Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders

Abstract

Described herein are compositions and methods for using these compositions in the treatment of cancer, tumors, and tumor-related disorders in a subject.

What is claimed is: 
     
         1 . A method for treating a subject having cancer, comprising administering to the subject, a therapeutically effective amount of a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor or their respective pharmaceutically acceptable salt, solvate, polymorph or prodrug. 
     
     
         2 . The method of  claim 1  wherein the 1,2-diphenylpyrrole derivative has the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R is a hydrogen atom, a halogen atom or an alkyl group having from 1 to 6 carbon atoms; 
         R 1  is an alkyl group having from 1 to 6 carbon atoms or an amino group; 
         R 2  is a phenyl group which is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents α and substituents β; 
         R 3  is a hydrogen atom, a halogen atom or an alkyl group which has from 1 to 6 carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms; 
         R 4  is a hydrogen atom; an alkyl group which has from 1 to 6 carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms; a cycloalkyl group having from 3 to 8 carbon atoms, an aryl group; or an aralkyl group; said aryl group having from 6 to 14 ring carbon atoms in a carbocyclic ring and are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents α and substituents β; 
         said aralkyl group are an alkyl group having from 1 to 6 carbon atoms and which are substituted by at least one aryl group as defined above; 
         said substituents α are selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms; 
         said substituents β are selected from the group consisting of an alkyl group which has from 1 to 6 carbon atoms and which is unsubstituted or are substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms; an alkanoyloxy group having from 1 to 6 carbon atoms; a mercapto group; an alkanoylthio group having from 1 to 6 carbon atoms; an alkylsulfinyl group having from 1 to 6 carbon atoms; a cycloalkloxy group having from 3 to 8 carbon atoms; a haloalkoxy group having from 1 to 6 carbon atoms; and an alkylenedioxy group having from 1 to 6 carbon atoms; or a pharmaceutically acceptable salt, solvate, or prodrug. 
       
     
     
         3 . The method of  claim 2  wherein:
 R is a hydrogen atom, a halogen atom or an alkyl group having from 1 to 4 carbon atoms; 
 R 1  is a methyl group or an amino group; 
 R 2  is an unsubstituted phenyl group or a phenyl group which is substituted by at least one substituent selected from the group consisting of a halogen atom; an alkoxy group having from 1 to 4 carbon atoms; an alkylthio group having from 1 to 4 carbon atoms; an unsubstituted alkyl group having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4 carbon atoms and which is substituted by at least one substituent selected from the group consisting of a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and an alkylthio group having from 1 to 4 carbon atoms; a haloalkoxy group having from 1 to 4 carbon atoms; and an alkylenedioxy group having from 1 to 4 carbon atoms; 
 R 3  is a hydrogen atom, a halogen atom, an unsubstituted alkyl group having from 1 to 4 carbon atoms or a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one substituent selected from the group consisting of a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and an alkylthio group having from 1 to 4 carbon atoms; 
 R 4  is a hydrogen atom; an unsubstituted alkyl group having from 1 to 4 carbon atoms; a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and an alkylthio group having from 1 to carbon atoms; a cycloalkyl group having from 3 to 6 carbon atoms; an aryl group which has from 6 to 10 ring carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from the group consisting of a halogen atom; an alkoxy group having from 1 to 4 carbon atoms; an alkylthio group having from 1 to 4 carbon atoms; an unsubstituted alkyl group having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4 carbon atoms and substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and an alkylthio group having from 1 to 4 carbon atoms; and a cycloalkyloxy group having from 3 to 7 carbon atoms; an aralkyl group having from 1 to 4 carbon atoms in the alkyl part and containing at least one said aryl group; or a pharmaceutically acceptable salt, solvate, or prodrug. 
 
     
     
         4 . The method of  claim 3  wherein:
 R is a hydrogen atom; 
 R 1  is an amino group; 
 R 2  is an unsubstituted phenyl group or a phenyl group which is substituted by at least one substituent selected from the group consisting of a halogen atom, an alkoxy group having from 1 to 4 carbon atoms, an alkylthio group having from 1 to 4 carbon atoms, an alkyl group having from 1 to 4 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms, a haloalkoxy group having from 1 to 4 carbon atoms and a alkylenedioxy group having from 1 to 4 carbon atoms; 
 R 3  is a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms or a haloalkyl group having from 1 to 4 carbon atoms; 
 R 4  is a hydrogen atom; an unsubstituted alkyl group having from 1 to 4 carbon atoms; a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one substituent selected from the group consisting of a hydroxy group and an alkoxy group having from 1 to 4 carbon atoms; a cycloalkyl group having from 3 to 6 carbon atoms; an aryl group which has from 6 to 10 ring carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from the group consisting of a hydroxy group; a halogen atom; an alkoxy group having from 1 to 4 carbon atoms; an unsubstituted alkyl group having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4 carbon atoms and which is unsubstituted or substituted by at least one halogen atom; and a cycloalkyloxy group having from 3 to 7 carbon atoms; and an aralkyl group having from 1 to 4 carbon atoms in the alkyl part and containing at least one said aryl group; or a pharmaceutically acceptable salt, solvate, or prodrug. 
 
     
     
         5 . The method of  claim 4  wherein the 1,2-diphenylpyrrole derivative is selected from the group consisting of: 4-methyl-2-(4-methylphenyl)-1-(4-sulfamoylphenyl)pyrrole; 2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole; 2-(4-chlorophenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole; 4-methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylphenyl)pyrrole; 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole; 2-(4-methoxy-3-methylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole; 2-(3-fluoro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole; 2-(3,4-dimethylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole; 4-methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylphenyl)pyrrole; 1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(4-methoxyphenyl)pyrrole; and 1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(3,4-dimethylphenyl)pyrrole. 
     
     
         6 . The method of  claim 5  wherein the 1,2-diphenylpyrrole derivative is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole. 
     
     
         7 . The method of  claim 1  wherein the EGFR inhibitor is erlotinib. 
     
     
         8 . The method of  claim 1  wherein the 1,2-diphenylpyrrole derivative is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the EGFR inhibitor is erlotinib. 
     
     
         9 . The method of  claim 1  wherein the 1,2-diphenylpyrrole derivative and the EGFR inhibitor are administered sequentially in either order or simultaneously. 
     
     
         10 . The method of  claim 1  wherein the 1,2-diphenylpyrrole derivative is administered first. 
     
     
         11 . The method of  claim 1  wherein the EGFR inhibitor is administered first. 
     
     
         12 . The method of  claim 1  wherein administering the combination enhances treatment of the subject. 
     
     
         13 . The method of  claim 1  wherein administering the combination reduces the side effects of the treatment of cancer compared to a treatment of the EGFR inhibitor alone or a treatment of the 1,2-diphenylpyrrole derivative alone. 
     
     
         14 . The method of  claim 1  wherein administering the combination is through oral, parenteral, buccal, intranasal, epidural, sublingual, pulmonary, local, rectal, or transdermal administration. 
     
     
         15 . The method of  claim 14  wherein administering the combination is through parenteral administration. 
     
     
         16 . The method of  claim 15  wherein parenteral administration is intravenous, subcutaneous, intrathecal, or intramuscular. 
     
     
         17 . The method of  claim 14  wherein oral administration is in a single dosage form. 
     
     
         18 . The method of  claim 17  wherein the single dosage form enhances patient compliance and/or reduces pill burden. 
     
     
         19 . The method of  claim 17  wherein the single dosage form is a single capsule or a single tablet. 
     
     
         20 . The method of  claim 19  wherein the composition is a single tablet. 
     
     
         21 . The method of  claim 20  wherein the single tablet comprises from about 1 mg to about 1200 mg of 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and from about 25 mg to about 450 mg of erlotinib. 
     
     
         22 . The method of  claim 21  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 25 mg of erlotinib. 
     
     
         23 . The method of  claim 21  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 100 mg of erlotinib. 
     
     
         24 . The method of  claim 21  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 150 mg of erlotinib. 
     
     
         25 . The method of  claim 21  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 200 mg of erlotinib. 
     
     
         26 . The method of  claim 21  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 300 mg of erlotinib. 
     
     
         27 . The method of  claim 21  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 450 mg of erlotinib. 
     
     
         28 . The method of  claim 1  wherein the cancer is selected from the group consisting of: oral cancer, prostate cancer, rectal cancer, non-small cell lung cancer, lip and oral cavity cancer, liver cancer, lung cancer, anal cancer, kidney cancer, vulvar cancer, breast cancer, oropharyngeal cancer, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, urethra cancer, small intestine cancer, bile duct cancer, bladder cancer, ovarian cancer, laryngeal cancer, hypopharyngeal cancer, gallbladder cancer, colon cancer, colorectal cancer, head and neck cancer, parathyroid cancer, penile cancer, vaginal cancer, thyroid cancer, pancreatic cancer, esophageal cancer, Hodgkin's lymphoma, leukemia-related disorders, mycosis fungoides, and myelodysplastic syndrome. 
     
     
         29 . The method of  claim 28  wherein the cancer is non-small cell lung cancer, pancreatic cancer, breast cancer, ovarian cancer, colorectal cancer, and head and neck cancer. 
     
     
         30 . The method of  claim 1  wherein the cancer is a carcinoma, a tumor, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma, and a blastoma. 
     
     
         31 . The method of  claim 30  wherein the carcinoma is selected from the group consisting of: carcinoma, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adrenocortical carcinoma, well differentiated carcinoma, squamous cell carcinoma, serous carcinoma, small cell carcinoma, invasive squamous cell carcinoma, large cell carcinoma, islet cell carcinoma, oat cell carcinoma, squamous carcinoma, undifferentiatied carcinoma, verrucous carcinoma, renal cell carcinoma, papillary serous adenocarcinoma, merkel cell carcinoma, hepatocellular carcinoma, soft tissue carcinomas, bronchial gland carcinomas, capillary carcinoma, bartholin gland carcinoma, basal cell carcinoma, carcinosarcoma, papilloma/carcinoma, clear cell carcinoma, endometrioid adenocarcinoma, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, cholangiocarcinoma, actinic keratoses, cystadenoma, and hepatic adenomatosis. 
     
     
         32 . The method of  claim 30  wherein the tumor is selected from the group consisting of: astrocytic tumors, malignant mesothelial tumors, ovarian germ cell tumor, supratentorial primitive neuroectodermal tumors, Wilm's tumor, pituitary tumors, extragonadal germ cell tumor, gastrinoma, germ cell tumors, gestational trophoblastic tumor, brain tumors, pineal and supratentorial primitive neuroectodermal tumors, pituitary tumor, somatostatin-secreting tumor, endodermal sinus tumor, carcinoids, central cerebral astrocytoma, glucagonoma, hepatic adenoma, insulinoma, medulloepithelioma, plasmacytoma, vipoma, and pheochromocytoma. 
     
     
         33 . The method of  claim 30  wherein the neoplasm is selected from the group consisting of: intaepithelial neoplasia, multiple myeloma/plasma cell neoplasm, plasma cell neoplasm, interepithelial squamous cell neoplasia, endometrial hyperplasia, focal nodular hyperplasia, hemangioendothelioma, and malignant thymoma. 
     
     
         34 . The method of  claim 30  wherein the lymphoma is selected from the group consisting of: nervous system lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, non-Hodgkin's lymphoma, lymphoma, and Waldenstrom's macroglobulinemia. 
     
     
         35 . The method of  claim 30  wherein the melanoma is selected from the group consisting of: acral lentiginous melanoma, superficial spreading melanoma, uveal melanoma, lentigo maligna melanomas, melanoma, intraocular melanoma, adenocarcinoma nodular melanoma, and hemangioma. 
     
     
         36 . The method of  claim 30  wherein the sarcoma is selected from the group consisting of: adenomas, adenosarcoma, chondosarcoma, endometrial stromal sarcoma, Ewing's sarcoma, Kaposi's sarcoma, leiomyosarcoma, rhabdomyosarcoma, sarcoma, uterine sarcoma, osteosarcoma, and pseudosarcoma. 
     
     
         37 . The method of  claim 30  wherein the glioma is selected from the group consisting of: glioma, brain stem glioma, and hypothalamic and visual pathway glioma. 
     
     
         38 . The method of  claim 30  wherein the blastoma is selected from the group consisting of: pulmonary blastoma, pleuropulmonary blastoma, retinoblastoma, neuroblastoma, medulloblastoma, glioblastoma, and hemangiblastomas. 
     
     
         39 . The method of  claim 1  wherein the EGFR inhibitor is a small molecule compound or an antibody. 
     
     
         40 . The method of  claim 39  wherein the small molecule compound is selected from the group consisting of: ZM-254530, BIBX-1382, reveromycin A, gefitinib, CGP-57148, CGP-59326, 4-(3-chloro)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine, tyrphostin, PKI-166, PD 153035, EKB-569, and 4-(phenylamino)quinazolines, or their pharmaceutically acceptable salts, solvates, or prodrugs. 
     
     
         41 . The method of  claim 39  wherein the antibody is selected from the group consisting of: EGF receptor antibody, MR1scFvPE38KDEL MDX-447, MDX-210, MD-72000, MDX-260, wayne anti-EGFR Mabs, anti-EGFr Mab, anti-EGFr MAb, Genen anti-EGFR Mab, MAb DC-101, trastuzumab, anti-VEGF monoclonal, anti-EGFR-DM1 Ab. MAb 4D5, BAB-447, EMD-55900, EMD-6200, -82633, anti-EGFR Mab, MAb 4D5, cetuximab, anti-EGFr MAb, anti-flk-1, CCX, CCZ, anti-flk-1, AG-514, AG-568, nti-EGFR-DM1 Ab, MDX-447, TgDCC-E1A, C225, matuzurnab, panitumumab, DWP-408, and RC-3940II. 
     
     
         42 . The method of  claim 1  wherein the EGFR inhibitor is selected from the group consisting of: muellerian-inhibiting hormone, TNP-470, tecogalan sodium, EGF receptor antisense, PI-88, oligonucleotide, bromelain molecules, amphiregulin, EGF fusion toxin, EGF fusion protein, Amphiregulin hbEGF-toxin, hbEGF-toxin, and EGF fusion protein. 
     
     
         43 . A method of inducing differentiation of tumor cells, the method comprising contacting the cells with an effective amount of a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor whereby the combination induces differentiation of tumor cells. 
     
     
         44 . A method of inhibiting proliferation of cancer cells, the method comprising contacting a cancer cell with a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor whereby the combination inhibits proliferation of cancer cells. 
     
     
         45 . A method for reducing proliferation of cancer cells, the method comprising delivering to the cells a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor, whereby the reduction of cell proliferation is greater than a reduction caused by either a 1,2-diphenylpyrrole derivative alone or an EGFR inhibitor alone. 
     
     
         46 . A method of modulating autophosphorylation with a molecule of ATP, the method comprising delivering to a cancer cell an effective amount of a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the combination inhibits autophosphorylation with a molecule of ATP. 
     
     
         47 . A method of inhibiting metastases of tumor cells, the method comprising administering an effective amount of a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor such that the combination inhibits metastatic activity of tumor cells. 
     
     
         48 . A method for inducing apoptosis in cancer cells, the method comprising contacting the cancer cells with a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR kinase sufficient to induce apoptosis. 
     
     
         49 . A method for sensitizing EGFR inhibitor resistant cancer cells to an EGFR inhibitor, the method comprising administering a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the combination sensitizes the cancer cells to the EGFR inhibitor. 
     
     
         50 . A method of treating EGFR resistance in a cancer cell, the method comprising, administering a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor. 
     
     
         51 . A method of modulating prostaglandin synthesis in a cancer cell, the method comprising contacting the cell with a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the combination inhibits prostaglandin synthesis in a cancer cell. 
     
     
         52 . A method of modulating cyclooxygenase expression in a cancer cell, the method comprising delivering to the cell a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the combination inhibits cyclooxygenase expression in a cancer cell. 
     
     
         53 . A method of modulating angiogenesis in a cancer cell, the method comprising contacting the cell with a combination comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the combination inhibits angiogenesis in a cancer cell. 
     
     
         54 . A method of reducing the dosage in conventional treatment for neoplasia and/or neoplasia related disorders in a subject, the method comprising administering to a subject a combination of a 1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the combination reduces the dosage in conventional treatment for neoplasia and/or neoplasia-related disorders. 
     
     
         55 . A method of treating neoplasia and/or neoplasia related disorders, the method comprising administering a combination of a 1,2-diphenylpyrrole derivative and an EGFR inhibitor. 
     
     
         56 . A composition for treating cancer comprising, a combination of a 1,2-diphenylpyrrole derivative and an EGFR inhibitor or their respective pharmaceutically acceptable salt, solvate or prodrug. 
     
     
         57 . The composition of  claim 56  wherein the 1,2-diphenylpyrrole derivative has the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R is a hydrogen atom, a halogen atom or an alkyl group having from 1 to 6 carbon atoms; 
         R 1  is an alkyl group having from 1 to 6 carbon atoms or an amino group; 
         R 2  is a phenyl group which is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents α and substituents β; 
         R 3  is a hydrogen atom, a halogen atom or an alkyl group which has from 1 to 6 carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms; 
         R 4  is a hydrogen atom; an alkyl group which has from 1 to 6 carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms; a cycloalkyl group having from 3 to 8 carbon atoms, an aryl group; or an aralkyl group; said aryl group having from 6 to 14 ring carbon atoms in a carbocyclic ring and are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents α and substituents β; 
         said aralkyl group are an alkyl group having from 1 to 6 carbon atoms and which are substituted by at least one aryl group as defined above; 
         said substituents α are selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms; 
         said substituents β are selected from the group consisting of an alkyl group which has from 1 to 6 carbon atoms and which is unsubstituted or are substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms; an alkanoyloxy group having from 1 to 6 carbon atoms; a mercapto group; an alkanoylthio group having from 1 to 6 carbon atoms; an alkylsulfinyl group having from 1 to 6 carbon atoms; a cycloalkloxy group having from 3 to 8 carbon atoms; a haloalkoxy group having from 1 to 6 carbon atoms; and an alkylenedioxy group having from 1 to 6 carbon atoms; or a pharmaceutically acceptable salt, solvate, or prodrug. 
       
     
     
         58 . The composition of  claim 57  wherein the 1,2-diphenylpyrrole derivative has the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R is a hydrogen atom, a halogen atom or an alkyl group having from 1 to 4 carbon atoms; 
         R 1  is a methyl group or an amino group; 
         R 2  is an unsubstituted phenyl group or a phenyl group which is substituted by at least one substituent selected from the group consisting of a halogen atom; an alkoxy group having from 1 to 4 carbon atoms; an alkylthio group having from 1 to 4 carbon atoms; an unsubstituted alkyl group having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4 carbon atoms and which is substituted by at least one substituent selected from the group consisting of a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and an alkylthio group having from 1 to 4 carbon atoms; a haloalkoxy group having from 1 to 4 carbon atoms; and an alkylenedioxy group having from 1 to 4 carbon atoms; 
         R 3  is a hydrogen atom, a halogen atom, an unsubstituted alkyl group having from 1 to 4 carbon atoms or a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one substituent selected from the group consisting of a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and an alkylthio group having from 1 to 4 carbon atoms; 
         R 4  is a hydrogen atom; an unsubstituted alkyl group having from 1 to 4 carbon atoms; a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and an alkylthio group having from 1 to carbon atoms; a cycloalkyl group having from 3 to 6 carbon atoms; an aryl group which has from 6 to 10 ring carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from the group consisting of a halogen atom; an alkoxy group having from 1 to 4 carbon atoms; an alkylthio group having from 1 to 4 carbon atoms; an unsubstituted alkyl group having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4 carbon atoms and substituted by at least one substituent selected from the group consisting of a hydroxy group, a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and an alkylthio group having from 1 to 4 carbon atoms; and a cycloalkyloxy group having from 3 to 7 carbon atoms; an aralkyl group having from 1 to 4 carbon atoms in the alkyl part and containing at least one said aryl group; or a pharmaceutically acceptable salt, solvate, or prodrug. 
       
     
     
         59 . The composition of  claim 57  wherein the 1,2-diphenylpyrrole derivative has the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R is a hydrogen atom; 
         R 1  is an amino group; 
         R 2  is an unsubstituted phenyl group or a phenyl group which is substituted by at least one substituent selected from the group consisting of a halogen atom, an alkoxy group having from 1 to 4 carbon atoms, an alkylthio group having from 1 to 4 carbon atoms, an alkyl group having from 1 to 4 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms, a haloalkoxy group having from 1 to 4 carbon atoms and a alkylenedioxy group having from 1 to 4 carbon atoms; 
         R 3  is a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms or a haloalkyl group having from 1 to 4 carbon atoms; 
         R 4  is a hydrogen atom; an unsubstituted alkyl group having from 1 to 4 carbon atoms; a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one substituent selected from the group consisting of a hydroxy group and an alkoxy group having from 1 to 4 carbon atoms; a cycloalkyl group having from 3 to 6 carbon atoms; an aryl group which has from 6 to 10 ring carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from the group consisting of a hydroxy group; a halogen atom; an alkoxy group having from 1 to 4 carbon atoms; an unsubstituted alkyl group having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4 carbon atoms and which is unsubstituted or substituted by at least one halogen atom; and a cycloalkyloxy group having from 3 to 7 carbon atoms; and an aralkyl group having from 1 to 4 carbon atoms in the alkyl part and containing at least one said aryl group; or a pharmaceutically acceptable salt, solvate, or prodrug. 
       
     
     
         60 . The composition of  claim 59  wherein the 1,2-diphenylpyrrole derivative is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole. 
     
     
         61 . The composition of  claim 56  wherein the EGFR inhibitor is erlotinib. 
     
     
         62 . The composition of  claim 56  wherein the 1,2-diphenylpyrrole derivative is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the EGFR inhibitor is erlotinib. 
     
     
         63 . The composition of  claim 56  wherein the composition is a single dosage form. 
     
     
         64 . The composition of  claim 63  wherein the single dosage form enhances patient compliance and/or reduces pill burden. 
     
     
         65 . The composition of  claim 62  wherein the combination is in an oral, parenteral, buccal, intranasal, epidural, sublingual, pulmonary, local, rectal, or transdermal form. 
     
     
         66 . The composition of  claim 65  wherein the combination is in the parenteral form. 
     
     
         67 . The composition of  claim 66  wherein the parenteral form is intravenous, subcutaneous, intrathecal, or intramuscular. 
     
     
         68 . The composition of  claim 63  wherein the single dosage form is a single capsule or a single tablet. 
     
     
         69 . The composition of  claim 68  wherein the composition is a single tablet. 
     
     
         70 . The composition of  claim 69  wherein the single tablet comprises from about 1 mg to about 1200 mg of 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and from about 25 mg to about 450 mg of erlotinib. 
     
     
         71 . The composition of  claim 70  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 25 mg of erlotinib. 
     
     
         72 . The composition of  claim 70  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 100 mg of erlotinib. 
     
     
         73 . The composition of  claim 70  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 150 mg of erlotinib. 
     
     
         74 . The composition of  claim 70  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 200 mg of erlotinib. 
     
     
         75 . The composition of  claim 70  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 300 mg of erlotinib. 
     
     
         76 . The composition of  claim 70  wherein the single tablet comprises from about 1 mg to about 1200 mg 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about 450 mg of erlotinib. 
     
     
         77 . The composition of  claim 70  wherein the composition is suitable for once-daily administration. 
     
     
         78 . The composition of  claim 56  wherein the EGFR inhibitor is a small molecule compound or an antibody. 
     
     
         79 . The composition of  claim 78  wherein the small molecule compound is selected from the group consisting of: ZM-254530, BIBX-1382, reveromycin A, gefitinib, CGP-57148, CGP-59326, 4-(3-chloro)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine, tyrphostin, PKI-166, PD 153035, EKB-569, and 4-(phenylamino)quinazolines, or their pharmaceutically acceptable salts, solvates, or prodrugs. 
     
     
         80 . The composition of  claim 78  wherein the antibody is selected from the group consisting of:
 EGF receptor antibody, MR1scFvPE38 KDEL MDX-447, MDX-210, MD-72000, MDX-260, wayne anti-EGFR Mabs, anti-EGFr Mab, anti-EGFr MAb, Genen anti-EGFR Mab, MAb DC-101, trastuzumab, anti-VEGF monoclonal, anti-EGFR-DM1 Ab, MAb 4D5, BAB-447, EMD-55900, EMD-6200, -82633, anti-EGFR Mab, MAb 4D5, cetuximab, anti-EGFr MAb, anti-flk-1, CCX, CCZ, anti-flk-1, AG-514, AG-568, nti-EGFR-DM1 Ab, MDX-447, TgDCC-E1A, C225, matuzumab, panitumumab, DWP-408, and RC-3940II. 
 
     
     
         81 . The composition of  claim 56  wherein the composition contains a lower dose of EGFR inhibitor than a conventional treatment for cancer. 
     
     
         82 . The composition of  claim 56  wherein the composition reduces the side effects of the treatment of cancer. 
     
     
         83 . The composition of  claim 56  wherein the composition enhances treatment of cancer. 
     
     
         84 . A pharmaceutical composition for treating cancer comprising, a combination of a 1,2-diphenylpyrrole derivative and an EGFR inhibitor, and a pharmaceutically acceptable excipient or carrier. 
     
     
         85 . The pharmaceutical composition of  claim 84  wherein the 1,2-diphenylpyrrole derivative is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole. 
     
     
         86 . The pharmaceutical composition of  claim 84  wherein the EGFR inhibitor is erlotinib. 
     
     
         87 . The pharmaceutical composition of  claim 84  wherein the 1,2-diphenylpyrrole derivative is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the EGFR inhibitor is erlotinib. 
     
     
         88 . A kit for treating cancer comprising a single dosage form comprising a combination of a 1,2-diphenylpyrrole derivative and an EGFR inhibitor and instructions on how to administer the dosage form. 
     
     
         89 . The kit of  claim 88  wherein the 1,2-diphenylpyrrole derivative is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the EGFR inhibitor is erlotinib. 
     
     
         90 . The method of  claim 6  further comprising administering to the subject one or more therapies in addition to the combination of 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the EGFR inhibitor. 
     
     
         91 . The method of  claim 90  wherein the one or more therapies comprise one or more of surgery, radiation therapy, chemotherapy, high dose chemotherapy with stem cell transplant; hormone therapy, and monoclonal antibody therapy. 
     
     
         92 . The method of  claim 91  wherein radiation therapy comprises internal and/or external radiation therapy. 
     
     
         93 . The method of  91  wherein the chemotherapy comprises administering to the subject gemcitabine. 
     
     
         94 . A method for treating a subject having cancer, comprising administering to the subject, a therapeutically effective amount of a combination comprising 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, erlotinib and gemcitabine, or their respective pharmaceutically acceptable salt, solvate, polymorph or prodrug. 
     
     
         95 . The method of  claim 94  wherein the 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole is administered at a dose of 100-1200 mg per day, the erlotinib is administered at a dose of 50-250 mg per day, and the gemcitabine is administered at a dose of 500-1500 mg per meter squared of body surface area per weekly intravenous administration. 
     
     
         96 . The method of  claim 95  wherein the 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole is administered at a dose of 400 mg per day, the erlotinib is administered at a dose of 100 mg per day, and the gemcitabine is administered at a dose of 1000 mg per meter squared of body surface area per weekly intravenous administration. 
     
     
         97 . The method of  claim 95  wherein the 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole is administered at a dose of 400 mg per day, the erlotinib is administered at a dose of 150 mg per day, and the gemcitabine is administered at a dose of 1000 mg per meter squared of body surface area per weekly intravenous administration.