A novel dosing regimen for erlotinib or a pharmaceutically acceptable salt thereof is described herein. The dosing regimen demonstrates impressive control of central nervous system disease, which is better than that reported with standard dose erlotinib. The use of the novel dosing regimen for treating patients in need thereof, including for controlling formation of metastatic brain, leptomeninges, or CNS lesions in a patient with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutation with or without pre-existing brain metastases, is also described herein.
A61K 31/517 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A novel dosing regimen for erlotinib or a pharmaceutically acceptable salt thereof is described herein. The dosing regimen demonstrates impressive control of central nervous system disease, which is better than that reported with standard dose erlotinib. The use of the novel dosing regimen for treating patients in need thereof, including for controlling formation of metastatic brain, leptomeninges, or CNS lesions in a patient with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutation with or without pre-existing brain metastases, is also described herein.
A61K 31/517 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A novel dosing regimen for erlotinib or a pharmaceutically acceptable salt thereof is described herein. The dosing regimen demonstrates impressive control of central nervous system disease, which is better than that reported with standard dose erlotinib. The use of the novel dosing regimen for treating patients in need thereof, including for controlling formation of metastatic brain, leptomeninges, or CNS lesions in a patient with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutation with or without pre-existing brain metastases, is also described herein.
A61K 31/517 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A novel dosing regimen for erlotinib or a pharmaceutically acceptable salt thereof is described herein. The dosing regimen demonstrates impressive control of central nervous system disease, which is better than that reported with standard dose erlotinib. The use of the novel dosing regimen for treating patients in need thereof, including for controlling formation of metastatic brain, leptomeninges, or CNS lesions in a patient with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutation with or without pre-existing brain metastases, is also described herein.
A61K 31/517 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
Compounds of Formula I, as shown below and defined herein:
pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as tumors driven or mediated at least in part by RSK. This Abstract is not limiting of the invention.
C07D 519/00 - Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups or
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
C07D 475/12 - Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
A61K 31/5025 - PyridazinesHydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
6.
REGIOSELECTIVE SYNTHESIS OF SUBSTITUTED PYRIMIDINES
Disclosed are compounds of the Formula I:(I) where R1, R4, and R5 are described herein, and methods of making the compounds, including regioselective functionalization.
C07D 403/04 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing two hetero rings directly linked by a ring-member-to-ring- member bond
C07D 403/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing three or more hetero rings
The present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of a combination of an inhibitor of MET kinase signaling (e.g. a small molecule MET kinase inhibitor, an anti-MET antibody, or an HGF binding protein) and an inhibitor of IGF-1R signaling (e.g. a small molecule IGF-1R kinase inhibitor (e.g. OSI-906), an anti-IGF-1R antibody, or one or more IGF binding proteins (e.g. IGFBP3)). The present invention also provides a pharmaceutical composition comprising a combination of an inhibitor of MET kinase signaling and an inhibitor of IGF-1R signaling, with a pharmaceutically acceptable carrier. The present invention also provides such methods or compositions where the inhibitory activities of MET kinase signaling and IGF-1R kinase signaling reside in the same molecule.
A61K 31/4985 - Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
A61K 31/517 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 31/713 - Double-stranded nucleic acids or oligonucleotides
A61P 35/04 - Antineoplastic agents specific for metastasis
A61K 31/53 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
8.
ANTI-CANCER MTOR INHIBITOR AND ANTI-ANDROGEN COMBINATION
Methods and compositions for treating cancer comprising administering to a patient a combination regimen comprising OS I - 027 and an androgen receptor antagonist.
A61K 31/277 - NitrilesIsonitriles having a ring, e.g. verapamil
A61K 31/53 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
Compounds of Formula (I): wherein variables are defined herein, and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers for which FAK inhibition is beneficial.
A61K 31/675 - Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
C07F 9/6584 - Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
C07D 401/04 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring- member bond
C07D 401/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
C07D 403/04 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing two hetero rings directly linked by a ring-member-to-ring- member bond
C07D 403/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing three or more hetero rings
A61K 31/5025 - PyridazinesHydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
A61P 19/02 - Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
High-Throughput Screening (HTS) of large compound libraries is the method of choice for discovery of lead compounds for drug development. The present invention provides novel, sensitive and broadly applicable NMR screening methods in which the H8 signal of a purine-containing substrate or product, or the H6 signal of a pyrimidine-containing substrate or product, is used to monitor enzymic reactions that utilize such substrates. Experiments can be performed in real time or in an endpoint assay format using protein and substrate concentrations comparable to the ones used by other HTS techniques. Application of the NMR method to the assay of the enzymes creatine kinase and phosphodiesterase 2A is presented. The methods are applicable to any of a multitude of enzymes that utilize purine nucleoside substrates (e.g. ATP, GTP) or pyrimidine nucleoside substrates (e.g. CTP, UDP-GlcNac), including protein kinases, GTPases, and lipid kinases.
C12Q 1/00 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions
C12Q 1/30 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving oxidoreductase involving catalase
C12Q 1/48 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving transferase
Compounds of Formula I, as shown below and defined herein: pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as tumors driven or mediated at least in part by RSK. This Abstract is not limiting of the invention.
C07D 403/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links
A61K 31/4985 - Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
Compounds of Formula (I), pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as tumors driven at least in part by at least one of MET, RON, ALK, IR, or IGF-1R. This Abstract is not limiting of the invention.
A61K 31/437 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
A61K 31/4985 - Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
The present invention provides diagnostic methods for assessing the EMT status of tumor cells, and for predicting the effectiveness of treatment of a cancer patient with an EGFR or IGF-1R kinase inhibitor, utilizing an EMT gene signature index score. The present invention further provides methods for treating patients with cancer that incorporate these methods.
A method of treating NSCLC comprising in some aspects administering OSI-906 and an EGFR inhibitor to a patient having NSCLC having an activating EGFR mutation, as disclosed herein.
A61K 31/4985 - Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
A61K 31/517 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
The present invention provides diagnostic methods for predicting the effectiveness of treatment of an hepatocellular carcinoma (HCC) patient with an IGF-IR kinase inhibitor. Methods are provided for predicting the sensitivity of HCC tumor cell growth to inhibition by an IGF-IR kinase inhibitor, by assessing whether the HCC tumor cells express a high level of AFP, or whether serum levels of AFP protein are high. Methods are also provided for predicting the sensitivity of HCC tumor cell growth to inhibition by an IGF-IR kinase inhibitor, by assessing the EMT status of the HCC cells. The present invention thus provides methods of identifying patients with hepatocellular carcinoma who are most likely to benefit from treatment with an IGF-IR kinase inhibitor. The present invention also provides diagnostic methods for predicting the effectiveness of treatment of HCC cancer patients with IGF-IR kinase inhibitors, based on a determination of the expression level of IR, IGF -2, IGFBP3 or IGFBP7 in HCC tumor cells, or a 4-gene index calculated using the HCC expression vales for each of these four genes, which can be used to identify HCC tumors that will be sensitive to IGF-IR kinase inhibitors, and also those that will be insensitive. The latter methods are also expected to be effective for other cancer types. Improved methods for treating cancer patients with IGF-IR kinase inhibitors that incorporate the above methods are also provided.
The present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of a combination of an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors, wherein said agent is an mTOR inhibitor that binds to and directly inhibits both mTORC1 and mTORC2 kinases. The present invention also provides a pharmaceutical composition comprising an EGFR kinase inhibitor and an mTOR inhibitor that binds to and directly inhibits both mTORC1 and mTORC2 kinases, in a pharmaceutically acceptable carrier. A preferred example of an EGFR kinase inhibitor that can be used in practicing the methods of this invention is the compound erlotinib HC1 (also known as TARCEVA®).
The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by EGFR kinase inhibitors. Improved methods for treating cancer patients with EGFR kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to EGFR kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by EGFR kinase inhibitors are also provided.
Compounds of Formula (I): wherein variables are defined herein, and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers for which FAK inhibition is beneficial.
Polymorphic forms of the tyrosine kinase inhibitor OSI-906, preparation, pharmaceutical compositions, and uses thereof. The invention includes methods of treating diseases such as cancer, including cancer mediated at least in part by IGF-1 R and/or IR, with the polymorphs and compositions. This Abstract is not limiting of the invention.
Compounds of Formula I, as shown below and defined herein: (I) pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as tumors driven at least in part by at least one of RON, MET or ALK. This Abstract is not limiting of the invention.
A61K 31/437 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
Compounds of Formula I, as shown below and defined herein:
pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as tumors driven at least in part by at least one of RON, MET or ALK. This Abstract is not limiting of the invention.
A61K 31/437 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
Compounds of Formula I, as shown below and defined herein: pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as but not limited to tumors driven at least in part by at least one of RON, MET, IR, IGF-1 R, or ALK. This Abstract is not limiting of the invention.
Methods and compositions for treating cancer comprising administering to a patient inhibitors of mT0RC1/C2, IGF-1 R, and IR. In some aspects, a combination of an mT0RC1/C2 inhibitor and an IGF-1 R/IR inhibitor is employed. Other aspects are described herein.
A61K 31/00 - Medicinal preparations containing organic active ingredients
A61K 31/4985 - Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
A61K 31/53 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
Compounds of Formula I, as shown below and defined herein: pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers mediated at least in part by RON and/or MET.
A61K 31/437 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
The present invention provides diagnostic methods for predicting the effectiveness of treatment of a cancer patient with an IGF-IR kinase inhibitor that inhibits both IGF-IR and IR kinases. Methods are provided for identifying patients with cancer who are likely to benefit from treatment with an IGF-IR kinase inhibitor that inhibits both IGF-IR and IR kinases. Methods are also provided for identifying patients with cancer who are likely to benefit from treatment with an IGF-IR kinase inhibitor that inhibits both IGF-IR and IR kinases, but who would likely not respond to therapy with an anti-IGF-lR antibody. Methods are also provided for identifying patients with cancer who are more likely to benefit from treatment with anti-IGF-lR antibody. Improved methods for treating cancer patients with IGF-IR kinase inhibitors that incorporate these methods are also provided.
The present invention provides diagnostic methods for predicting the effectiveness of treatment of an ovarian cancer patient with an IGF- IR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an IGF-IR kinase inhibitor, comprising assessing whether the tumor cells possess mutant K-RAS. The present invention thus provides a method of identifying patients with ovarian cancer who are most likely to benefit from treatment with an IGF- IR kinase inhibitor. Improved methods for treating cancer patients with IGF-IR kinase inhibitors that incorporate this methodology are also provided. The present invention also provides diagnostic methods for predicting the effectiveness of treatment of cancer patients with IGF-IR kinase inhibitors, based on a determination of the mutation status of the genes K-RAS, B-RAF, PTEN and PIK3CA, which can be used to identify tumor cell types that will be sensitive to IGF-IR kinase inhibitors, and also those that will be insensitive.
C07D 403/04 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing two hetero rings directly linked by a ring-member-to-ring- member bond
C07D 403/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing three or more hetero rings
A61K 31/519 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
A61P 19/02 - Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
A method for determining whether to administer a therapeutically effective amount of a receptor tyrosine kinase-inhibiting drug for tumor treatment, by determining a glucose uptake response in the tumor of a mammal. 18FDG-PET (2- deoxy-2-[18F]fluoro-D-glucose positron emission tomography imaging) is used as a predictive, non-invasive, pharmacodynamic biomarker of response following administration of drug.
Compounds of Formula (1), as shown below and defined herein: pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as tumors driven at least in part by TAK1 or for which an appropriate TAK1 inhibitor is effective. This Abstract is not limiting of the invention.
C07D 491/048 - Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
A61K 31/4355 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
Compounds of Formula 1, as shown below and defined herein:
and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers mediated at least in part by FAK.
C07D 413/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Compounds of Formula I, as shown below and defined herein: enriched in deuterium, and pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers mediated at least in part by IGF-1 R and/or IR.
A61K 31/53 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
Cancer therapy comprising treatment with an mTOR inhibitor, such as a dual mTORC1/mTORC2 inhibitor, such as OSI-027, in combination with an angiogenesis inhibitor.
A61K 31/53 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
A61K 39/395 - AntibodiesImmunoglobulinsImmune serum, e.g. antilymphocytic serum
35.
PROCESS FOR SUBSTITUTED 3-AMINO-5-OXO-4,5-DIHYDRO-[1,2,4]TRIAZINES
Processes including preparation of trans-4-[(3-amino-5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-carbamoyl]-cyclohexanecarboxylic acid methyl ester, and its conversion to trans-4-(4-amino-5-susbtituted-imidazo[5,1-ƒ][1,2,4]triazin-7-yl)-cyclohexanecarboxylic acid compounds.
C07D 403/04 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing two hetero rings directly linked by a ring-member-to-ring- member bond
Compounds of Formula (1), as shown below and defined herein: and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers mediated at least in part by FAK.
C07D 401/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
C07D 403/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links
C07D 403/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing three or more hetero rings
A process for preparing a compound of formula (I) or a salt thereof: (I) wherein R1 is H or optionally substituted aryl or heteroaryl; comprising reacting 2,3- dichloropyrazine with a suitable diaryl imine followed by hydrolysis.
C07D 401/06 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
39.
BIOLOGICAL MARKERS PREDICTIVE OF ANTI-CANCER RESPONSE TO EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITORS
The present invention provides diagnostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. These methods are based on the surprising discovery that the effectiveness of treatment with an EGFR kinase inhibitor is predicted by whether a patient's tumor cells express a high or a low level of the biomarkers vimentin and E-cadherin, such that patients whose tumors express a high level of at least one of the biomarkers vimentin and E-cadherin have a longer overall survival and progression free survival than patients whose tumors express a low level of both vimentin and E-cadherin. The present invention further provides a method for treating tumors or tumor metastases in a patient, comprising the steps of diagnosing a patient's likely responsiveness to an EGFR kinase inhibitor by assessing whether tumor cells express a high level of at least one of the biomarkers vimentin and E-cadherin, and administering to said patient a therapeutically effective amount of an EGFR kinase inhibitor (e.g. erlotinib), particularly when effectiveness of the inhibitor is predicted.
A method of treating cancer comprising: (a) identifying a patient having cancer that initially responded to IRS1 agent therapy and that has resumed progression; (b) administering an effective regimen comprising the same or a different IRS1 agent and an IGF-1 R inhibitor administered together or sequentially.
The invention provides methods of determining in situ the EMT status of the cells of a tumor in a patient in vivo, including :(a) providing an EMT-status-detecting conjugate containing an antibody that binds to an EMT-status biomarker, and a reporter molecule; (b) introducing the conjugate into a patient with a tumor, such that the conjugate contacts the EMT-status biomarker of of the cells of the tumor; (c) employing a means for detection of the signal from the conjugate at the tumor site; and (d) using a means for image analysis to localize and quantify the signal from the conjugate at the tumor site, a positive signal indicating the presence of epithelial tumor cells if the EMT-status biomarker is an epithelial biomarker, and mesenchymal tumor cells if the EMT-status biomarker is a mesenchymal biomarker. Such methods are useful for diagnosing patients who might benefit from treatment with drugs such as EGFR or IGF-IR kinase inhibitors, and for identifying and testing agents that inhibit tumor cells from undergoing an epithelial to mesenchymal transition. This invention also provides the above methods where an AFFIBOD Y® molecule that binds to an EMT-status biomarker is used instead of an antibody.
The present invention provides tumor cell preparations for use as models of the EMT process for use in the identification of anti-cancer agents, wherein said tumor cell preparations comprise cells of the epithelial tumor cell line H1650, which are stimulated by receptor ligands to induce EMT, or which have been engineered to inducibly express a protein that stimulates EMT. The present invention also provides methods of identifying potential anti-cancer agents by using such tumor cell preparations to identify agents that inhibit EMT, stimulate MET, or inhibit the growth of mesenchymal-like cells. Such agents should be particularly useful when used in conjunction with other anti-cancer drugs such as EGFR and IGF-1R kinase inhibitors, which appear to be less effective at inhibiting tumor cells that have undergone an EMT.
The present invention provides tumor cell preparations for use as models of the EMT process for use in the identification of anti-cancer agents, wherein said tumor cell preparations comprise cells of the epithelial tumor cell line H292, which are stimulated by receptor ligands to induce EMT, or which have been engineered to inducibly express a protein that stimulates EMT. The present invention also provides methods of identifying potential anti-cancer agents by using such tumor cell preparations to identify agents that inhibit EMT, stimulate MET, or inhibit the growth of mesenchymal-like cells. Such agents should be particularly useful when used in conjunction with other anti-cancer drugs such as EGFR and IGF-IR kinase inhibitors, which appear to be less effective at inhibiting tumor cells that have undergone an EMT.
The present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of a combination of either an anti-IGF-lR antibody or an IGF binding protein (e.g. IGFBP3), and a small molecule IGF-IR kinase inhibitor (e.g. OSI-906). The present invention also provides a pharmaceutical composition comprising either an anti-IGF-lR antibody or an IGF binding protein (e.g. IGFBP3), and a small molecule IGF-IR kinase inhibitor (e.g. OSI-906), with a pharmaceutically acceptable carrier.
The present invention provides tumor cell preparations for use as models of the EMT process for use in the identification of anti-cancer agents, wherein said tumor cell preparations comprise cells of the epithelial tumor cell line CFPAC-I, which are stimulated by receptor ligands to induce EMT, or which have been engineered to inducibly express a protein that stimulates EMT. The present invention also provides methods of identifying potential anti-cancer agents by using such tumor cell preparations to identify agents that inhibit EMT, stimulate MET, or inhibit the growth of mesenchymal-like cells. Such agents should be particularly useful when used in conjunction with other anti-cancer drugs such as EGFR and IGF-IR kinase inhibitors, which appear to be less effective at inhibiting tumor cells that have undergone an EMT.
The present invention provides a method for treating NSCL, pancreatic, colon or breast cancer tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of a combination of an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors, wherein the agent is an mTOR inhibitor, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy. The present invention also provides a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of a combination of an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors, wherein said agent is an mTOR inhibitor that binds to and directly inhibits both mTORC1 and mTORC2 kinases. The present invention also provides a pharmaceutical composition comprising an EGFR kinase inhibitor and an mTOR inhibitor that binds to and directly inhibits both mTORC1 and mTORC2 kinases, in a pharmaceutically acceptable carrier. A preferred example of an EGFR kinase inhibitor that can be used in practicing the methods of this invention is the compound erlotinib HCl (also known as TARCEVA®).
Fused pyridine-based bicyclic compounds having the structure of Formula I, as defined herein, pharmaceutically acceptable salts thereof, preparation, compositions, and disease treatment therewith. This abstract does not define or limit the invention.
C07D 403/04 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group containing two hetero rings directly linked by a ring-member-to-ring- member bond
A61K 31/4985 - Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
Methods and compositions for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially (a) a therapeutically effective amount of an anti-cancer agent and (b) an IGF1R inhibitor compound of Formula I, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy. Suitable IGF1R inhibitor may be represented by Formula I:
1 are defined herein.
A01N 43/64 - Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
A61K 31/53 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
A61K 31/495 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
49.
Combined treatment with cisplatin and an epidermal growth factor receptor kinase inhibitor
The present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of an EGFR kinase inhibitor and cisplatin combination, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy. The invention also encompasses a pharmaceutical composition that is comprised of an EGFR kinase inhibitor and cisplatin combination in combination with a pharmaceutically acceptable carrier. A preferred example of an EGFR kinase inhibitor that can be used in practicing this invention is the compound erlotinib HCl (also known as Tarceva™).
A61K 31/517 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
50.
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and monohydrate
The present invention relates to the anhydrous and hydrate forms of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate. The invention also relates to pharmaceutical compositions containing N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate and to methods of treating hyperproliferative disorders, such as cancer, by administering N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate.
A61K 31/517 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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