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WO 2015/161078 Al 22 October 2015 (22.10.2015) P O P C T

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WO 2015/161078 Al 22 October 2015 (22.10.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/161078 Al 22 October 2015 (22.10.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every GOIN 30/02 (2006.01) G OIN 33/74 (2006.01) kind of national protection available): AE, AG, AL, AM, G01N 33/48 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US20 15/026 174 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 16 April 2015 (16.04.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/981,087 17 April 2014 (17.04.2014) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: THE REGENTS OF THE UNIVERSITY TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, OF CALIFORNIA [US/US]; Office of Technology Tran s TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, fer, 1111 Franklin St., 12th Floor, Oakland, California DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 94607 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventor: GAIKWAD, Nilesh W.; The Regents of the GW, KM, ML, MR, NE, SN, TD, TG). University of California, 1111 Franklin St., 12th Floor, Oakland, California 94607 (US). Published: (74) Agents: HAO, Joe C. et al.; Kilpatrick Townsend and — with international search report (Art. 21(3)) Stockton LLP, Two Embarcadero Center, Eighth Floor, San Francisco, California 94 111 (US). (54) Title: METHODS FOR COMPREHENSIVE PROFILING OF STEROID METABOLOME (57) Abstract: The present invention provides a method for quantitating at least 100 steroids in a biological sample using ultra-per- © formance liquid chromatography-tandem mass spectrometry. The present invention also provides a method for detecting an imbal - o ance in steroid metabolism or the presence of cancer in an individual. METHODS FOR COMPREHENSIVE PROFILING OF STEROID METABOLOME CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 61/981,087, filed April 17, 2014, the disclosure of which is herein incorporated by reference in its entirety for all purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] This invention was made with Government support under Grant No. CA-DNTR- 2 04- , awarded by The United States Department of Agriculture. The Government has certain rights in this i e ion. BACKGROUND OF THE INVENTION [0003] Steroids, such as androgens, corticosteroids, estrogens and progestogens control many physiological processes in humans including reproduction, secondary sexual characteristics, maturation, gene expression, cardiovascular health and neurological functions (Gniber et al, N. Engl. J. Med., 2002, 346: 340-352). In addition, steroids, especially estrogens, are implicated in the development and/or progression of ma y diseases, such as breast cancer (demons and Goss, N. Engl J Med., 2001, 344:276-285), ovarian cancer (Bulun et al, J Steroid iochem Mol Biol, 2007,106: 81-96), prostate cancer (Carruba G. Ann. N.Y. Acad. Set., 2006, 1089, 201-217), endometrial cancer (Shang Y., Nat. Rev. Cancer, 2010, 6:360-368), osteoporosis (Khosla S., J. Clin. Endocrinol. Metabol, 2010, 95:3569- 3577), neurodegenerative diseases (Chakraborti et al., Rev. Neurosciences, 2010, 18: 395- 416), cardiovascular disease (Bechlioulis et al., Curr. Vascular Pharmacol., 2010, 8 : 249- 258) and obesity (Mayes and Watson, Obesity Rev., 2004, 5:197-2169). [ΘΘ04] There is a clear association between cumulative exposure of exogenous and endogenous estrogens and the risk of breast and other cancers (Persson I., J. Steroid. Biochem. Mol. Biol, 2000, 74, 357-364). Furthermore, epidemiologic studies have indicated that breast cancer risk is higher in women with early menarche and late menopause, who have longer exposure to estrogens. Estrogen-replacement therapy has also been implicated as a risk factor for breast cancer in postmenopausal women (Feigelson and Henderson, Carcinogenesis, 1996, , 2279-2284) Obese postmenopausal women have higher serum concentrations of estrogen and are at risk of breast cancer(Simpson and Brown, Exp. Rev. Endocrinol. Metabol, 201 1, 6, 383-395; Cieary and Grossmann, Endocrinology, 2009 6:2537-2542). [0005] Evidence suggests that oxidative metabolism of estrogens plays a significant role in the carcinogenicity, which are oxidized to the 2-QH and 4-OH catechol estrogens by the phase I enzymes {see, FIG. 1). 4-hydroxyestrone was found to be carcinogenic in the male Syrian golden hamster kidney tumor model, whereas 2-hydroxylated metabolites were not (Liehr et al, J. Steroid Biochem., 1986, 24:353-356; Li and Li, Fed. Pro , 1987, 46: 1858- 1863). Similarly, Newbold and Liehr have shown that 4-hydroxyestradiol induced uterine tumors in 66% of CD-I mice, whereas mice treated with 2-hydroxyestradiol or E2 had much lower incidence of uterine tumor (Newbold and Liehr, Cancer Res., 2000, 60:235-237). Oxidative enzymes, metal ions, and in some cases molecular oxygen can catalyze the oxidation of catechols to reactive o-quinones, which can cause damage within cells by alkyiation of cellular nucleophiles (proteins, DNA) (Yager and Davidson, N. Engl. J Med., 2006, 354:270-282). In an earlier study, it was shown that in healthy women the urinary levels of methoxy-estrogens and thiol conjugates of catechol estrogen are high and the level of estrogen-DNA adduces are low. in contrast, women with breast cancer had lower levels of estrogen metabolites and conjugates and higher levels of estrogen-DNA adducts (Gaikwad et al, t J Cancer, 2008, 122:1949-1957; Gaikwad et al, Breast Cancer: Basic & Clin. Res., 2009, 3:1-8). Taken together, the findings indicate that comprehensive analysis of steroid and steroid metaboiite levels in individuals may be useful for diagnosing disease, such as cancer, neurodegenerative disease {e.g., Alzheimer's disease and Parkinson's disease), cardiovascular disease and obesity. [0006] The most widely used techniques for measuring steroids include radioimmunoassay (Andrew, Best Pract. Res. Clin. Endocrinol. Metab., 2001, 15: 1-16), gas chromatography- mass spectrometry (GC-MS) (Hoffmann et al., Steroids, 2010, 75:1067-1074; Sadanalaa et al., Mass Spectrometry Letters, 2012, 3:4-9), and liquid chromatography-mass spectrometry (LC-MS) (Hauser et al, Chromatogr. B, 2008, 862:100-1 12). Immunoassay-based methods are simple and sensitive, but are subject to problematic issues such as lack of reproducibility, cross-reactivity, limited dynamic range, and matrix effects. Immunoassay also cannot analyze multiple steroids in a single assay (Andrew, Best Pract. Res. Clin. Endocrinol. Metab., 2001, 15:1-16; Wudy et al, Pediatr. Res., 1995, 38, 76-80; Tate and Ward, Clin. Biochem. Rev., 2004, 25, 105-120). GC-MS and LC-MS methods have large dynamic range and can measure multiple steroids simultaneously. GC-MS has been used extensively, but steroid measurements from biological samples require elaborate and tedious sample preparation procedures. For instance, prior to GC-MS analysis, steroid derivatization is required to increase the volatility and thermal stability of the molecules and to improve chromatographic separation and detection (Sadanalaa et al., Mass Spectrometry Letters, 2012, 3:4-9; Zhou et al., Environ. Sci. (China), 2007, 19: 879-884). LC-MS has been shown to be useful in determining steroid levels in the biological samples. Electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) are routinely used in qualitative and quantitative analysis of steroids. For instance, LC-ESI-MS methods were used to quantitate 28 steroids in animal tissue (Flores-Valverde and Hill, Anal. Chem., 2008, 80, 8771-8779) and 24 steroid hormones in human urine in a single 50 min LC-ESI-MS ran (Weidong et al., Anal. Chem., 2012, 84: 10245-10251). LC-APCI-MS methods were used to measure the levels of 7 endogenous adrenal steroids in human serum (Carvalho et al., Chromatogr. B, 2008, 872:154-161), 16 estrogen derivatives in rat hepatocytes, 4 catechol estrogens in rat brains (Mitamura et al, Analyst. 2000, 125:81 1-814) and human urine (Xu et al, J Chromatogr B, 2002, 780: 15-330), and 34 anabolic steroids in bovine muscle (Vanhaecke et al, Analytica Chimica Acta, 201 1,700, 70-77). In addition, LC-atmospheric pressure photo ionization (APPI)-MS methods have been use to measure the levels of non-polar steroids in biological samples (Hintikkaa et al, J. Chromatogr. A , 2010, 1217: 8290-8297). As such, there remains a need for a method to comprehensively and globally profile the steroid metabolome (e.g., over 00 steroids and metabolites thereof) in a sample from an individual in a single quantitative assay. The present invention satisfies this need and provides related advantages as well. BRIEF SUMMARY OF THE INVENTION [0007] In one aspect, the present invention provides a method for profiling a steroid metabolome in a biological sample. The method comprises (a) extracting at least 100 steroids from the biological sample using liquid-liquid extraction (LLE) to form a steroid extract, wherein the at least 100 steroids in the steroid extract are not derivatized; and (b) detecting the presence and/or level of the at least 00 steroids in the steroid extract using ultra-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS).
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