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(12) Patent Application Publication (10) Pub. No.: US 2013/0230511 A1 HEYMACH Et Al US 2013 0230511A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0230511 A1 HEYMACH et al. (43) Pub. Date: Sep. 5, 2013 (54) BIOMARKERS FOR RESPONSE TO Publication Classification TYROSINE KNASE PATHWAY INHIBITORS IN CANCER (51) Int. Cl. GOIN33/74 (2006.01) (71) Applicant: Board of Regents, The University of A 6LX39/395 (2006.01) Texas System, (US) A613 L/506 (2006.01) A613 L/4439 (2006.01) (72) Inventors: John V. HEYMACH, Pearland, TX CI2O I/68 (2006.01) (US); Ignacio I. WISTUBA, Houston, A613 L/4045 (2006.01) TX (US); Monique B. NILSSON, Sugar (52) U.S. Cl. Land, TX (US); Lauren A. BYERS, CPC .............. G0IN33/74 (2013.01); C12O 1/6886 Houston, TX (US); Ximing TANG, (2013.01); A61 K3I/4045 (2013.01); A61 K Houston, TX (US); Fei YANG, Houston, 3 1/506 (2013.01); A61 K3I/4439 (2013.01): TX (US); Edward KIM, Houston, TX A6IK39/39558 (2013.01) (US); Anne S. TSAO, Houston, TX USPC ...... 424/133.1: 435/7.23; 435/6.11: 514/.414: (US); Scott M. LIPPMAN, Houston, 514/252.18; 514/338 TX (US); Waun Ki HONG, Houston, TX (US); Roy S. HERBST, Houston, TX (US) (57) ABSTRACT (73) Assignee: BOARD OF REGENTS, THE Copy number gains detected in tumors and associated with UNIVERSITY OF TEXAS SYSTEM, drug sensitivity and resistance in vivo and in vitro can be used Austin, TX (US) as biomarkers to select, predict and monitor drug treatment outcomes in cancer patients treated with tyrosine kinase (21) Appl. No.: 13/758,728 inhibitors. Methods to identify patients with NSCLC or other malignancies who are more likely to benefit from tyrosine (22) Filed: Feb. 4, 2013 kinase inhibitors Such as VEGF or VEGFR inhibitors when O O used either as monotherapy or in combination with other Related U.S. Application Data therapies such as chemotherapy or EGFR inhibitors, and who (60) Provisional application No. 61/594,800, filed on Feb. are in the advanced stages of disease and/or who have under 3, 2012. gone adjuvant therapy are also provided herein. Patent Application Publication Sep. 5, 2013 Sheet 1 of 14 US 2013/0230511 A1 & is: - Kof sesssssssss x 3. a 3. 3. aw w w w w w w www. 3. s: : g : 8s s : 8. 3. 3. x : : s 3. & & :8 : : - v 8 : 8 s 8& ;3 : & 3. XXX83. x - 3. x 3. x's w 3. w 3. & K - a w'''''''''' ' ' ' ' a'a 's 888 & 8 8888 . 3. ; : .333& : -...----. 3. * {88: Rif (x:y 8::::::38: 8.8 x:y 8:::::::::. FG. A-E Patent Application Publication Sep. 5, 2013 Sheet 6 of 14 US 2013/0230511 A1 is: s: KER Ampified 8x8 xic g: sk $º&» ••|+gununs •+auteur F.G. 6 Patent Application Publication Sep. 5, 2013 Sheet 7 of 14 US 2013/0230511 A1 -3 x8 aspiifix; F.G. 7A-C Patent Application Publication Sep. 5, 2013 Sheet 8 of 14 US 2013/0230511 A1 : 3: 388: 8. & & 8: : 8: 4:38 88 &;8 w w & F.G. 8 Patent Application Publication Sep. 5, 2013 Sheet 9 of 14 US 2013/0230511 A1 8; 88: 888 & ;38 3x3 & 3.3 x 8. 8 *xo :::::::::::::3:38:::::::::883: X i88 8. 38 3. 8 8-8- 3 8. 3. 8 3. 8 3. 3. : & & -& 3. : : & 3. : 3. 338 Yeats 88 Y&383 $83883:8 &; 3rgiosta iii. 388 ::s is 383 &f: 8 3. was: 83:3& 8:8:33:38 & : 8. wis-type: AA Ex:288; FG, 9 Patent Application Publication US 2013/0230511 A1 3-33 SSR. Airpääex i: FIG 10 A-C Patent Application Publication Sep. 5, 2013 Sheet 11 of 14 US 2013/0230511 A1 3. Cotro: «Sinitini $ iatio s F.G. Patent Application Publication Sep. 5, 2013 Sheet 12 of 14 US 2013/0230511 A1 s w -- s & S. 888 copy Nunias; SNP {Rogy 8::it: SNs opy 8::::::: FG, 12 Patent Application Publication Sep. 5, 2013 Sheet 13 of 14 US 2013/0230511 A1 120 CC82. Control VEGF (50ngimi) . Erlotinib (M) - 0.05 0.1 ...::::::::::::::::::::... US 2013/023051 1 A1 Sep. 5, 2013 BOMARKERS FOR RESPONSE TO KIT pathway inhibitor, respectively. In a further aspect, a TYROSINE KNASE PATHWAY INHIBITORS patient determined to have elevated levels of two or three of IN CANCER KDR, PDGFR, and KIT may be treated with two or more inhibitors of the VEGF/VEGFR, PDGFR, or KIT pathways. BACKGROUND OF THE INVENTION In another aspect, a patient determined to have elevated levels 0001. This application claims the benefit of U.S. Provi of two or three of KDR, PDGFR, and KIT may be treated with sional Patent Application No. 61/594,800, filed Feb. 3, 2012, an inhibitor that inhibits two, or all three, of the VEGF/ the entirety of which is incorporated herein by reference. VEGFR, PDGFR, and KIT pathways, for example, sunitinib 0002 This invention was made with government support or imatinib. under Prospect Grant W81XWH-07-1-0306 awarded by the 0007. In one aspect, an elevated KDR, PDGFR, or KIT U.S. Department of Defense, Grant W81XWH-06-1-0303 level may be a gain in the gene copy number of one or more awarded by the U.S. Department of Defense, and Grants 5P50 of the genes. In another aspect, an elevated KDR, PDGFR, or CA070907-14 and CA-16672 awarded by the National Insti KIT level may be an increased mRNA expression. In yet tutes of Health. The government has certain rights in the another aspect, an elevated KDR, PDGFR, or KIT level may invention. be an increased protein expression. In certain aspects, an 0003 Pursuant to 37 C.F.R. 1.821(c), a sequence listing is elevated KDR level may be an increased mRNA or protein submitted herewith as an ASCII compliant text file named expression level of a KDR-regulated gene, for example, HIF “UTSCP1203US.txt, created on Feb. 4, 2013 and having a 1C. size of 4 KB. The content of the aforementioned file is hereby 0008. In some preferred embodiments, a cancer patient for incorporated by reference in its entirety. treatment or assessment accordingly the embodiments may have a NSCLC or a glioblastoma. In some further aspects, the FIELD OF INVENTION cancer may be a metastatic cancer or a cancer that has devel oped resistance to one or more anti-cancer agent. In certain 0004. This invention relates generally to cancer treatments aspects, the cancer patient for treatment according to the with tyrosine kinase inhibitors and more particularly, to meth embodiments, may receive or have received a secondary ods of predicting cancer treatment outcome for a cancer therapy Such as a Surgery or radiotherapy. Thus, in some patient through copy number gain of the KDR, PDGFR, aspects, a treatment of the embodiments is used as an adjuvant and/or KIT genes. treatment. In other aspects, the cancer patient may be treated With a secondary therapy Such as a second drug (e.g., that is BACKGROUND OF THE INVENTION not a platinum-based chemotherapeutic agent) or an EGFR 0005 Successful treatment of cancer has remained elusive inhibitor. A secondary therapy for used according to the despite rapid advances in the field in recent years. One major embodiments may be applied before, after or essentially complicating factor in effective treatment is that conventional simultaneously with a treatment of the embodiments. diagnostics to characterize tumors offer limited insight as to 0009 Certain aspects of the embodiments concern what types of anti-cancer therapy may be successful for treat PDGFR, VEGF/VEGFR and/or KIT pathway inhibitors. For ing any given cancer. In fact, cancer cells exhibit a wide range example, VEGF/VEGFR pathway inhibitors may be, without of resistance/susceptibility to various anti-cancer therapies, limitation, ramucirumab, Sunitinib, bevacizumab, afliber thus it has been difficult to predict whether a particular cancer cept, BIBF1120, Sorafenib, cediranib, dovitinib, paZopanib, will be resistant or susceptible to any given therapy. The ponatinib, semaxanib, axitinib, PP-121, tellatinib, TSU-68, vascular endothelial growth factor receptor-2 (“VEGFR-2), Ki8751, tivoZanib, motesanib, regorafenib, Vatalanib, or van for example, is known to be present on tumor vascular endot detanib. PDGFR pathway inhibitor include, without limita helial cells Inhibitors of VEGFR-2 (KDR) have been devel tion, imatinib, Sunitinib, axitinib, BIBF1120, paZopanib, oped with the goal of inhibiting tumorangiogenesis in cancer pnoatinib, MK-2461, dovitinib, crenolanib, PP-121, tella patients. However, there are currently no validated markers tinib, CP 673451, TSU-68, Ki8751, tivoZanib, masitinib, for predicting which cancer patients are likely to respond to motesanib, MEDI-575, or regorafenib. KIT pathway inhibi inhibitors of the VEGF/VEGFR pathway. Likewise, powerful tors include, but are not limited to, imatinib, axitinib, paZo inhibitors of the PDGFR and KIT pathways are being devel panib, dovitinib, tellatinib, Ki8751, tivozanib, masitinib, oped for anti-cancer therapy, but it is unclear what types of motesanib, Sunitinib, IMG-3G3, nilotinib, dasatinib, rego cancers would be most responsive to such therapies. Methods rafenib, or Vatalanib. are needed to help select cancer patients who will experience 0010. In another embodiment, the present invention pro greater benefit from these inhibitors and who are potentially vides a method of predicting the sensitivity of a cancer in a spared the toxicities of these drugs if they are less likely to patient to a VEGF/VEGFR, PDGFR, and/or KIT pathway benefit. inhibitor comprising obtaining a sample of the cancer and determining the KDR, PDGFR, and/or KIT level in the cells SUMMARY OF THE INVENTION comprising the sample, wherein if the KDR, PDGFR, and/or 0006. In one embodiment, the present invention provides a KIT level is elevated, then the cancer is predicted to be sen method of treating a cancer patient comprising selecting a sitive to a corresponding VEGF/VEGFR, PDGFR, or KIT patient determined to have a cancer with an elevated KDR, pathway inhibitors.
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