclitaxel agent) for a second period of time (i.e., with administration of the hedgehog inhibitor ceased).
  • administration of the second agent (e.g., the paclitaxel agent) continues immediately after (i.e., on the same day as) concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor ceases.
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor ceases.
  • administration of the second agent begins after a period of time (e.g., one day, two days, one week, two weeks, one month, two months, six months, one year, etc.) after concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor ceases.
  • a period of time e.g., one day, two days, one week, two weeks, one month, two months, six months, one year, etc.
  • the second agent (e.g., the paclitaxel agent) treatment regimen during the second period of time can be the same as the treatment regimen when the second agent (e.g., the paclitaxel agent) is concurrently administered with the hedgehog inhibitor during the first period of time, or the second agent (e.g., the paclitaxel agent) treatment regimen during the second period of time can different than the treatment regimen when the second agent (e.g., the paclitaxel agent) is concurrently administered with the hedgehog inhibitor during the first period of time.
  • the second agent e.g., the paclitaxel agent
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor for a second period of time.
  • concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor begins immediately following (i.e., on the same day as) administration of the second agent (e.g., the paclitaxel agent) ceases.
  • concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor begins after a period of time (e.g., one day, two days, one week, two weeks, one month, two months, six months, one year, etc.) after administration of the second agent (e.g., the paclitaxel agent) ceases.
  • the second agent (e.g., the paclitaxel agent) treatment regimen during the second period of time can be the same as the treatment regimen during the first period of time, or the second agent (e.g., the paclitaxel agent) treatment regimen during the second period of time can be different than the treatment regimen during the first period of time.
  • administration of the hedgehog inhibitor continues after the concurrent administration has ceased (i.e., administration of second agent (e.g., the paclitaxel agent) for a first period of time, followed by concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor for a second period of time, followed by administration of the hedgehog inhibitor for a third period of time).
  • second agent e.g., the paclitaxel agent
  • concurrent administration of the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor for a third period of time
  • administration of the second agent continues after the concurrent administration has ceased (i.e., administration of second agent (e.g., the paclitaxel agent) for a first period of time, followed by concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor for a second period of time, followed by administration of the second agent (e.g., the paclitaxel agent) for a third period of time).
  • the hedgehog inhibitor is administered to the patient for a first period of time, followed by concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor for a second period of time.
  • concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor begins immediately following (i.e., on the same day as) administration of the hedgehog inhibitor ceases.
  • I2041-7000WO/3020PCT concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor begins after a period of time (e.g., one day, two days, one week, two weeks, one month, two months, six months, one year, etc.) after administration of the hedgehog inhibitor ceases.
  • the hedgehog inhibitor treatment regimen during the second period of time can be the same as the treatment regimen during the first period of time, or the hedgehog inhibitor treatment regimen during the second period of time can be different than the treatment regimen during the first period of time.
  • administration of the hedgehog inhibitor continues after the concurrent administration has ceased (i.e., administration of hedgehog inhibitor for a first period of time, followed by concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor for a second period of time, followed by administration of the hedgehog inhibitor for a third period of time).
  • the concurrent administration i.e., administration of hedgehog inhibitor for a first period of time, followed by concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor for a second period of time, followed by administration of the hedgehog inhibitor for a third period of time).
  • administration of the second agent continues after the concurrent administration has ceased (i.e., administration of hedgehog inhibitor for a first period of time, followed by concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor for a second period of time, followed by administration of the second agent (e.g., the paclitaxel agent) for a third period of time).
  • second agent e.g., the paclitaxel agent
  • hedgehog inhibitor and additional therapeutic agent can be concurrently administered, sequentially administered, or can be administered using a combination of concurrent and sequential administration.
  • the second agent e.g., the paclitaxel agent
  • hedgehog inhibitor and an additional therapeutic agent are administered concurrently.
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor and the third agent are administered on the same day to the patient, or, in certain embodiments, are administered simultaneously on the same day to the patient.
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor and the third agent are administered on different days Attorney Docket No. I2041-7000WO/3020PCT and/or on different schedules (e.g., one administered daily or every other day while the others are administered weekly), provided that the treatment regimen for all begin and end on the same day.
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor and the third agent are administered sequentially.
  • the additional therapeutic agent is administered for a first period of time, followed by concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor for a second period of time.
  • concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor begins immediately following (i.e., on the same day as)
  • concurrent administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor begins after a period of time (e.g., one day, two days, one week, two weeks, one month, two months, six months, one year, etc.) after administration of the third agent ceases.
  • the current methods also contemplate administration of the hedgehog inhibitor for a first period of time followed by administration of the second agent (e.g., the paclitaxel agent) and the third agent for a second period of time, as well as administration of the second agent (e.g., the paclitaxel agent) for a first period of time followed by administration of the hedgehog inhibitor and the third agent for a second period of time.
  • any one of the second agent (e.g., the paclitaxel agent), hedgehog inhibitor, and/or third agent can be administered for a third period of time following the concurrent administration in the second period of time.
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor or the third agent can be administered for a first period of time, followed by concurrent administration of the second agent (e.g., the paclitaxel agent), hedgehog inhibitor and the third agent for a second period of time.
  • the second agent e.g., the paclitaxel agent
  • the second agent can be administered for a first period of time, followed by concurrent administration of the second agent (e.g., the paclitaxel agent), hedgehog inhibitor and the third agent for a second period of time.
  • any one of the second agent e.g., the paclitaxel agent
  • hedgehog inhibitor, and/or the third agent can be administered for a third period of time.
  • the second agent e.g., the paclitaxel agent
  • hedgehog inhibitor and the third agent can be administered for a first period of time, followed by
  • the second agent e.g., the paclitaxel agent
  • hedgehog inhibitor and the third agent for a second period of time
  • administration of one or two of the second agent (e.g., the paclitaxel agent), hedgehog inhibitor and additional therapeutic agent can cease while administration of the other agent(s) continues.
  • the second agent e.g., the paclitaxel agent
  • hedgehog inhibitor and the third agent can be administered for a first period of time, followed by administration of the hedgehog inhibitor for a second period of time.
  • any one of the second agent e.g., the paclitaxel agent
  • hedgehog inhibitor, and/or the third agent can be administered for a third period of time.
  • a second agent e.g., the paclitaxel agent
  • a hedgehog inhibitor e.g., the paclitaxel agent
  • a third agent e.g., the paclitaxel agent
  • the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor can be concurrently administered, sequentially administered or can be administered using a combination of concurrent and sequential administration.
  • the second agent (e.g., the paclitaxel agent) and/or the hedgehog inhibitor are administered concurrently with the cancer therapy.
  • the second agent (e.g., the paclitaxel agent) and/or the hedgehog inhibitor can continue to be administered after the cancer therapy has ceased.
  • the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor can continue to be administered after the cancer therapy has ceased.
  • the second agent (e.g., the paclitaxel agent) and/or the hedgehog inhibitor are administered after cancer therapy has ceased (i.e., with no period of overlap with the cancer therapy).
  • the second agent (e.g., the paclitaxel agent) and/or the hedgehog inhibitor can be administered immediately after cancer therapy has ceased, or there can be a gap in time (e.g., up to about a day, a week, a month, six months, or a year) between the end of cancer therapy and the administration of the second agent (e.g., the paclitaxel agent) and/or the hedgehog inhibitor.
  • Treatment with the second agent (e.g., the paclitaxel agent) and/or the hedgehog inhibitor can continue for as long as relapse-free Attorney Docket No. I2041-7000WO/3020PCT survival is maintained (e.g., up to about a day, a week, a month, six months, a year, two years, three years, four years, five years, or longer).
  • the second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor can continue for as long as relapse-free Attorney Docket No. I2041-7000WO/3020PCT survival is maintained (e.g., up to about a day, a week, a month, six months, a year, two years, three years, four years, five years, or longer).
  • a second agent e.g., the paclitaxel agent
  • the hedgehog inhibitor can be concurrently administered, sequentially administered, or can be administered using a combination of concurrent and sequential administration.
  • the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor can be administered immediately after cancer therapy has ceased, or there can be a gap in time (e.g., up to about a day, a week, a month, six months, or a year) between the end of cancer therapy and the administration of the second agent (e.g., the paclitaxel agent) and the hedgehog inhibitor.
  • a gap in time e.g., up to about a day, a week, a month, six months, or a year
  • a second agent e.g., the paclitaxel agent
  • a hedgehog inhibitor can be concurrently administered, sequentially administered, or can be administered using a combination of concurrent and sequential administration.
  • the hedgehog inhibitor and the combination therapies described herein can be used further in combination with one or more of: other chemotherapeutic agents, radiation, or surgical procedures.
  • Hedgehog pathway specific cancer cell killing effects can be ascertained using the following assay.
  • C3H10T1/2 cells differentiate into osteoblasts when contacted with the sonic hedgehog peptide (Shh-N). Upon differentiation, these osteoblasts produce high levels of alkaline phosphatase (AP) which can be measured in an enzymatic assay
  • Mouse embryonic mesoderm fibroblasts C3H10T1/2 cells obtained from ATCC were cultured in Basal MEM Media (Gibco/Invitrogen) supplemented with 10% heat inactivated FBS (Hyclone), 50 units/ml penicillin and 50ug/ml streptomycin
  • C3H10T1/2 cells were plated in 96 wells with a density of 8xl 0 3 cells/well. Cells were grown to confluence (72 hrs.). After sonic hedgehog (250ng/ml) and/or compound treatment, the cells were lysed in 1 10 ⁇ iL of lysis buffer (50 mM Tris pH 7.4, 0.1% TritonXl OO), plates were sonicated and lysates spun through 0.2 ⁇ PVDF plates (Corning). 40 ⁇ L of lysates was assayed for AP activity in alkaline buffer solution
  • Animals bearing BxPC-3 pancreatic cancer xenografts were treated with the chemotherapeutic drug gemcitabine in concurrent combination with IPI-926.
  • Gemcitabine was administered at a dose of 100 mg/kg twice weekly by intraperitoneal injection while IPI-926 was administered at a dose of 40 mg/kg daily by oral gavage. As shown in Figure 3, under these conditions the tumors showed a 33% response to gemcitabine alone, a 55% response to IPI-926 alone, and a 67% response to the combination of IPI-926 and gemcitabine.
  • Gemcitabine was administered at a dose of 100 mg/kg once weekly by
  • LX22 cells were implanted subcutaneously into the flank of the right leg of male Ncr nude mice.
  • LX22 is primary xenograft model of SCLC derived from chemo-naive patients, which has been maintained by mouse to mouse passaging. This tumor responds to etoposide/carboplatin chemotherapy in way that closely resembles a clinical setting. LX22 regresses during chemotherapy treatment, goes through a period of remission, and then begins to recur.
  • etoposide was administered at a dose of 12 mg/kg by intravenous route on three consecutive days followed by a single administration two weeks after the initial dose.
  • Carboplatin was administered at a dose of 60 mg/kg weekly for three weeks by intravenous injection.
  • IPI-926 was administered at a dose of 40 mg/kg daily by oral gavage either at the same time as etoposide/carboplatin or immediately following etoposide/carboplatin treatment. As shown in Figure 5, under these conditions the tumors showed an overall 40% response to all treatments when compared to those animals receiving etoposide/carboplatin alone.
  • mice were randomized into three dosing groups to receive vehicle (30% HBPCD), IPI-926, or the chemotherapy combination of etoposide and carboplatin (E/P).
  • IPI-926 was administered at a dose of 40mg/kg/day, etoposide was administered i.v. at 12mg/kg on days 34, 35, 36, Attorney Docket No. I2041-7000WO/3020PCT and 48, and carboplatin was administered i.v. at 60mg/kg on days 34, 41 , and 48, post tumor implant.
  • Tumor bearing animals are administered paclitaxel for such a time that their tumors respond to chemotherapy treatment. These animals are randomized into two groups, one receiving vehicle and one receiving IPI-926. Tumor response to the different therapies is determined as discussed herein.
  • Colo205 colon cancer cells are implanted into experimental animals. Tumor bearing animals will be administered 5-fluorouracil for such a time that their tumors respond to chemotherapy treatment. These animals are then randomized into two groups, one receiving vehicle and one receiving IPI-926. Tumor response to the different therapies is determined as discussed herein.
  • mice bearing IGROV-1 ovarian cancer xenografts were treated with daily doses of IPI-926 at 40 mg/kg for 21 consecutive days. No substantive effect on tumor growth Attorney Docket No. I2041-7000WO/3020PCT was observed at this dosage with this particular ovarian cancer cell xenograft.
  • mice bearing IGROV-1 ovarian cancer xenografts were treated with 5 consecutive daily doses of paclitaxel at 15 mg/kg followed by IPI-926 at 40 mg/kg for 21 consecutive days. Again, no substantive effect on tumor growth was observed at these dosages with this particular ovarian cancer cell xenograft.
  • ovarian cancer cells are implanted into experimental animals.
  • tumor bearing animals are administered paclitaxel or carboplatin alone, IPI-926 alone, or IPI-926 and paclitaxel or carboplatin in combination.
  • tumor bearing animals are administered paclitaxel or carboplatin for such a time that their tumors respond to chemotherapy treatment. These animals are then randomized into two groups, one receiving vehicle and one receiving IPI-926. Tumor response to the different therapies is determined as discussed herein.
  • mice are implanted with UMUC-3 bladder cancer cells. Tumor bearing animals are then administered gemcitabine/cisplatin alone, IPI-926 alone, or the three agents in combination. Tumor response to the different therapies is determined as discussed herein.
  • mice are implanted with UMUC-3 bladder cancer cells, and tumor bearing animals are then administered a combination of gemcitabine and cisplatin for such a time that their tumors respond to chemotherapy treatment. These animals are then randomized into two groups, one receiving vehicle and one receiving IPI-926. Tumor response to the different therapies is determined as discussed herein.
  • SW780 bladder cancer cells are implanted into experimental animals.
  • tumor bearing animals are administered gemcitabine/cisplatin alone, IPI-926 alone, or the three agents in combination.
  • tumor bearing animals are administered a combination of gemcitabine and cisplatin for Attorney Docket No. I2041-7000WO/3020PCT such a time that their tumors respond to chemotherapy treatment. These animals are then randomized into two groups, one receiving vehicle and one receiving IPI-926. Tumor response to the different therapies is determined as discussed herein.
  • Example 10 Non-Small Cell Cancer Models
  • mice are implanted with NCI-H1650 non-small cell lung cancer cells. Tumor bearing animals are then administered gefitinib alone, IPI-926 alone, or the two agents in combination. Tumor response to the different therapies is determined as discussed herein.
  • mice are implanted with NCI-H1650 non-small cell lung cancer cells, and tumor bearing animals are then administered gefitinib for such a time that their tumors respond to gefitinib treatment. These animals are then randomized into two groups, one receiving vehicle and one receiving IPI-926. Tumor response to the different therapies is determined as discussed herein.
  • Hh ligand specifically Indian Hh (IHH) was up-regulated in the human tumor cells and the surrounding murine stroma cells following chemotherapy, as measured both by RT-PCR and immunohistochemistry (see Attorney Docket No. I2041-7000WO/3020PCT
  • FIGS 7A and 7B stromal-derived murine Gli-1 and tumor-derived human Gli-1 were induced in response to tumor-derived ligand.
  • Murine Gli-1 expression remained elevated compared to the expression level in naive tumors for at least 14 days post the cessation of E/P treatment and was inhibited by administration of IPI-926 (see Figure 8 A), while human Gli-1 expression was not affected by administration of IPI-926 (see Figure 8B).
  • up- regulation of tumor-derived Hh ligand post-chemotherapy can confer upon the surviving cell population a dependency upon the Hh pathway that is important for tumor recurrence.
  • mice bearing UMUC-3 bladder cancer xenografts were treated with lOOmg/kg gemcitabine once- weekly for 4 weeks. Tumors showed increased IHH expression similar to that observed in the LX22 model 24 hours post administration of the final dose (see Figures 9A and 9B).
  • In vitro studies showed that in UMUC-3 cells exposed to either doxorubicin or gemcitabine for 12-24 hours, all 3 Hh ligands (Sonic, Indian and Desert) were up-regulated (see doxorubicin data in Figure 10).
  • Hh ligands post chemotherapy exhibit up-regulation of Hh ligands post chemotherapy.
  • the type of Hh ligand that is up-regulated i.e., Sonic, Indian and/or Desert
  • the degree of up-regulation vary depending upon the tumor type and the chemotherapeutic agent.
  • stress including chemotherapy
  • a surviving sub-population can be dependent upon the Hh pathway and thus can be susceptible to Hh pathway inhibition.
  • Hedgehog inhibition can increase relapse free survival in clinical indications (such as small cell lung cancer, non-small cell lung cancer, bladder cancer, colon cancer, or ovarian cancer) that are initially chemo-responsive but eventually relapse.
  • clinical indications such as small cell lung cancer, non-small cell lung cancer, bladder cancer, colon cancer, or ovarian cancer
  • TMA neuroendocrine tissue microarray
  • DFCI Dana-Farber Cancer Institute
  • Rabbit anti-human SHH antibody (EP1190Y) (Abeam catalog # ab53281) was used as the primary antibody at 1 :2000 dilution.
  • Rabbit- on-Rodent Polymer (Biocare catalog # RMR622L) was used as the secondary polymer system.
  • DAB Liquid Substrate Buffer+ Chromogen System (DAKO catalog # K3468) was used for developing and detection of the staining.
  • Bon-1 cells were implanted into male Ncr nude mice (5x10 6 cells/mouse).
  • Bon-1 obtained from Purdue University
  • RPMI1460 medium supplemented with 10% FBS and 1% penicillin/streptomycin.
  • Treatment with IPI-926 was initiated once the tumor volume reached approximately 200 mm 3 .
  • Tumor bearing mice were treated with a single dose of IPI-926 in 5% HPBCD at 40mg/kg by oral gavage (8ml/kg).
  • IHC SHH immunohistochemistry
  • Rabbit anti- human SHH antibody (EP1190Y) (Abeam catalog # ab53281) was used as the primary antibody at 1 :2000 dilution.
  • Rabbit-on-Rodent Polymer (Biocare catalog # RMR622L) was used as the secondary polymer system.
  • DAB Liquid Substrate Buffer+ Chromogen System (DAKO catalog # K3468) was used for developing and detection of the staining. As shown in Figure 17, expression of human SHH was detected in the human tumor cells and the surrounding murine stroma cells.
  • Example 15 Efficacy of IPI-926, Alone or in Combination with Sunitinib in a Neuroendocrine Cancer Model
  • Bon-1 cells were implanted into male Ncr nude mice (5xl0 6 cells/mouse). Before implantation Bon-1 cells were cultured in RPMI1460 medium supplemented with 10% FBS and 1% penicillin/streptomycin. Treatment was initiated once tumor volume reached approximately 200 mm 3 .
  • mice were randomized into three dosing groups to receive vehicle control (5% HPBCD), IPI-926 in 5% HPBCD, sunitinib (in water), or sunitinib in combination with IPI-926. From day 13 through day 33, IPI-926 was administered at a dose of 40mg/kg every other day by oral gavage (8ml/kg).
  • vehicle control 5% HPBCD
  • IPI-926 was administered at a dose of 40mg/kg every other day by oral gavage (8ml/kg).
  • Sunitinib was administered at a dose of 40mg/kg every day by oral gavage (8ml/kg).
  • mice bearing Bon-1 pancreatic neuroendocrine cancer cells received a total of ten doses of IPI-926 and/or twenty doses of sunitinib.
  • Bodyweight and tumor measurements were taken three times a week. Tumor measurements were made in Attorney Docket No. I2041-7000WO/3020PCT two dimensions (width x length) using calipers and the tumor volume equals to length x width 12.
  • Body weight loss greater than 20% from the initial day of treatment or tumor volumes greater than 3000 mm resulted in euthanasia.
  • Samples for analysis were collected 24 hours post the final dose. Tumors collected were snap frozen for analytical evaluation and qRT-PCR analysis. For histopathology tumors were fixed in 10% formalin for 24 hours prior to transferring the samples into 70% ethanol.
  • TGI tumor growth inhibition
  • sunitinib shown as "Sutent”
  • Example 16A Efficacy of IPI-926 in Neoadjuvant and Adjuvant Therapy in a Rat Syngeneic Chondrosarcoma Model
  • Chondrosarcomas constitute a heterogeneous group of neoplasms that have in common the production of cartilage-like matrix by the tumor cells. Clinical management of these second most common types of skeletal malignancies has remained largely unchanged over the last 3 decades. It is generally believed that, because of their extracellular matrix, low percentage of dividing cells, and poor vascularity, chondrogenic tumors are relatively chemo- and radiotherapy resistant. Thus, surgery still prevails as the primary treatment modality of this tumor. Improving chondrosarcoma clinical management is a challenging problem and developing innovative therapeutic approaches is an important goal in the treatment of patients with chondrosarcoma. Attorney Docket No. I2041-7000WO/3020PCT
  • Hedgehog (Hh) gene is important in the signaling pathways of proliferation and differentiation during embryonic development. There is evidence that uncontrolled activation of this pathway results in specific types of cancer and that inhibition of Hh signaling is able to suppress tumour growth.
  • Preclinical studies using inhibitors of hedgehog signaling in chondrosarcoma and osteosarcoma cell lines provided evidence for the potency of Hh- inhibitors as future agents for musculoskeletal sarcoma treatment.
  • Inhibiting Hh pathway is believed to have antitumor activity, and can be used to limit or prevent sarcoma invasion (local and metastatic). Previous studies established that inhibiting mTOR pathway had a strong antitumor activity towards chondrosarcoma (not shown). Based on these data, a combination of Hh inhibitor and an inhibitor of mTOR constitutes an attractive combination for an additive antitumor effect.
  • Hh-specific inhibitor IPI-926 also referred to herein as Compound 42
  • a specific inhibitor of mTOR could inhibit
  • a rat syngeneic chondrosarcoma model can be characterized in two main settings:
  • combination with mTOR inhibitor can be compared to the one of conventional chemotherapy (adryamicin) and to an inhibitor of mTOR.
  • the comparison of therapeutic efficiency of IPI-926 and conventional cytotoxic agent therapy will use tumor volume evolution (MRI and tumor measure using a caliper), tumor necrosis percentage and mitotic index, tumor MVD quantification and overall survival analysis between the IPI-926 treated and control groups.
  • IPI-926 is expected to have a beneficial effect in vivo reducing chondrosarcoma tumor progression. A slower tumor progression in the IPI-926-treated groups in comparison to the other groups is expected.
  • the same protocol could be conducted on an osteosarcoma model to evaluate the antitumor and antimetastatic effect of IPI-926 used alone or in combination with an mTOR inhibitor.
  • the data generated herein provide a strong experimental rationale for designing further studies to evaluate the benefit of an addition of IPI-926 for adjuvant treatment of patients with chondrosarcoma or relapsed/refractory osteosarcoma.
  • Chondrosarcoma model Transplantable orthotopic Schwarm chondrosarcoma model can be used. Tumors are grafted on 21- to 28-day-old Sprague-Dawley rats according to a method previously described. Shorty, using a lateral approach, a 6-8 mnr ' tumor fragment is placed contiguous to tibial diaphysis after periostal abrasion; then the cutaneous and muscular wounds are sutured. Tumors can be detected at the graft site 8- 1 1 days after transplantation by palpation and MR! imaging (A) of Figure 20.
  • Osteosarcoma model an intramedular and metastatic osteosarcoma model in rat has been developed. Briefly, small tumor fragments (100 mm') taken from a
  • hyperproliferative osteogenic tumor area are grafted on 3 -weeks old immunocompetent Attorney Docket No. I2041-7000WO/3020PCT rats.
  • a tumor fragment is placed within the femoral diaphysis of the animals; then the cutaneous and muscular wounds are sutured. Tumors can be detected 9 days post transplantation in 95% of the animals, at the graft site by palpation
  • I IPI-926 as curative treatment for sarcoma.
  • Ten days after tumor transplantation animals can be divided into the following treatment groups (8 animals/group; 5 treatment groups) (i) IPI-926 (ii) Adryamicine (iii) mTOR inhibitor, (iv) IPI-926 + mTOR inhibitor (v) control (saline).
  • Each rat in the treated or control groups can be given the
  • IPI-926 and IPI-926-based drug combination can be chosen based on IPI-926 rat P /PD studies.
  • IPI-926 as adjuvant treatment for sarcoma.
  • treatment can start 1 day after intralesional tumor curretage.
  • intralesional curretage can be performed on animals with progressive tumors (i.e. when tumors will reach a volume of 1000 mm3).
  • the animals will be divided into the following treatment groups (8 animals/group; 5 treatment groups): (i) IPI-926 (ii) Adryamicine (iii) mTOR inhibitor, (iv) IPI- 926+mTOR inhibitor (v) control (saline).
  • IPI-926 treated-groups will receive IPI- 926-based combination (IPI-926 dose and frequency currently under determination), started at day 1 after intralesional curetage until euthanasia (day 40). Animals from the Attorney Docket No. I2041-7000WO/3020PCT adryamicin, mTOR inhibitor and the control groups will be given the corresponding solution at the same frequency. Animals will be sacrificed when tumor become too bulky and when life of the animal would be threatened. Assessment of IPI-926 therapeutic efficacy .
  • Tumors can be measured twice a week with a calliper and tumor volume can be calculated according to the Carlsonn's formula. Chondrosarcoma evolution throughout treatment will also be followed using MRI. Imaging sessions will be performed on animals at the beginning of treatment (TO), then every ten days till euthanasia. At the end of the experiments, tumor, muscle, bone, lungs from all the animals will be collected. Samples of the collected tissues will be snap-frozen and stored at, -80° for
  • the imaging observations can be correlated to immunohistochemistry analyses performed on tumor and tissue sections of animals from treated and control groups.
  • anti-MMPs, CD31 , Glut-1 , Ki67 antibodies will be used.
  • Tumor necrosis induced by IPI-926 will be assessed by microscopic examination of H&E-stained tumor specimens collected at the time of euthanasia.
  • necrosis and mitotic index will be estimated on whole transverse sections from the 1 ⁇ 4 distal, middle and 1 ⁇ 4 proximal of the tumor and expressed as percentage of whole tumor volume according to the system.
  • Analysis of calcification/bone differentiation markers as well as markers of invasiveness will be performed by RT-PCRq using appropriate sets of primers i.e (Runx2, type I, II collagene, sox9, Indian Hh integrins).
  • the experiments can be performed in two steps. In the first step, the efficiency of IPI-926 as curative treatment in chondrosarcoma will be evaluated. Then in a second step, the effect of IPI-926 on relapsed chondrosarcoma will be assessed.
  • the two settings of administration represent two clinically different situations and are complementary.
  • Example 16B IPI-926 Affects the Growth and Survival of Osteosarcomas and Chondrosarcomas In Vivo
  • This Example provides experimental evidence of the effects of IPI-926 on the growth and survival of osteosarcomas and chondrosarcomas in vivo.
  • mRNA expression of Hh ligand and Hh receptor in tumor cells and stromal cells from osteosarcoma xenograft models was quantified using human and mouse specific primers. Elevated expression of IHH mRNA and Glil mRNA was detected in tumor cells compared to tumor-stromal associated cells (data not shown). The expression of PTCHl mRNA was elevated in both tumor cells and tumor-associated stromal cells (data not shown).
  • IPI-926 decreased tumor growth and possibly vascularization is osteosarcoma xenograft models relative to control animals.
  • the mean tumor weight was decreased to 1.83 grams in IPI-926-treated animals, compared to 2.49 grams in controls, with a P-value of 0.23.
  • the mean tumor volume was decreased to 2.95 cm 3 in IPI-926-treated animals, compared to 5.19 cm 3 in controls, with a P-value of 0.04; the mean tumor weight was decreased to 2.05 grams in IPI-926-treated animals, compared to 3.34 grams in controls, with a P-value of 0.05.
  • No difference in volume or weight was observed for treated Xenograft B.
  • Figures 21A-21D show the effects of IPI-926 in decreasing Hh signaling in tumor and stromal cells of osteosarcoma xenograft models.
  • Figures 21A-21B show a decrease in PTCHl and Glil mRNA expression in tumor cells from Xenograft A and B aninals treated with IPI-926 compared to controls. Similar decreases in PTCHl and Glil mRNA expression is detected in stromal cells treated with IPI-926 compared to controls ( Figures 21C-21D). No change in tumor cell Hh signaling was detected in Xenograft B.
  • Figures 22A-22D show the effects of IPI-926 in proliferation and apoptosis in osteosarcoma xenograft models.
  • Figures 22A and 22C show a decrease in proliferation of tumor cells detected by the percentage of cells showing Ki-67 staining in two different animals in response to IPI-926 compared to controls.
  • Figures 22B and 22D show an increase in apoptosis detected by Tunel Staning in response to IPI-926 compared to controls.
  • Hh pathway genes such as IHH, PTCH1 and Glil (Tiet et al. (2006) American J. Pathology 168(1):321-330). Hh ligand increases the proliferation of primary chondrosarcoma cells in vitro.
  • IPI-926 administered at 40 mg QD oral daily treatment for 6-10 weeks was found to decrease tumor volume by 37-55% in three independent tumor models.
  • IPI-926 was shown to have a direct effect in inhibiting the growth of tumor cells, and not through the stroma.
  • Figure 23 is a bar graph showing the inhibition of expression of human Glil and PTCH1 in human cells.
  • chondrosarcoma provides an example of a solid tumor having a Hh ligand-dependent signaling directly to tumor cells. Hh inhibition has also been shown to have an effect on the surrounding tumor stroma.
  • calcification is detected in treated samples, which show little to no detectable chondrocytes (data not shown). In contrast, many chondrocytes are detected in untreated primary tumors (data not shown).
  • IPI-926-treated tumors show a tumor growth inhibition of 44%, p+0.0123, compared to other chemotherapies of primary chondrosarcoma xenografts (Figure 24).
  • Treatment of the primary chondrosarcoma xenografts studies summarized in Figure 24 were initiated one month after tumor implant into NSG mice.
  • Oral IPI-926 was administered at 40 mg/kg for 5 days/week for a total of three weeks.
  • IPI-926 were the only group showing a statistically significant change in human Hh pathway (Glil) gene expression compared to the control group ( Figure 25).
  • chondrocytes and in chondrosarcoma leads to tumor growth inhibition in ⁇ chondrosarcoma tumor xenografts. Inhibition of Hh pathway in chondrosarcoma xenografts leads to morphology changes
  • Example 17 Combination Study of a Paclitaxel Agent and a Hedgehog Inhibitor in L3.6pl Tumor Bearing Mice
  • IPI-926 (HC1 salt) in L3.6pl tumor bearing animals.
  • mice Five week old male Ncr nude mice (weight 20-25 g) were purchased from
  • L3.6pl is a pancreatic tumor model purchased from ATCC. The cells were cultured in advanced DMEM supplemented with 10% FBS and 1%P/S. Cells were harvested with trypsin and a viable cell count was performed using trypan blue exclusion of dead cells. Cells were re-suspended in DMEM (no serum) and subcutaneously implanted at 2x10 6 cells /lOOuL/ mouse into the right flank.
  • ABRAXANE® was dosed at 2 mg/kg i.v., and on Days 13, 20, and 27 ABRAXANE® was dosed at 20mg/kg i.v (on Day 9, there was a miscalculation during the preparation of Attorney Docket No. I2041-7000WO/3020PCT the ABRAXANE® dose. On Day 13, 20 and 27, the calculation was corrected, and the full dose of 20mg/kg was administered on those days). On Day 27, the ABRAXANE® alone and ABRAXANE® + IPI-926 groups received their final dose of treatment.
  • the control animals were taken down on Day 20 due to multiple animals having ulcertions in their tumors, which is a criteria for the animal to be sacrificed under the IACUC guidelines.
  • the ABRAXANE® alone group showed 27% tumor growth inhibition (TGI) when compared to the control group receiving vehicle, while the ABRAXANE® + IPI-926 combination group showed 68% TGI when compared to the control group receiving vehicle.
  • the ABRAXANE® + IPI-926 combination group showed a 71 % TGI when compared to the ABRAXANE® group.
  • Phospho histone 3 (PH3) is a nuclear marker of cells in the late G 2 /M phase.
  • Paclitaxel inhibits the depolymerization of tubules which can arrest cells in the late G 2 /M phase, and can prevent cells from undergoing mitosis. If IPI-926 enhances tumor dug levels, then an increase in PH3 staining will be detected in the IPI-926 + Abraxane treated tumor sections.
  • DAB liquid substrate buffer + Chromogen system (DAKO#K3468) was used for developing and detection of the stain.
  • PH3 stained sections were scanned using the Aperio scanner system, and images were subjected to morphometric analysis (see Figure 27A; 200x images of PH3 staining on the L3.6pl tumor model).
  • the Genie pattern recognition tool and nuclear algorithm were used to quantitate the % PH3 positive neoplastic nuclei per stained tumor section ( Figure 27B).
  • a count of the positive neoplasm nuclei showed an increase of 30% PH3 positive in the combination IPI-926 + ABRAXANE® group, versus 20% in the
  • ABRAXANE® group alone demonstrate an increase of PH3 staining in L3.6pl tumors treated with the combination of IPI-926 + ABRAXANE® and suggests enhancement of ABRAXANE® delivery when used in combination with IPI-926 compared to control or ABRAXANE® alone.
  • ABRAXANE® 50-300mg of the L3.6pl tumor was snap frozen from each mouse for pharmacokinetic (PK) evaluation of tumor paclitaxel levels.
  • PK analysis of these tumors indicated a 28% increase of tumor paclitaxel levels (ng/g of tissue) in the ABRAXANE® + IPI-926 combination treated tumors versus the ABRAXANE® alone treated animals.
  • ASPC-1 is a pancreatic tumor model.
  • Cells were cultured in advanced RPMI 8226 supplemented with 10% FBS and 1%P/S. Cells were purchased from ATCC. Cells were harvested using trypsin, and viability was assessed by trypan blue exclusion. Cells were implanted 5x106
  • IPI-926 was administered in 5% HPBCD @ 40mg/kg (8 mL/kg) by oral gavage every other day, QOD.
  • ABRAXANE® or Paclitaxel in saline were administered at 20mgA kg i.v. with a 27 gauge needle Ql W.
  • Bodyweight and tumor measurements were taken twice weekly. Body weight loss greater than 20% from the initial day of treatment or tumor volumes greater than 3000mm 3 resulted in euthanasia.
  • Table 2 The study design is summarized in Table 2.
  • mice were randomized into six dosing groups to receive vehicle control, IPI-926 alone, Abraxane® +/- IPI-926 or paclitaxel +/- IPI-926 ( Figures 28A-28B).
  • IPI-926 was administered at 40mg/kg orally QOD, from day 21 to 41 for a total of 11 doses total. Both Abraxane and paclitaxel were dosed on days 21 , 28 and 35 at 20mg/kg i.v. oncer per week, Q1W.
  • the last dose of IPI-926 was administered and re-growth was monitored.
  • Table 3 summarizes the % tumor growth inhibition (TGI) obtained on day 41 of all the test groups versus the control Attorney Docket No. I2041-7000WO/3020PCT group, and p values calculated using the JMP stats program (a means comparison Student's T test).
  • Abraxane® + IPI-926 showed a synergistic effect when dosed in combination, compared to the Vehicle control, IPI-926 alone, or Abraxane® alone group. Tumor re-growth was monitored and the Abraxane® + IPI-926 group showed at least a 15 day delay in reaching the same tumor volume as the IPI-926 or Abraxane® alone treated groups.
  • Example 19 Thee-way Combination Study of a Paclitaxel Agent, a Hedgehog Inhibitor and an Additional Therapeutic Agent in L3.6pl Tumor-bearing Mice
  • This Example describes the combination effect of Abraxane®, IPI-926 (HC1 salt) and gemcitabine (GEMZAR) in L3.6pl tumor bearing animals.
  • mice Five week old male Ncr nude mice (weight 20-25 g) were purchased from Taconic Farms, Inc. (Hudson, NY).
  • L3.6pl is a pancreatic tumor model purchased from ATCC.
  • the cells were cultured in advanced DMEM supplemented with 10% FBS and 1%P/S. Cells were harvested with trypsin and a viable cell count was performed using trypan blue exclusion of dead cells. Cells were re-suspended in DMEM (no serum) and subcutaneously implanted at 2x10 6 cells /lOOuL/ mouse into the right flank.
  • mice On day 10 post tumor cell implant, the mice were randomized into eight dosing groups to receive vehicle, IPI-926 alone, Abraxane® alone, Gemzar alone, Abraxane® + IPI-926, Gemzar + IPI-926, Abraxane® + Gemzar, and Abraxane® + Gemzar + IPI-926 (see Figure 29A for cummulative results.
  • Figure 29B depicts a subset of the results of Figure 29A).
  • IPI-926 was dosed at 40mg/kg orally QOD, from day 10 to 31 for a total of 11 doses administered. Starting on Day 10, Abraxane was dosed on Days 10, 17 and 24 at 20mg/kg i.v. oncer per week, Ql W.
  • Figure 29C depicts a subset of the results of Figure 29C).
  • %TGI percent tumor growth inhibtion
  • Progression while on treatment was measured as the time it took for each tumor to reach 1000mm 3 . Once a tumor measured 1000mm 3 , the animal was sacrificed and the day was recorded to plot the data as a Kaplan-Meier curve. Mean time to progression was found significantly increased in the Abraxane® + IPI-926 combination group when compared to all other groups.
  • This Example evaluated whether the synergistic effect of the combination of IPI- 926 (HCl salt) and ABRAXANE® is by enhanced drug delivery of ABRAXANE® to the tumor through the effect of IPI-926 on the mouse stroma via increased tumor perfusion.
  • mice Five week old male Ncr nude mice (weight 20-25 g) were purchased from Taconic Farms, Inc. (Hudson, NY).
  • L3.6pl is a pancreatic tumor model purchased from ATCC. The cells were cultured in advanced DMEM supplemented with 10% FBS and 1%P/S. Cells were harvested with trypsin and a viable cell count was performed using trypan blue exclusion of dead cells. Cells were re-suspended in DMEM (no serum) and subcutaneously implanted at 2x10 6 cells /lOOuL/ mouse into the right flank. Attorney Docket No. I2041-7000WO/3020PCT
  • IPI-926 HC1 salt
  • untreated animals using contrast enhanced ultrasound.
  • the L3.6pl tumor cell line was injected subcutaneously and treatment with IPI-926 was initiated.
  • IPI-926 or vehicle was administered orally at 40 mg/kg for seven consecutive days.
  • animals were subjected to ultrasound image analysis using perfusion contrast enhancement (microbubbles) during the imaging procedure.
  • FIG 31 depicts the results of Q-RT-PCR analysis of excised IPI-926 treated tumors of Example 17 (L3.6pl pancreatic cell lines) and Example 18 (ASPC-1 pancreatic cell lines).
  • Q-RT-PCR analysis revealed inhibition of murine Gli-1 with IPI-926 treament.
  • Human Hh ligand was detected and human Gli- 1 levels were not modulated with treatment.
  • Hh paracrine signaling can occur in a paracrine manner in pancreatic xenograft tumor models, where the tumor cells are providing Hh ligand and activate murine Glil , which is inhibited by IPI-926 treatment.
  • Example 22 Head and Neck Cancer Model
  • Example 22 The aim of Example 22 was to elucidate the relevance of the Hedgehog pathway in head and neck squamous cell carcinoma (HNSCC) and the effect of the hedgehog inhibitor, IPI-926, in combination with ERBITUX® (cetuximab) in a direct patient tumor model (DPTM) of HNSCC, and the role of cancer stem cells (CSC) in relapses after therapy.
  • HNSCC head and neck squamous cell carcinoma
  • IPI-926 the effect of the hedgehog inhibitor
  • ERBITUX® cetuximab
  • DPTM direct patient tumor model
  • CSC cancer stem cells
  • UMMC22 were positive or strongly positive.
  • Treatment in vivo of the three DTPM cases with ERBITUX® (cetuximab), IPI-926, and the combination showed in all three cases that ERBITUX®-treated tumors re-grew 4-8 weeks post-therapy, whereas combination- treated mice were homogenously relapse-free three months post-therapy (Figure 32).
  • Isolated CD24/44 and CD24/ALDH positive cells each generated tumors at a higher rate than negative cells despite a 100-fold cell number dilution, and the key Hh signaling component SMO and the GLI1 transcription factor genes were 200-fold and 700-fold more highly expressed in CSC than in negative cells.
  • HNSCC The Hedghog pathway is active in HNSCC, with over-expression seen in the CSC subpopulation where data suggest autologous signaling.
  • Hh pathway inhibition with IPI-926 diminishes CSC (which can be, in part, responsible for repopulation of the original tumor) prevents relapse of tumor growth of HNSCC.
  • Example 23 Non-Small Cell Lung Cancer NCI-H1650 Xenograft Model Post Gefitinib Therapy
  • This Example evaluates the activity of IPI-926 in the NCI-H1650 tumor xenograft model post targeted therapy with gefitinib.
  • NCI-H1650 lung carcinoma cell line (ATCC #CRL-5883) is an adenocarcinoma that was isolated from a 27 year old Caucasian male smoker in 1987. These cells have an acquired mutation in the EGFR tyrosine kinase domain (E746 - A750 deletion). This mutation makes them sensitive to EGFR-tyrosine kinase inhibitors such as gefitinib.
  • HI 650 cells were obtained from ATCC and cultured in RPMI 1640 supplemented with 1% pen/strep and 10% fetal bovine serum. Cells were harvested with trypsin and a viable cell count was performed using trypan blue exclusion of dead cells.
  • mice Once tumor volumes reached between 150-200 mm 3 mice were randomized and treatment was initiated. Randomized mice were treated with vehicle (5% HPBCD), 40 mg/kg gefitinib p.o QD for 7 days then followed by either 40 mg/kg IPI-926 or vehicle.
  • Vehicle 5% HPBCD
  • 40 mg/kg gefitinib p.o QD for 7 days then followed by either 40 mg/kg IPI-926 or vehicle.
  • mice were randomized in two dosing groups receiving either vehicle p.o Q.D, or gefitinib (40 mg/kg p.o, Q.D).
  • gefitinib treated mice were then randomized and received either vehicle p.o Q.D, or IPI- 926 (40 mg/kg, p.o Q.O.D) for 25 days.
  • Samples for analysis were collected 24 hours post the final dose.
  • the gefitinib followed-by IPI-926 (gefitinib - IPI-926) group showed 65% tumor growth inhibition (TGI) when compared to gefitinib followed- by vehicle (gefitinib - vehicle) group ( Figure 33).
  • TGIs and p values are summarized in Table 7 below. The data from this study show a statistically significant increase in tumor growth inhibition when IPI-926 is dosed post regression with gefitinib.
  • Example 24 Non-Small Cell Lung Cancer HCC827 Xenograft Model Post Gefitinib Therapy Attorney Docket No. I2041-7000WO/3020PCT
  • This Example evaluates the activity of IPI-926 in the HCC827 tumor xenograft model post targeted therapy with gefitinib.
  • HCC827 tumor cells were isolated from patients with non-small lung cancer (SCLC). These cells have an acquired mutation in the EGFR tyrosine kinase domain (E746 - A750 deletion). This mutation makes them sensitive to targeted therapy with gefitinib, a tyrosine kinase inhibitor.
  • HCC827 cells were obtained from ATCC and cultured in RPMI 1640 supplemented with 1% pen/strep and 5% fetal bovine serum. Cells were harvested with trypsin and a viable cell count was performed using trypan blue exclusion of dead cells.
  • mice Once tumor volumes reached between 150-200mm 3 mice were randomized and treatment were initiated. Randomized mice were treated with vehicle (5% HPBCD) or 10 mg/kg gefitinib p.o QD for 3 days then followed by either 40 mg/kg IPI-926 or vehicle. Dosing Groups
  • Gefitinib p.o QD for 3 days at dose volume of 8 ml/kg; IPI-926 p.o QOD for 3 weeks at dose volume of 8 ml/kg.
  • mice were randomized in three dosing groups receiving either vehicle (p.o. Q.D), gefitinib (40 mg/kg p.o. Q.D) or IPI-926 (40mg/kg p.o. Q.O.D).
  • vehicle p.o. Q.D
  • gefitinib 40 mg/kg p.o. Q.D
  • IPI-926 40mg/kg p.o. Q.O.D
  • Samples for analysis were collected 24 hours post the final dose.
  • TGIs and p values are summarized in Table 8 below. The data from this study show a statistically significant increase in tumor growth inhibition when IPI-926 is dosed post regression with gefitinib.
  • Example 25 Hh Pathway Profile Expression In Non-Small Cell Lung Cancer NCI- H1650 Xenograft Model Post Gefitinib Regression
  • NCI-H1650 lung carcinoma cell line (ATCC #CRL-5883) is an adenocarcinoma that was isolated from a 27 year old Caucasian male smoker in 1987. These cells have an acquired mutation in the EGFR tyrosine kinase domain (E746 - A750 deletion). This mutation makes them sensitive to EGFR-tyrosine kinase inhibitors such as gefitinib.
  • HI 650 cells were obtained from ATCC and cultured in RPMI 1640 supplemented with 1% pen/strep and 10% fetal bovine serum. Cells were harvested with trypsin and a viable cell count was performed using trypan blue exclusion of dead cells.
  • mice Once tumor volumes reached between 150-250mm 3 mice were randomized and treatment was initiated. Randomized mice were treated with vehicle (5% HPBCD), 40 mg/kg gefitinib p.o QD x 5 days or when tumor regress 50%, then followed by 40 mg/kg IPI-926 or vehicle.
  • vehicle 5% HPBCD
  • 40 mg/kg gefitinib p.o QD x 5 days or when tumor regress 50% then followed by 40 mg/kg IPI-926 or vehicle.
  • IPI-926 p.o. QD for 1 , 4, 7 or 10 days at dose volume of 8 ml/kg; gefitinib p.o.
  • Example 23 In NCSLC xenograft models NCI-H1650 of Example 23, IPI-926 significantly inhibits tumor re-growth post-gefitinib therapy.
  • Example 25 data indicates that Hh ligands are upregulated post-gefitinib therapy in this xenograft model, and that the hedgehog inhibitor IPI-926 down regulates stromal Glil and Gli2.
  • the Example 23 and Example 25 data combined suggest that therapeutic inhibition of the Hh signaling pathway is an important strategy to extend progression free survival in patients who initially respond to therapy but later relapse and provide a rationale for evaluating IPI- 926 in patients with NSCLC.
  • This example describes the effects of IPI-926 and Avastin® on the vasculature and stroma of the BXPC3 tumor, a pancreatic tumor model.
  • Treatment can be initiated once tumor volume reaches 100-200mm 3 .
  • Oral administration of IPI-926 will administered at 40mg/kg orally, QOD.
  • Avastin will be administered at 5mg/kg i.p. two times per week. Post ⁇ two weeks of treatment, isolectin and maleimide will be injected i.v., 30 minutes prior to euthanizing.
  • Avastin® i.p. @ 5mg/kg twice weekly
  • Cells were cultured in advanced RPMI 8226 supplemented with 1% FBS and 1%P/S. Cells were purchased from ATCC. Cells were harvested and implanted 1x107 cells/mouse.
  • Husbandry Male mice are housed in groups of 4 per cage in suspended, stainless- steel cages and offered food and water ad libitum. Environmental controls for the animal room were set to maintain 18 to 26°C, a relative humidity of 30 to 70%, a minimum of 10 room air changes/hour, and a 12-hour light/ 12-hour dark cycle.
  • IPI-926 can be administered orally via a gavage at 8ml/kg dose volume daily.
  • Avastin will be administered i.p. via a 27G needle at 8ml/kg volume, two times per week.
  • Tumor collected will be snap frozen for analytical evaluation and RT-PCR (Gli, Ptch, Smo, HH and potential stem cell markers currently under development).
  • Tumors will be fixed in 10% formalin for 24hrs prior to transferring the samples into 70% ethanol.
  • Tumor volume length x width 2 /2
  • Treatment was initiated once tumor volumes were on average 100mm 3 .
  • IPI-926 was administered in 5% HPBCD @ 40mg/kg (8 mL/kg) by oral gavage every other day, QOD.
  • AVASTIN® or bevacizumab in saline were administered at 5mgA/kg i.p. with a 27 gauge needle 2x per week.
  • Bodyweight and tumor measurements were taken twice weekly. Body weight loss greater than 20% from the initial day of treatment or tumor volumes greater than 3000mm 3 resulted in euthanasia.
  • mice On day 31 post tumor cell implant, the mice were randomized into four dosing groups to receive vehicle control, IPI-926 alone, Avastin® +/- IPI-926. IPI-926 was administered at 40mg/kg orally QOD for a total of 13 doses. Avastin® was administered at 5mg/kg i.p. 2x week for a total of 8 doses.
  • Table 1 1 summarizes the % tumor growth inhibition (TGI) obtained on day 56 of all the test groups versus the control group, and p values calculated using the JMP stats program (a means comparison Student's T test). These results are summarized in Figure 37.
  • TGI % tumor growth inhibition

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Abstract

La présente invention concerne des procédés et des compositions de traitement ou de prévention d'un cancer associé à hedgehog (par exemple, une croissance de cellules cancéreuses dépendantes du ligand hedgehog choisie parmi un cancer neuroendocrinien, un sarcome (par exemple, un sarcome musculosquelettique, tel qu'un chondrosarcome et un ostéosarcome)), un cancer de la tête et du cou, ou un cancer des poumons par administration à un sujet d'un inhibiteur hedgehog, seul ou en combinaison avec un autre anticancéreux (par exemple, le paclitaxel ou un agent du paclitaxel, un inhibiteur de la tyrosine kinase (par exemple, un inhibiteur du récepteur de la tyrosine kinase (RTK)) ou un inhibiteur mTOR).
PCT/US2010/057534 2009-11-20 2010-11-19 Procédés et compositions de traitement de cancers associés à hedgehog WO2011063309A1 (fr)

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JP2012540121A JP2013511549A (ja) 2009-11-20 2010-11-19 ヘッジホッグ関連癌の治療のための方法及び組成物
AU2010321773A AU2010321773A1 (en) 2009-11-20 2010-11-19 Methods and compositions for treating hedgehog-associated cancers
EP10832305A EP2502078A1 (fr) 2009-11-20 2010-11-19 Procédés et compositions de traitement de cancers associés à hedgehog
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WO2013148775A1 (fr) * 2012-03-30 2013-10-03 Merck Sharp & Dohme Corp. Biomarqueur prédictif utile pour thérapie anticancéreuse médiée par un inhibiteur de cdk
WO2014002922A1 (fr) * 2012-06-26 2014-01-03 アステラス製薬株式会社 Méthode de traitement du cancer par l'utilisation combinée d'un agent anti-cancéreux
JP2014515394A (ja) * 2011-05-31 2014-06-30 ピラマル エンタープライズィズ リミテッド 頭頸部扁平上皮癌の治療のための相乗的薬剤組合せ
WO2014143613A1 (fr) * 2013-03-13 2014-09-18 Abraxis Bioscience, Llc Méthodes de traitement de tumeur solide pédiatrique
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US9238672B2 (en) 2007-12-27 2016-01-19 Infinity Pharmaceuticals, Inc. Methods for stereoselective reduction
WO2016037194A1 (fr) * 2014-09-05 2016-03-10 The Trustees Of Columbia University In The City Of New York Polythérapie à base d'inhibiteur des voies akt et shh destinée au traitement de carcinomes de cellules basales
US9376447B2 (en) 2010-09-14 2016-06-28 Infinity Pharmaceuticals, Inc. Transfer hydrogenation of cyclopamine analogs
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US9879293B2 (en) 2009-08-05 2018-01-30 Infinity Pharmaceuticals, Inc. Enzymatic transamination of cyclopamine analogs
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US10369147B2 (en) 2015-06-04 2019-08-06 PellePharm, Inc. Topical formulations for delivery of hedgehog inhibitor compounds and use thereof
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US9238672B2 (en) 2007-12-27 2016-01-19 Infinity Pharmaceuticals, Inc. Methods for stereoselective reduction
US9879293B2 (en) 2009-08-05 2018-01-30 Infinity Pharmaceuticals, Inc. Enzymatic transamination of cyclopamine analogs
US9394313B2 (en) 2010-09-14 2016-07-19 Infinity Pharmaceuticals, Inc. Transfer hydrogenation of cyclopamine analogs
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US9655909B2 (en) 2012-01-12 2017-05-23 Board Of Regents, The University Of Texas System Personalized medicine for the prediction of therapy targeting the hedgehog pathway
WO2013106812A1 (fr) * 2012-01-12 2013-07-18 Board Of Regents, The University Of Texas System Médicament personnalisé pour la prédiction de thérapie ciblant la voie hedgehog
WO2013148775A1 (fr) * 2012-03-30 2013-10-03 Merck Sharp & Dohme Corp. Biomarqueur prédictif utile pour thérapie anticancéreuse médiée par un inhibiteur de cdk
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US10597294B2 (en) 2014-05-30 2020-03-24 Novomer, Inc. Integrated methods for chemical synthesis
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US11078172B2 (en) 2015-02-13 2021-08-03 Novomer, Inc. Integrated methods for chemical synthesis
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