Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors

Abstract

The present invention provides diagnostic methods for predicting the effectiveness of treatment of a cancer patient with an IGF-1R kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an IGF-1R kinase inhibitor, comprising assessing whether the tumor cell expresses certain sensitivity or resistance biomarkers, or genomic classifiers. Improved methods for treating cancer patients with IGF-1R kinase inhibitors that incorporate this methodology are also provided.

1 . A method of predicting whether a cancer patient is afflicted with a tumor that will respond effectively to treatment with an IGF-1R kinase inhibitor, comprising:
 obtaining a sample of the patient's tumor;   assessing the level of a sensitivity biomarker expressed by cells of the tumor;   
       determining whether said level is statistically more similar to the level of the same sensitivity biomarker of tumor cells that are known to be sensitive to the IGF-1R kinase inhibitor or to the level of the same sensitivity biomarker of tumor cells that are known to be resistant to the IGF-1R kinase inhibitor; and
 predicting that the tumor will respond effectively to treatment with an IGF-1R kinase inhibitor if the level of the sensitivity biomarker is statistically more similar to the level of the sensitivity biomarker of tumor cells that are known to be sensitive to the IGF-1R kinase inhibitor, 
 wherein the sensitivity biomarker is selected from aldehyde dehydrogenase 1 family, member A1 (ALDH1A1, GeneID: 216); ring finger protein 128 (RNF128, GeneID: 79589); mitogen-activated protein kinase kinase 6 (MAP2K6, GeneID: 5608); quinolinate phosphoribosyltransferase (nicotinate-nucleotide pyrophosphorylase (carboxylating)) (QPRT, GeneID: 23475); interleukin 15 (IL15, GeneID: 3600); phospholipase D1, phosphatidylcholine-specific (PLD1, GeneID: 5337); hypothetical protein LOC157860 (LOC157860, GeneID: 157860); Muscleblind-like 2 ( Drosophila ) (MBNL2, GeneID: 10150); TBC1 domain family, member 8B (with GRAM domain) (TBC1D8B, GeneID: 54885); Galactokinase 2 (GALK2, GeneID: 2585); UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 4 (GalNAc-T4) (GALNT4, GeneID: 8693); PAN3 polyA specific ribonuclease subunit homolog ( S. cerevisiae ) (PAN3, GeneID: 255967); dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2, GeneID: 8445); pellino homolog 2 ( Drosophila ) (PELI2, GeneID: 57161); phosphoinositide-3-kinase, regulatory subunit 1 (p85 alpha) (PIK3R1, GeneID: 5295); phosphoglucomutase 2-like 1 (PGM2L1, GeneID: 283209); phosphorylase kinase, beta (PHKB, GeneID: 5257); Hypothetical protein LOC644009 (LOC644010, GeneID: 644010); CDC14 cell division cycle 14 homolog B ( S. cerevisiae )///CDC14 cell division cycle 14 homolog B ( S. cerevisiae ) (CDC14B, GeneID: 8555); hypothetical protein LOC128977 (C22orf39, GeneID: 128977); solute carrier family 44, member 1 (SLC44A1, GeneID: 23446); hypothetical protein LOC202451 (LOC202451, GeneID: 202451); transmembrane protein 164///similar to hypothetical protein FLJ22679 (TMEM164, GeneID: 84187); similar to cervical cancer suppressor-1 (ST20, GeneID: 400410 (also known as LOC400410)); hypothetical protein FLJ30596 (C5orf33, GeneID: 133686); lysosomal-associated membrane protein 2 (LAMP2, GeneID: 3920); protein phosphatase 1B (formerly 2C), magnesium-dependent, beta isoform (PPM1B, GeneID: 5495); Dehydrogenase/reductase (SDR family) member 3 (DHRS3, GeneID: 9249); Leucine zipper and CTNNBIP1 domain containing (LZIC, GeneID: 84328); ubiquitin specific peptidase like 1 (USPL1, GeneID: 10208); golgi autoantigen, golgin subfamily b, macrogolgin (with transmembrane signal), 1 (GOLGB1, GeneID: 2804); chromosome 20 open reading frame 74 (C20orf74, GeneID: 57186); Coiled-coil domain containing 52 (CCDC52, GeneID: 152185); RAB40B, member RAS oncogene family (RAB40B, GeneID: 10966); frequently rearranged in advanced T-cell lymphomas 2 (FRAT2, GeneID: 23401); hsa-miR-224 (GeneID: 407009); hsa-miR-181a (GeneID: 406995); hsa-miR-194 (GeneID: 406969, 406970); hsa-miR-192 (GeneID: 406967); hsa-miR-215 (GeneID: 406997); hsa-miR-200b (GeneID:); hsa-miR-429 (GeneID: 554210); hsa-miR-200a (GeneID: 406983); hsa-miR-192* (GeneID: 406967); hsa-miR-200b* (GeneID: 406984); and hsa-miR-584 (GeneID: 693169). 
 
     
     
         2 . The method of  claim 1 , wherein the IGF-1R kinase inhibitor is a small molecule kinase inhibitor 
     
     
         3 . The method of  claim 1 , wherein the IGF-1R kinase inhibitor is OSI-906. 
     
     
         4 . The method of  claim 1 , wherein the IGF-1R kinase inhibitor is an anti-IGF-1R antibody. 
     
     
         5 . A method of treating a cancer patient with an IGF-1R kinase inhibitor, comprising:
 predicting whether the patient is afflicted with a tumor that will respond effectively to treatment with an IGF-1R kinase inhibitor, by:   obtaining a sample of the patients tumor;   assessing the level of a sensitivity biomarker expressed by cells of the tumor;   determining whether said level is statistically more similar to the level of the same sensitivity biomarker of tumor cells that are known to be sensitive to the IGF-1R kinase inhibitor or to the level of the same sensitivity biomarker of tumor cells that are known to be resistant to the IGF-1R kinase inhibitor; and   predicting that the tumor will respond effectively to treatment with an IGF-1R kinase inhibitor if the level of the sensitivity biomarker is statistically more similar to the level of the sensitivity biomarker of tumor cells that are known to be sensitive to the IGF-1R kinase inhibitor; and   treating the patient with a therapeutically effective amount of an IGF-1R kinase inhibitor if the patient is afflicted with a tumor that is predicted to respond effectively to treatment with an IGF-1R kinase inhibitor;   wherein the sensitivity biomarker is selected from aldehyde dehydrogenase 1 family, member A1 (ALDH1A1, GeneID: 216); ring finger protein 128 (RNF128, GeneID: 79589); mitogen-activated protein kinase kinase 6 (MAP2K6, GeneID: 5608); quinolinate phosphoribosyltransferase (nicotinate-nucleotide pyrophosphorylase (carboxylating)) (QPRT, GeneID: 23475); interleukin 15 (IL15, GeneID: 3600); phospholipase D1, phosphatidylcholine-specific (PLD1, GeneID: 5337); hypothetical protein LOC157860 (LOC157860, GeneID: 157860); Muscleblind-like 2 ( Drosophila ) (MBNL2, GeneID: 10150); TBC1 domain family, member 8B (with GRAM domain) (TBC1D8B, GeneID: 54885); Galactokinase 2 (GALK2, GeneID: 2585); UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 4 (GalNAc-T4)(GALNT4, GeneID: 8693); PAN3 polyA specific ribonuclease subunit homolog ( S. cerevisiae ) (PAN3, GeneID: 255967); dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2, GeneID: 8445); pellino homolog 2 ( Drosophila ) (PELI2, GeneID: 57161); phosphoinositide-3-kinase, regulatory subunit 1 (p85 alpha) (PIK3R1, GeneID: 5295); phosphoglucomutase 2-like 1 (PGM2L1, GeneID: 283209); phosphorylase kinase, beta (PHKB, GeneID: 5257); Hypothetical protein LOC644009 (LOC644010, GeneID: 644010); CDC14 cell division cycle 14 homolog B ( S. cerevisiae )///CDC14 cell division cycle 14 homolog B ( S. cerevisiae ) (CDC14B, GeneID: 8555); hypothetical protein LOC128977 (C22orf39, GeneID: 128977); solute carrier family 44, member 1 (SLC44A1, GeneID: 23446); hypothetical protein LOC202451 (LOC202451, GeneID: 202451); transmembrane protein 164///similar to hypothetical protein FLJ22679 (TMEM164, GeneID: 84187); similar to cervical cancer suppressor-1 (ST20, GeneID: 400410 (also known as LOC400410)); hypothetical protein FLJ30596 (C5orf33, GeneID: 133686); lysosomal-associated membrane protein 2 (LAMP2, GeneID: 3920); protein phosphatase 1B (formerly 2C), magnesium-dependent, beta isoform (PPM1B, GeneID: 5495); Dehydrogenase/reductase (SDR family) member 3 (DHRS3, GeneID: 9249); Leucine zipper and CTNNBIP1 domain containing (LZIC, GeneID: 84328); ubiquitin specific peptidase like 1 (USPL1, GeneID: 10208); golgi autoantigen, golgin subfamily b, macrogolgin (with transmembrane signal), 1 (GOLGB1, GeneID: 2804); chromosome 20 open reading frame 74 (C20orf74, GeneID: 57186); Coiled-coil domain containing 52 (CCDC52, GeneID: 152185); RAB40B, member RAS oncogene family (RAB40B, GeneID: 10966); frequently rearranged in advanced T-cell lymphomas 2 (FRAT2, GeneID: 23401); hsa-miR-224 (GeneID: 407009); hsa-miR-181a (GeneID: 406995); hsa-miR-194 (GeneID: 406969, 406970); hsa-miR-192 (GeneID: 406967); hsa-miR-215 (GeneID: 406997); hsa-miR-200b (GeneID:); hsa-miR-429 (GeneID: 554210); hsa-miR-200a (GeneID: 406983); hsa-miR-192* (GeneID: 406967); hsa-miR-200b* (GeneID: 406984); and hsa-miR-584 (GeneID: 693169).   
     
     
         6 . The method of  claim 6 , wherein the IGF-1R kinase inhibitor is a small molecule kinase inhibitor. 
     
     
         7 . The method of  claim 7 , wherein the IGF-1R kinase inhibitor is OSI-906. 
     
     
         8 . The method of  claim 5 , wherein the IGF-1R kinase inhibitor is an anti-IGF-1R antibody.