Methods for treating drug resistant cancers

Abstract

Provided are methods for determining whether a glioblastoma (GBM) tumor or GBM cancer cell will be sensitive to a treatment targeting the integrin avb3 (αvβ3) pathway, comprising determining whether the GBM tumor or the GBM cancer cell expresses both avb3+ and Glut3+ along with a specific genetic signature associated with Glut3 addiction, where in alternative embodiments a cell is Glut3 addiction if the GBM tumor or the GBM cancer cell has markers consistent with the Classical or the Proneural molecular subtypes of GBM, or, expresses markers consistent with a Glut3-addicted molecular signature, e.g., as listed in FIG. 11 or FIG. 23 . Also provided herein are methods of treating glioblastoma (GBM) tumors found to be sensitive to agents targeting or inhibiting the integrin avb3 (αvβ3) pathway, wherein the sensitivity is determined by methods as provided herein.

1 . A method for determining whether a tumor or a cancer cell will be sensitive to or can be killed or induced to senescence by a treatment targeting the integrin avb3 (αvβ3) pathway, comprising:
 (a) determining or having determined whether the tumor or the cancer cell expresses both avb3+ and Glut3+, or determining whether the tumor or the cancer cell is a avb3+/Glut3+ tumor or cancer cell, and 
 (b) determining or having determined whether the tumor or the cancer cell is Glut-3 addicted. 
 
     
     
         2 . The method of  claim 1 , wherein the treatment targeting the integrin avb3 (αvβ3) pathway targets avb3, Glut3, PAK4, or YAP/TAZ. 
     
     
         3 . The method of  claim 2 , wherein the treatment comprises administering or having administered to an individual in need thereof cilengitide (or, 2-[(2S,5R,8S,11S)-5-benzyl-11-{3-[(diaminomethylidene)amino]propyl}-7-methyl-3,6,9,12,15-pentaoxo-8-(propan-2-yl)-1,4,7,10,13-pentaazacyclopentadecan-2-yl]acetic acid). 
     
     
         4 . The method of  claim 1 , wherein the determining or having determined if the tumor or the cancer cell expresses both avb3+ and Glut3+ comprises determining if the tumor or the cancer cell expresses both an avb3+ and a Glut3+ protein, or both an avb3+ and a Glut3+ message (mRNA, transcript), or both an avb3+ and a Glut3+ protein and message. 
     
     
         5 . The method of  claim 1 , wherein the determining or having determined if the tumor or the cancer cell expresses a marker consistent with a Classical or Proneural subtype or has a Glut3 addicted gene/molecular signature, optionally expressing at least one of the genes at levels as listed in  FIG. 11  or  FIG. 23 , comprises determining or having determined if the tumor or the cancer cell expresses an mRNA and/or a protein consistent with a Classical or a Proneural subtype, or has a Glut3 addicted gene/molecular signature,
 optionally expressing an mRNA or protein from a gene as listed in  FIG. 11  or  FIG. 23 . 
 
     
     
         6 . The method of  claim 1 , wherein the determining or having determined if the tumor or the cancer cell expresses both avb3+ and Glut3+ comprises taking or isolating a cell or a sample of cells, optionally cancer cells or tumors cells, from a patient, optionally a patient tentatively diagnosed or definitely diagnosed with the tumor or cancer, optionally GBM, and determining if the cell or sample of cells expresses both avb3+ and Glut3+ and is Glut-3 addicted. 
     
     
         7 . A method for treating or ameliorating, or killing, or inducing into senescence, a tumor or a cancer cell in a patient or ex vivo, wherein optionally the tumor or cancer cell is a glioblastoma (GBM) tumor or a GBM cancer cell, or a melanoma or a primitive neuroectodermal tumor (PNET), or treating or ameliorating a tumor or cancer, optionally GBM, a melanoma or a primitive neuroectodermal tumor (PNET), in an individual in need thereof, comprising:
 (a) determining or having determined whether the tumor or cancer, optionally a glioblastoma (GBM) tumor or a GBM cancer cell, will be sensitive to a treatment targeting the integrin avb3 (αvβ3) pathway using a method of  claim 1 , and   (b) if the method of step (a) determines, or has had determined, that the tumor or cancer, optionally a glioblastoma (GBM) tumor or a GBM cancer cell, will be sensitive to a treatment targeting the integrin avb3 (αvβ3) pathway, administering or having administered the treatment targeting the integrin avb3 (αvβ3) pathway to an individual in need thereof, or,   administering or having administered the treatment to the tumor or cancer cell, optionally to a glioblastoma (GBM) tumor or GBM cancer cell, if the tumor or cancer cell is derived from or isolated from the individual in need thereof, or if the tumor or cancer cell is determined to be sensitive to a treatment targeting the integrin avb3 (αvβ3) pathway using a method of  claim 1  (e.g., if the glioblastoma (GBM) tumor or the GBM cancer cell is found to express both avb3+ and Glut3+ and is Glut-3 addicted).   
     
     
         8 . The method of  claim 7 , wherein the treatment targets avb3, Glut3, PAK4, or YAP/TAZ. 
     
     
         9 . The method of  claim 7 , wherein the treatment comprises administering or having administered to an individual in need thereof cilengitide (or, 2-[(2S,5R,8S,11S)-5-benzyl-11-{3-[(diaminomethylidene)amino]propyl}-7-methyl-3,6,9,12,15-pentaoxo-8-(propan-2-yl)-1,4,7,10,13-pentaazacyclopentadecan-2-yl]acetic acid). 
     
     
         10 . The method of  claim 1 , wherein determining or having determined whether the tumor or the cancer cell is Glut-3 addicted comprises:
 (i) determining or having determined whether the tumor or the cancer cell expresses a marker consistent with a Classical or Proneural subtype, or determining or having determined whether the tumor or the cancer cell expresses a marker consistent with the Classical or Proneural molecular subtypes of GBM, or   (ii) determining or having determined whether the tumor or the cancer cell expresses a marker consistent with a Glut3 addicted gene signature.   
     
     
         11 . The method of  claim 10 , wherein the marker comprises an mRNA or a protein. 
     
     
         12 . The method of  claim 10 , wherein the marker consistent with a Classical or Proneural subtype comprises an EGFR, GLI1, NES, DLL3 or OLIG2 gene transcript or an EGFR, GLI1, NES, DLL3 or OLIG2 protein. 
     
     
         13 . The method of  claim 10 , wherein gene expression consistent with a Glut3 addicted gene signature comprises gene expression consistent with a high or a Glut3 addicted signature, or a low or a Glut3 non-addicted signature expression, of at least one of the genes, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or all 30 of the genes, as listed in  FIG. 11  or  FIG. 23 , or optionally all of the genes listed in  FIG. 11  or  FIG. 23 . 
     
     
         14 . The method of  claim 10 , wherein if a tumor or a cancer cell expresses both avb3+ and Glut3+ and is Glut-3 addicted, the tumor or the cancer cell will be sensitive to, or will be substantially sensitive to, or will be successfully treated by, or can be killed or induced to senescence by, the treatment targeting the integrin avb3 (αvβ3) pathway. 
     
     
         15 . The method of  claim 10 , wherein the tumor or cancer cell is a glioblastoma (GBM) tumor or cell, a melanoma tumor or melanoma cell or a primitive neuroectodermal tumor (PNET) or PNET cell. 
     
     
         16 . The method of  claim 4 , wherein the determining or having determined if the tumor or the cancer cell expresses both an avb3+ and a Glut3+ protein is by a method comprising use of antibodies that specifically bind to a protein of the integrin avb3 pathway, optionally comprising an avb3, Glut3, PAK4, or YAP/TAZ binding antibody (an antibody that specifically binds avb3, Glut3, PAK4, or YAP/TAZ). 
     
     
         17 . The method of  claim 4 , wherein the determining or having determined if the tumor or the cancer cell expresses both an avb3+ and a Glut3+ message, mRNA, or transcript is by a method comprising use of a polymerase chain reaction (PCR); or, gene expression profiling, an array, or a probe hybridization to a message, optionally a Northern blot,
 optionally the PCR comprises use of primers capable of amplifying an avb3+ and a Glut3+ message,   and optionally comprising use of primers capable of specifically hybridizing to an avb3+ and a Glut3+ message.   
     
     
         18 . The method of  claim 5 , wherein the determining or having determined if the tumor or the cancer cell expresses a protein consistent with a Classical or a Proneural subtype, or has a Glut3 addicted gene/molecular signature, optionally expressing a protein from a gene as listed in  FIG. 11  or  FIG. 23 , is by a method comprising use of antibodies that specifically bind to a protein consistent with a Classical or a Proneural subtype, or a protein from a gene as listed in  FIG. 11  or  FIG. 23 . 
     
     
         19 . The method of  claim 5 , wherein the determining or having determined if the tumor or the cancer cell expresses a message (mRNA, transcript) consistent with a Classical or a Proneural subtype, or has a Glut3 addicted gene/molecular signature, optionally expressing an mRNA from a gene as listed in  FIG. 11  or  FIG. 23 , is by a method comprising use of a polymerase chain reaction (PCR); or,
 by gene expression profiling, optionally by using an array, or optionally by using a probe hybridization to a message of interest, optionally a Northern blot, 
 optionally comprising use of primers capable of specifically hybridizing to: a message, mRNA or transcript consistent with a Classical or a Proneural subtype, or optionally an mRNA from a gene as listed in  FIG. 11  or  FIG. 23 . 
 
     
     
         20 . The method of  claim 19 , wherein the PCR comprises use of primers capable of amplifying a message, mRNA or transcript consistent with a Classical or a Proneural subtype, or has a Glut3 addicted gene/molecular signature, optionally an mRNA from a gene as listed in  FIG. 11  or  FIG. 23