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Supplementary Table 8 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Tables 10-15 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Table 1 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Table 6 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

The androgen receptor (AR) is the principal target for treatment of non–organ-confined prostate cancer (PCa). Androgen deprivation therapies (ADT) directed against the AR ligand–binding domain do not fully inhibit androgen-dependent signaling critical for PCa progression. Thus, information that could direct the development of more effective ADTs is desired. Systems and bioinformatics approaches suggest that considerable variation exists in the mechanisms by which AR regulates expression of effector genes, pointing to a role for secondary transcription factors. A combination of microarray and in silico analyses led us to identify a 158-gene signature that relies on AR along with the transcription factor SRF (serum response factor), representing less than 6% of androgen-dependent genes. This AR-SRF signature is sufficient to distinguish microdissected benign and malignant prostate samples, and it correlates with the presence of aggressive disease and poor outcome. The AR-SRF signature described here associates more strongly with biochemical failure than other AR target gene signatures of similar size. Furthermore, it is enriched in malignant versus benign prostate tissues, compared with other signatures. To our knowledge, this profile represents the first demonstration of a distinct mechanism of androgen action with clinical relevance in PCa, offering a possible rationale to develop novel and more effective forms of ADT. Cancer Res; 71(5); 1978–88. ©2011 AACR.

Supplementary Methods, Figure Legends 1-4, Table Legends 1-15 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Table 9 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Table 2 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Table 7 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Table 4 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Figures 1-4 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Table 3 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Supplementary Table 5 from Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer

Background: MK-1092, a first-in-class insulin receptor partial agonist, is being developed as a novel basal insulin to treat diabetes. Primary objectives were to assess safety and tolerability of single subcutaneous (SC) doses of MK-1092 in T1DM and T2DM and to determine safe single SC doses of MK-1092 in T1DM with a maximum glucose infusion rate (GIRmax) between 1.5 and 4.5 mg/kg/min. Secondary objectives were to estimate PK profiles in T1DM and T2DM and to determine the GIRmax in T2DM. Methods: All subjects received blinded treatments of MK-1092 or glargine and placebo matched to the alternative active treatment under euglycemic clamp conditions. T1DM: 2 cohorts (n=8/cohort) were each randomized (3:1) to receive MK-1092 (8 nmol/kg in cohort 1 or 32 nmol/kg in cohort 2) or glargine (3 nmol/kg [0.5 units/kg]). T2DM: 1 cohort (n=9) was randomized to receive either MK-1092 (n=6) or glargine (n=3). Each subject underwent 3 dosing periods. MK-1092 was dosed at 32, 16 and 64 nmol/kg in periods 1, 2, and 3, respectively and glargine was dosed at 3 nmol/kg in all periods. Results: All doses tested were safe and well tolerated. There were no SAEs or discontinuations due to AEs. AEs were mild or moderate and resolved spontaneously. No anti-MK-1092 or anti-insulin antibodies were observed. In T1DM, the geometric mean of apparent terminal t1/2 was 8.54 and 6.70 hr; Tmax was 15.00 and 15.04 hr; AUC0-∞ was 21.5 and 74.9 nM*hr and Cmax was 0.79 and 3.43 nM for 8 and 32 nmol/kg MK-1092, respectively. PK parameters for 32 nmol/kg MK-1092 were comparable for T1DM and T2DM except for a ~40-50% lower AUC0-∞ and Cmax in T2DM. In T1DM, the mean GIRmax was 1.33 and 2.74 mg/kg/min for 8 and 32 nmol/kg MK-1092, respectively and 2.32 mg/kg/min for glargine. In T2DM, the mean GIRmax was 1.90, 1.40 and 2.83 mg/kg/min for 32, 16 and 64 nmol/kg MK-1092, respectively and ~ 1.2 mg/kg/min for glargine. Conclusion: Single doses of MK-1092 are well-tolerated and lower glucose in patients with diabetes. Disclosure L. Morrow: Employee; Spouse/Partner; Lilly Diabetes. Employee; Self; ProSciento. M. Grimm: None. C. Beysen: Employee; Self; ProSciento. G. Walford: Employee; Self; Merck & Co., Inc. K. Duncan: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. P.K. Mitra: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Bristol-Myers Squibb. P. Vaddady: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. M. Hompesch: Board Member; Self; ProSciento. Employee; Self; ProSciento. Stock/Shareholder; Self; ProSciento.

Background: MK-1092, a first-in-class insulin receptor partial agonist, is being developed as a novel basal insulin for patients with T1DM and T2DM. The primary objective of this first-in-human study was to assess safety and tolerability of single subcutaneous (SC) doses of MK-1092 in HS. Secondary objectives were to estimate PK profiles, to determine the maximal glucose infusion rate (GIRmax) required to maintain target glucose levels during euglycemic clamp conditions and to explore the glycemic effect of insulin lispro when added to a single dose of MK-1092 in HS. Methods: In part 1 of this single-site study, 5 cohorts of HS (n=8/cohort) were blinded and randomized (3:1) to receive MK-1092 (4, 8, 16, 32 or 64 nmol/kg) or glargine (3 nmol/kg [0.5 units/kg]). Subjects received single SC doses of MK-1092 or glargine and placebo matched to the alternative active treatment under euglycemic clamp conditions. Part 2 of the study was started once a safe and tolerated MK-1092 dose that achieved GIRmax ~1-2 mg/kg/min was identified in Part 1. In the open-label part 2 of the study, 4 HS received lispro (1.2 nmol/kg [0.2 units/kg], IV) approximately 12 hr after a single SC dose of MK-1092 (8 nmol/kg) to confirm high dose lispro could reduce hyperglycemia (defined as GIRmax > 4mg/kg/min) after MK-1092 dosing. Results: All doses tested were safe and well tolerated. There were no SAEs and no discontinuations due to AEs. AEs were mild or moderate and resolved spontaneously. The geometric mean of apparent terminal t1/2 ranged from 5.4 to 9.3 hr, Tmax ranged from 12 to 18 hr, AUC0-∞ ranged from 10.6 to 161 nM*hr and Cmax ranged from 0.38 to 6.82 nM at 4 to 64 nmol/kg MK-1092. Mean GIRmax for glargine was 2.72 mg/kg/min and 0.92, 1.69, 3.10, 3.32 and 4.39 mg/kg/min for 4, 8, 16, 32 and 64 nmol/l MK-1092, respectively. Adding lispro to 8.0 nmol/kg MK-1092 resulted in a mean GIRmax of 11.34 mg/kg/min. Conclusion: Single doses of MK-1092 are well-tolerated and lower glucose in healthy subjects. Disclosure L. Morrow: Employee; Spouse/Partner; Lilly Diabetes. Employee; Self; ProSciento. M. Grimm: None. C. Beysen: Employee; Self; ProSciento. G. Walford: Employee; Self; Merck & Co., Inc. K. Duncan: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. P.K. Mitra: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Bristol-Myers Squibb. P. Vaddady: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. M. Hompesch: Board Member; Self; ProSciento. Employee; Self; ProSciento. Stock/Shareholder; Self; ProSciento.