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(12) Patent Application Publication (10) Pub. No.: US 2007/0292883 A1 Ossovskaya Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0292883 A1 Ossovskaya Et Al US 20070292883A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0292883 A1 Ossovskaya et al. (43) Pub. Date: Dec. 20, 2007 (54) METHOD OF TREATING DISEASES WITH (52) U.S. Cl. ............................. 435/6: 435/723: 514/394; PARP INHIBITORS 514/543; 514/309; 514/312: 435/91.2: 514/415: 514/457 (76) Inventors: Valeria S. Ossovskaya, San Francisco, CA (US); Barry M. Sherman, Hillsborough, CA (US) (57) ABSTRACT Correspondence Address: SSSSSS(pDRICH & ROSAT The present invention relates to methods of identifying a PALO ALTO, CA 94304-1050 (US) disease treatable with PARP modulators by identifying a 9 level of PARP in a sample of a subject, making a decision (21) Appl. No.: 11/818,210 regarding identifying the disease treatable by the PARP modulators wherein the decision is made based on the level (22) Filed: Jun. 12, 2007 of PARP. The method further comprises of treating the O O disease in the subject with the PARP modulators. The Related U.S. Application Data methods relate to identifying up-regulated PARP in a disease (60) Provisional application No. 60/804,563, filed on Jun. and making a decision regarding the treatment of the disease 12, 2006. Provisional application No. 60/866,602, with PARP inhibitors. The extent of PARP up-regulation in filed on Nov. 20, 2006. a disease can also help in determining the efficacy of the treatment with PARP inhibitors. The present invention dis Publication Classification closes various diseases that have up-regulated or down regulated PARP and can be treated with PARP inhibitors or (51) , C. I/68 2006.O1 PARP activators, respectively. The examples of the diseases GO8. 33/574 30 283 include cancer, inflammation, metabolic disease, CVS dis CI2P 19/34 (2006.015 ease, CNS disease, disorder of hematolymphoid system, A6 IK 3/4704 (200601) disorder of endocrine and neuroendocrine, disorder of uri A6 IK 3/484 (2006.01) nary tract, disorder of respiratory system, disorder of female A6 IK 3/404 (2006.01) reproductive system, and disorder of male reproductive A6 IK 3L/235 (2006.01) system. Patent Application Publication Dec. 20, 2007 Sheet 1 of 9 US 2007/0292.883 A1 Figure 1 Collect a sample from a subject suffering from a PARP mediated disease identify a up-regulated 102 level of PARP in the sample Identify the PARP 103 mediated disease treatable by PARP inhibitor . Treatment of the disease with PARP 104 inhibitor alone or in combination Patent Application Publication Dec. 20, 2007 Sheet 2 of 9 US 2007/0292.883 A1 Figure 2 F.G. 2 200 - Central Processing Unit Input/Output Devices ldentification module Patent Application Publication Dec. 20, 2007 Sheet 3 of 9 US 2007/0292.883 A1 Figure 3 C 9(A) 5 (A) 2 s X Cl d) 8 va CZ sY O. ? () s cyo icsgly s Group 1 Group 2 (low PARP1) (high PARP1) (low PARP1) (high PARP1) (n=17) (n=9) (n=17) (n=9) Patent Application Publication Dec. 20, 2007 Sheet 4 of 9 US 2007/0292.883 A1 Figure 4 Figure 4a: Plot of Expression Intensities within Various IDC subtypes Breast Tissue Infiltrating Duct Carcinoma - Multiple Classes Percent Tumor ------None +++25-50 +++50-75 -----|-75-90 ------>90 Breast Infiltrating Duct Carcinoma Class Figure 4b; Rescaled Plot of Expression Intensities within Various IDC subtypes Breast Tissue Infiltrating Duct Carcinoma - Multiple Classes Percent Tumor +++ None +++25-50 ------50-75 ------75-90 ------>90 --- at 3 ///a^.drés 48 fif's Breast Infiltrating Duct Carcinoma Class Patent Application Publication Dec. 20, 2007 Sheet 5 of 9 US 2007/0292.883 A1 Figure 5a: Plot of Expression Intensities within Various IDC subtypes Breast Tissue Infiltrating Duct Carcinoma - Multiple Classes Percent Tumor ------ None +++25-50 +++50-75 +++75-90 ------>90 1400 1300 12OO 1100 1000 800 700 600 500 400 300 200 100 Breast Infiltrating Duct Carcinoma Class Figure 5b: Rescaled Plot of Expression Intensities within Various IDC subtypes Breast Tissue Infiltrating Duct Carcinoma - Multiple Classes Percent Tumor -----None ------25-50 ------50-75 ------75-90 ----->90 700. O Breast Infiltrating Duct Carcinoma Class Patent Application Publication Dec. 20, 2007 Sheet 6 of 9 US 2007/0292.883 A1 Figure 6 Plot of Expression Intensities within Various Cancerous Ovary subtypes OVarian Tissue Multiple Classes Patent Application Publication Dec. 20, 2007 Sheet 7 of 9 US 2007/0292.883 A1 Figure 7 Plot of expression intensities within cancerous endometroid subtypes Endometrium & N is . &ssRS sistsPass, is & e ss' s <s s 8 C S&S IS" KS&S gi'sSr.9's sks.$39° s ce F&sjigsS.S. s <&SC's s s gssigp s an - still skull - - - - - - gul gg" Patent Application Publication Dec. 20, 2007 Sheet 8 of 9 US 2007/0292.883 A1 Figure 8 Plot of expression intensities within cancerous lung subtypes Lung gol" - - - g55, UL 933. CL" gg, JCL re Patent Application Publication Dec. 20, 2007 Sheet 9 of 9 US 2007/0292.883 A1 Figure 9 Plot of expression intensities within cancerous prostate subtypes Prostate 5OO 450 4 O O 3 5 O 3. O O 250 200 150 100L g- - - - - g55, U g3 ggg. UCL ra Ea -- US 2007/0292.883 A1 Dec. 20, 2007 METHOD OF TREATING DSEASES WITH PARP SUMMARY OF THE INVENTION INHIBITORS 0006. In one aspect, the present invention provides meth RELATED APPLICATIONS ods to identify diseases treatable by PARP inhibitor in a 0001. This application is related to U.S. Provisional subject by measuring the level of PARP in the subject and if Application No. 60/804,563, filed Jun. 12, 2006 and U.S. PARP is up-regulated in the subject further providing treat Provisional Application No. 60/866,602, filed Nov. 20, ment of the subject with PARP inhibitors itself or in a 2006, which is incorporated herein by reference in its combination with other agents or treatments. entirety. 0007 One aspect of the invention relates to a method of identifying a disease or a stage of a disease treatable by BACKGROUND OF THE INVENTION PARP modulator comprising identifying a level of PARP in 0002 PARP (poly-ADP ribose polymerase) participates a sample of a Subject, making a decision regarding identi in a variety of DNA-related functions including cell prolif fying the disease treatable by the PARP modulators wherein eration, differentiation, apoptosis, DNA repair and also the decision is made based on the level of expression of effects on telomere length and chromosome stability PARP. In some preferred embodiments, the level of PARP is (d. Adda di Fagagna et al., 1999, Nature Gen., 23(1): 76–80). up-regulated. One aspect of the invention relates to a method Oxidative stress-induced overactivation of PARP consumes of identifying a disease or a stage of a disease treatable by NAD+ and consequently ATP, culminating in cell dysfunc PARP modulator in a combination with other agents com tion or necrosis. This cellular Suicide mechanism has been prising identifying a level of PARP in a sample of a subject, implicated in the pathomechanism of cancer, stroke, myo making a decision regarding identifying the disease treatable cardial ischemia, diabetes, diabetes-associated cardiovascu by the PARP modulators in a combination with other agents lar dysfunction, shock, traumatic central nervous system wherein the decision is made based on the level of expres injury, arthritis, colitis, allergic encephalomyelitis, and vari sion of PARP. In some preferred embodiments, the level of ous other forms of inflammation. PARP has also been shown PARP is up-regulated. to associate with and regulate the function of several tran 0008 Another aspect of the invention relates to a method scription factors. The multiple functions of PARP make it a of treating a disease by PARP modulators in a subject target for a variety of serious conditions including various comprising identifying a level of PARP in a sample of the types of cancer and neurodegenerative diseases. subject, making a decision based on the level of PARP 0003) Breast cancer is a malignant tumor that develops regarding identifying the disease treatable by the PARP from cells in the breast. It is a common cancer among modulators, and treating the disease in the Subject by the women, other than skin cancer, and it is the second leading PARP modulators. In some preferred embodiments, the level cause of cancer-related death in women. Node-positive of PARP is up-regulated. breast cancers often overexpresse the HER/neu oncogene, 0009. In some embodiments, the disease is selected from meaning there were more copies than normal of the HER2 the group consisting of cancer, inflammation, metabolic protein on the cell surface. Women whose breast cancers disease, CVS disease, CNS disease, disorder of hematolym have more copies of the HER2 gene spread the fastest and phoid system, disorder of endocrine and neuroendocrine, had a worse prognosis. This Subset of breast cancers is disorder of urinary tract, disorder of respiratory system, typically treated with Her-2 antibody called Trastuzumab. disorder of female reproductive system, and disorder of male 0004 Women carrying non-functional BRCA1 and reproductive system. In some preferred embodiments, the BRCA2 genes and their molecular pathways have up to an cancer is selected from the group consisting of colon adeno 85% chance of developing breast cancer by the age of 70. carcinoma, esophagus adenocarcinoma, liver hepatocellular According to the conclusions of the Breast Cancer Linkage carcinoma, squamous cell carcinoma, pancreas adenocarci Consortium (1997), the histology of breast cancers in noma, islet cell tumor, rectum adenocarcinoma, gastrointes women predisposed by reason of carrying BRCA1 and tinal stromal tumor, stomach adenocarcinoma, adrenal cor BRCA2 (600185) mutations differs from that in sporadic tical carcinoma, follicular carcinoma, papillary carcinoma, cases, and there are differences between breast cancers in breast cancer, ductal carcinoma, lobular carcinoma, intra carriers of BRCA1 and BRCA2 mutations.
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