Aram Oganesian

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study

BACKGROUND Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. METHODS In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). INTERPRETATION Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. FUNDING Astex Pharmaceuticals, Stand Up To Cancer.

SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome

The DNA methyltransferase (DNMT) inhibitor vidaza (5‐Azacytidine) in combination with the histone deacetylase inhibitor entinostat has shown promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model. However, the effectiveness of DNMT inhibitors against solid tumors is likely impacted by their limited stability and rapid inactivation by cytidine deaminase (CDA) in the liver. These studies were initiated to test the efficacy of SGI‐110, a dinucleotide containing decitabine that is resistant to deamination by CDA, as a single agent and in combination with entinostat. Evaluation of in vivo plasma concentrations and pharmacokinetic properties of SGI‐110 showed rapid conversion to decitabine and a plasma half‐life of 4 hr. SGI‐110 alone or in combination with entinostat reduced tumor burden of a K‐ras/p53 mutant lung adenocarcinoma cell line (Calu6) engrafted orthotopically in nude rats by 35% and 56%, respectively. SGI‐110 caused widespread demethylation of more than 300 gene promoters and microarray analysis revealed expression changes for 212 and 592 genes with SGI‐110 alone or in combination with entinostat. Epigenetic therapy also induced demethylation and expression of cancer testis antigen genes that could sensitize tumor cells to subsequent immunotherapy. In the orthotopically growing tumors, highly significant gene expression changes were seen in key cancer regulatory pathways including induction of p21 and the apoptotic gene BIK. Moreover, SGI‐110 in combination with entinostat caused widespread epigenetic reprogramming of EZH2‐target genes. These preclinical in vivo findings demonstrate the clinical potential of SGI‐110 for reducing lung tumor burden through reprogramming the epigenome.

Abstract LB-214: Interim results from a randomized Phase 1-2 first-in-human (FIH) study of PK/PD guided escalating doses of SGI-110, a novel subcutaneous (SQ) second generation hypomethylating agent (HMA) in relapsed/refractory MDS and AML

SGI-110 is a novel second generation HMA, formulated as a low volume SQ injection. It is designed as a dinucleotide incorporating decitabine and guanosine, to prolong in vivo exposure and potentially improve efficacy of its active component, decitabine by protecting decitabine from rapid deamination by cytidine deaminase. Preclinically, SGI-110 demonstrated potent activity in-vivo using different routes of administration. A randomized Phase 1-2 FIH PK/PD-guided, dose-escalation study is being conducted in subjects with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage of the study is to determine the safety and tolerability of SGI-110 and to establish the MTD and the biologically effective dose (BED). Subjects are randomized to one of two SQ regimens (daily x5 or once weekly x3, both given in 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage of the study will be a randomized Phase 2 dose expansion, once the BED and MTD have been determined. Currently, 5 dose-cohorts have been fully enrolled, (n= 55) at doses ranging from 3mg/m2 to 60 mg/m2 daily x5, and 6mg/m2 to 90 mg/m2 weekly x3 but are not yet fully evaluable. PK guidance has allowed rapid dose escalation, and PD assessment of global hypomethylation has been correlated with increased dose and exposure levels. Apart from manageable local injection site pain, SGI-110 has been well tolerated. Other AE9s were neutropenia, thrombocytopenia, or anemia. There have been 3 remissions in relapsed AML subjects: 1 CR with weekly (60mg/m2) and 1 PR and 1 CR with daily (36 and 60 mg/m2 respectively). The PK profile showed efficient conversion of SGI-110 to decitabine achieving exposures in the therapeutic range as predicted from the SGI-110 rational design, characterized by decitabine AUC in therapeutic range (cohorts 4-5), lower Cmax, and longer effective half life, as compared to historical data based on molar equivalent doses of IV decitabine. Dose-dependent hypomethylation induction in the first 5 cohorts was observed. The subject who achieved a CR had the highest degree of hypomethylation induction of all subjects tested to date, and also the highest decitabine AUC in the cohort. Updated efficacy, safety, PK, and PD data of both regimens will be presented. SGI-110 is safe and well tolerated to date; biologically effective and therapeutic dose levels have been achieved with little toxicity so far with both regimens. Preliminary efficacy (PR+CR) has been observed in relapsed AML subjects. The PK profile showed efficient conversion of SGI-110 to decitabine with achievable therapeutic exposures, longer apparent half life, and lower Cmax than predicted equivalent decitabine doses given IV. Global Hypomethylating effects were observed at all dose levels, evaluated to date with both regimens. The results justify the progress of the study to the second dose-expansion Phase 2 stage after establishing the BED and MTD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-214. doi:1538-7445.AM2012-LB-214

A phase i clinical trial of guadecitabine and carboplatin in platinum-resistant, recurrent ovarian cancer: Clinical, pharmacokinetic, and pharmacodynamic analyses

Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here, we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase I study of guadecitabine and carboplatin in patients with recurrent, platinum-resistant high-grade serous ovarian cancer, primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC). Experimental Design: Guadecitabine was administered once daily on days 1 to 5 followed by carboplatin i.v. on day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4. Results: Twenty patients were enrolled and treated. Median age was 56 years (38–72 years). The median number of prior regimens was 7 (1–14). In the first cohort (N = 6), the starting doses were guadecitabine 45 mg/m2 and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia), leading to dose deescalation of guadecitabine to 30 mg/m2 and of carboplatin to AUC4. No DLTs were observed in the subsequent 14 patients. Grade ≥3 adverse events ≥10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small-intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR), and 6 patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene reexpression in paired tumor biopsies/ascites were recorded. Conclusions: Guadecitabine and carboplatin were tolerated and induced clinical responses in a heavily pretreated platinum-resistant ovarian cancer population, supporting a subsequent randomized phase II trial. Clin Cancer Res; 24(10); 2285–93. ©2018 AACR.

Simultaneous Modeling of Biomarker and Toxicity Response Predicted Optimal Regimen of Guadecitabine (SGI-110) in Myeloid Malignancies

Guadecitabine (SGI‐110) is a novel next‐generation hypomethylating agent (HMA) administered as s.c. injection with extended decitabine exposure. Dose/exposure‐response analyses of longitudinal measures of long interspersed nucleotide element‐1 (LINE‐1) methylation and absolute neutrophil counts (ANC) pooled from 79 and 369 patients in 2 phase I/II trials, respectively, were performed to assist, through modeling and simulation, the selection of dosing regimens for phase III. Simulation of ANC predicted a decrease after a 5‐day regimen of 60 mg/m2 with partial recovery before the next cycle, whereas the nadir of 90 mg/m2 on the same schedule was below 100/µl. ANC following a 60 mg/m2 10‐day regimen was predicted to be suppressed below 100/µl as long as treatment continued without recovery. The developed models provided useful tools to assist simultaneous evaluation of the relative dynamics of the two effects (DNA demethylation and the effect on ANC).

Abstract 2947: Pharmacodynamic (PD) and pharmacokinetic (PK) results of the second-generation hypomethylating agent, SGI-110, in patients with hepatocellular carcinoma (HCC) after progression on sorafenib

Background: HCC is the sixth most common cancer and the third most common cause of cancer death worldwide. Sorafenib treatment improves survival in advanced disease, but no therapy has demonstrated significant activity after progression on sorafenib. Increased methylation of genes implicated in tumorigenesis has been described in HCC and has been associated with outcome and etiology. We evaluated the therapeutic and biologic effects of SGI-110, a hypomethylating agent in patients with HCC. SGI-110, a dinucleotide of decitabine and deoxyguanosine, increases decitabine exposure by protecting it from deamination due to slow release on subcutaneous (SC) injection. PK and PD results of an open-label, phase 2 study in patients with HCC are presented here. Methods: Adults with histologically confirmed, advanced-stage HCC who had received sorafenib, had evidence of disease progression, and ECOG PS 0-1 were enrolled. SGI-110 (SC) was given on D1-5 of a 28-day cycle. Blood samples were taken for PK/PD analysis and, when possible, paired tumor biopsies were taken for analysis of global DNA (LINE-1) and gene-specific methylation and gene expression. Patients were imaged every 8 weeks and allowed to continue treatment after radiologic but not clinical progression. End points include disease control rate (DCR) at 16 weeks, overall response rate, progression-free survival, and overall survival. Results: 50 HCC patients (43M/7F; median age 60 years [range 32-82]; ECOG PS 0/1: 21/29) were enrolled. The initial dose of SGI-110 was 60 mg/m2 (4 patients treated), but due to grade 4 neutropenia, the dose was decreased to 45 mg/m2 for subsequent patients. SGI 110 was well tolerated at 45 mg/m2; myelosuppression was the major adverse event. Full PK was available from 16 patients (3F/13M). The PK profile for SGI-110 after 45 mg/m2 showed protracted conversion to deliver active metabolite decitabine with exposure window lasting beyond 8-hr and mean(SD) decitabine AUC exposures of 94(22) ng*hr/mL that were comparable to those achieved in AML/MDS after 60 mg/m2. Potent LINE-1 demethylation was observed in blood (-35.6%, n = 27) and in tumor (-12.9%, n = 10) DNA; significant demethylation (-27.4%, n = 6) was also observed on promoter of tumor suppressor gene MZB1 which is frequently hypermethylated and silenced in HCC. Conclusions: SGI-110 was well tolerated at a dose of 45 mg/m2 administered SC on D1-5 of a 28-day cycle. PK was consistent with that seen in another solid tumor study and provided more persistent decitabine exposures compared with PK in hematologic malignancies. The PD changes in blood and tumor LINE-1 and MZB-1 methylation are promising and consistent with the desired biologic effect of SGI-110. Analysis for clinical efficacy is ongoing. Citation Format: Anthony El-Khoueiry, Mary F. Mulcahy, Tanios Bekaii-Saab, Richard Kim, Crystal Denlinger, Rakesh Goel, Shweta Gupta, Simone Jueliger, Aram Oganesian, Harold Keer, John Nemunaitis. Pharmacodynamic (PD) and pharmacokinetic (PK) results of the second-generation hypomethylating agent, SGI-110, in patients with hepatocellular carcinoma (HCC) after progression on sorafenib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2947. doi:10.1158/1538-7445.AM2015-2947

Abstract 4076: SGI-110, a novel subcutaneous (SQ) second generation DNA hypomethylating agent achieves improved pharmacodynamics (PD), safety and pharmacokinetics (PK) in comparison to IV decitabine in a non-human primate in vivo study

SGI-110, is a novel second generation DNA methylation inhibitor that is currently in Phase I/II clinical study for treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). SGI-110 is a dinucleotide of DAC and deoxyguanosine designed to be more stable than decitabine to deamination by cytidine deaminase, thus offering a promising alternative to current hypomethylating agents approved in MDS. We report here the results of a preclinical study in which safety, PK, and PD of different dosing regimens of SGI-110 SQ were compared to the clinical dose and regimen of DAC IV in 4 groups of male cynomolgus monkeys (n=4). The treatment groups consisted of: 1) Control group of DAC IV 1-h infusion at a dose equivalent to the clinically approved regimen of 20 mg/m2 x 5 (1.7 mg/kg daily x5); 2) 1.7 mg/kg SGI-110 SQ daily x 5 (molar equivalent to 42% of the clinical DAC dose); 3) 3.0 mg/kg SGI-110 SQ daily x 5 (molar equivalent to 75% of the clinical DAC dose); and 4) 3.0 mg/kg of SGI-110 SQ once weekly x3 (molar equivalent to 44% of the total clinical DAC dose). DAC and SGI-110 plasma levels were measured and monkeys were monitored for 28 days for hematological changes, and global DNA methylation (LINE-1). Reversible hematological changes included a reduction in leukocytes, red blood cells (RBCs), and neutrophil counts with the nadir counts generally occurring between D8 and D14 and recovery occurring D21 to D28. The DAC-treated group showed the greatest reduction and slowest recovery compared to all SGI-110 treated groups. Changes in methylation patterns of LINE-1 and miRNA-29b were evaluated in DNA extracted from monkey blood as PD markers of biological efficacy after treatment with SGI-110 or DAC. All groups achieved a decrease in LINE-1 methylation of approximately 15-20% from baseline between Day 8 and 21 with remethylation back to baseline levels by day 28. Both SGI-110 SQ dailyx5 regimens achieved slightly more hypomethylation than DAC IV on days 8 (group 3) and 11 (group 2). Overall, the magnitude and duration of the decrease in DNA methylation at lower molar equivalent doses of SQ SGI-110 were similar to or better than DAC IV. SGI-110 appeared to convert to DAC resulting in similar exposure window compared to IV DAC. The dose-adjusted plasma DAC exposures, on molar equivalence basis, were somewhat lower compared to the DAC group. The C max ranged 52-163 vs 215-525(DAC) ng/mL, while dose-adjusted AUCs were 21.6-51.6 vs 98.6-221(DAC) ng*hr/mL. In conclusion, these preclinical studies showed that SQ SGI-110 may represent a more convenient and tolerable option for delivering DAC where either the weeklyx3 or dailyx5 regimens at a lower dose achieved DNA hypomethylating effects that were similar to or better than seen with DAC IV and with less myelosuppressive effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4076. doi:1538-7445.AM2012-4076

Abstract A091: Phase 1 study of IAP inhibitor ASTX660 in adults with advanced cancers and lymphomas

Background: We report dose escalation results from a phase 1/2 trial of ASTX660 (NCT02503423). This non-peptidomimetic, dual XIAP and cIAP antagonist inhibits tumor cell lines at nanomolar concentrations and is active against xenografts. Methods: Study ASTX660-01, an open-label, multi-center, dose-escalation study in subjects with advanced cancers and lymphomas, used a 3+3 dose escalation design. Study drug was administered orally once daily in 28 day cycles of alternating 7 days on, then 7 days off therapy. Dose escalation was planned from a starting fixed 15 mg dose until the maximum tolerated dose (MTD) was reached. Endpoints included safety, MTD, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and antitumor effects. Results: Forty-five subjects received at least 1 dose of ASTX660 (range 15 mg - 270 mg). Mean age was 62 years (range 36-77); 60% of subjects were female. Median duration of study therapy was 2 cycles (range 1-8). Four dose-limiting toxicities (DLTs) were observed: 3 at 270 mg QD (grade 3/4 lipase increased), and 1 at 210 mg QD (grade 3 lipase increased). These lipasemia DLTs were all asymptomatic. Most declined after dose interruption and did not recur after dose reduction. The MTD was 210 mg QD, and the RP2D was 180 mg QD. Common adverse events (AEs) included fatigue, lipasemia, and vomiting (29%); nausea and lymphopenia (27%); anemia (24%); rash and edema (20%); ALT increase and pruritus (18%); AST increase (16%); appetite decrease and diarrhea (13%); and amylasemia and hyponatremia (11%). Lipasemia and amylasemia appeared to be dose-related. Most AEs were CTCAE grades 1-2 and manageable with supportive treatment. Median time to peak plasma concentration (tmax) was 1 hour. ASTX660 t ½ was 15.3 hours at the RP2D. Day 1 and 7 AUC0-24h plasma exposures after 180 mg ASTX660 were 1450 (67%) and 2080 (62%) ng*hr/mL (geometric mean [CV]), respectively. Modest accumulation (1.4 fold) at Day 7 vs Day 1 was observed for ASTX660 AUC0-24h exposures but not for Cmax. Human RP2D exposure levels reached the biologically active exposure range seen in preclinical models. ASTX660 at all dose levels suppressed cIAP1 in peripheral blood mononuclear cells (PBMCs). At 180 mg cIAP1 suppression was sustained beyond the off-therapy week. A clinical response in cutaneous T cell lymphoma was observed at the 180-mg dose level. Conclusions: In phase 1, ASTX660 caused manageable toxicities, achieved target study drug exposures, and demonstrated both biologic and clinical activity at the RP2D. Enrollment to phase 2 expansion cohorts in lymphoma and other selected cancers is ongoing. Citation Format: Monica Mita, Patricia LoRusso, Michael S. Gordon, Aram Oganesian, Xiaoping Zhang, Roberta Ferraldeschi, Simone Jueliger, Harold N. Keer, Purvee Kumar, Chihche Lin, Edwin P. Rock, Alain Mita, Anthony W. Tolcher. Phase 1 study of IAP inhibitor ASTX660 in adults with advanced cancers and lymphomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A091.

Abstract 2321: SGI-110 SQ provides superior disposition profile for active metabolite decitabine than decitabine IV infusion: Results from mass balance and tissue distribution study in cynomolgus monkeys and in vitro human studies

Introduction: SGI-110 is 2nd generation hypomethylating agent (HMA) formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume and pharmaceutically stable subcutaneous (SQ) injection allowing longer effective half-life and more extended DAC exposure window than IV infusion. As previously reported, the differentiated PK profile offers the potential for improved biological and clinical activity and safety over currently available HMAs (Kantarjian et al. ASH, 2012). Objective: The aim of this study was to characterize the mass balance and tissue distribution of [14C]SGI-110 compared to IV DAC and evaluate the potential uptake into cells of SGI-110 in parent form prior to conversion to active metabolite DAC. Methods: The mass balance (MB) of administered radioactivity was evaluated in cynomolgus monkeys following a single SQ dose of [14C]SGI-110 or a single molar equivalent IV infusion dose of [14C]decitabine. Tissue distribution of the radiolabel was determined using quantitative whole-body autoradiography (QWBA) up to 24 hours following dosing. The position of the radiolabel was within the DAC structure of SGI-110 and the same as on DAC. SGI-110 was evaluated as a substrate in human transporter panel and its uptake into cells was also assessed by incubation with fresh human whole blood. Results: Excretion of radioactivity after SGI-110 SQ dosing was predominantly urinary while only 3% of the dose was detected in feces. Recovery of the radioactive dose was complete over 24 hr. For bone marrow, blood, plasma, red blood cells (RBC), white blood cells and most tissues examined, total radioactivity-derived concentrations following SGI-110 dosing were consistently higher than for IV DAC (based on molar equivalency comparison), suggesting that higher levels of DAC-related exposures are achieved at potential target sites with SGI-110. SGI-110 was detected at appreciable levels in RBC lysates from monkey MB study suggesting intracellular presence, which was then confirmed in incubation with fresh human whole blood where intracellular SGI-110 was detected in RBC and WBC lysates. In vitro transporter panel study showed SGI-110 to be a substrate for uptake by human CNT2-expressing MDCK-II cells, while decitabine was a substrate for human nucleoside transporters CNT1 and ENT1. Conclusions: Results show that SQ SGI-110 delivers consistently higher decitabine-related exposures at target tissues confirming its potential for improved clinical activity over DAC IV infusion. This is likely the result of the enhanced disposition profile conferred by protracted SGI-110 conversion affording a more extended exposure window of active metabolite decitabine and the intracellular uptake of SGI-110 for overall increased exposure at target sites of action. Citation Format: Aram Oganesian, Robert H. McClanahan, Eric Solon, Mohammad Azab. SGI-110 SQ provides superior disposition profile for active metabolite decitabine than decitabine IV infusion: Results from mass balance and tissue distribution study in cynomolgus monkeys and in vitro human studies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2321. doi:10.1158/1538-7445.AM2014-2321

Abstract 679: SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome .

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The DNA methyltransferase inhibitors (DNMTi) Vidaza (5-azacytidine) and Dacogen (5-aza-2′-deoxycytidine, decitabine) are approved by the FDA for chemotherapy against myelodysplastic syndrome, a heterogeneous bone marrow disorder. Vidaza in combination with the HDAC inhibitor entinostat has shown some promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model. However, the effectiveness of these DNMTi against solid tumors is likely impacted in part, by their stability and rapid inactivation by cytidine deaminase in the liver. These studies were initiated to test the efficacy of SGI-110, a prodrug for decitabine. SGI-110, a dinucleotide consisting of 5-aza-2′-deoxycytidine followed by a deoxyguanosine, has been shown to be effective in vitro as a DNA methylation inhibitor and less prone to deamination by cytidine deaminase. In this study, we used our in vivo lung cancer model to explore the potential therapeutic effect of SGI-110 alone and in combination with entinostat. In vivo plasma concentrations and pharmacokinetic properties of SGI-110 and its metabolite decitabine were evaluated in nude rats after a single SC dose of SGI-110. Upon SC administration, SGI-110 is rapidly converted to decitabine. Dose proportional pharmacokinetics showed no significant difference in accumulation of SGI-110 or decitabine, while the half life of decitabine was increased to 4hrs. SGI-110 alone or in combination with entinostat significantly reduced tumor burden by 56% of Calu-6, a K-ras/p53 mutant lung adenocarcinoma cell line engrafted orthotopically in nude rats. On a molecular level, global changes in gene profiles were associated with a reduction in tumor burden. Microarray analysis revealed that a 212 and 592 genes were differentially expressed in SGI-110 alone or with combination therapy. Highly significant gene expression changes were seen in key cancer regulatory pathways. In addition, SGI-110 treatment activated p21 and apoptotic genes BIK and BAK in these tumors. SGI-110 caused widespread epigenetic reprogramming that induced demethylation of an average of 291 genes; in particular 208 genes were polycomb target genes. The polycomb targets were enriched for transcription factors. These preclinical in vivo findings demonstrate that SGI-110 alone shows strong demethylating activity and when combined with entinostat more effectively retards tumor growth. (Supported by Astex Pharmaceutical and SU2C) Citation Format: Carmen S. Tellez, Marcie J. Grimes, Maria A. Picchi, Yushi Liu, Tom H. March, Aram Oganesian, Pietro Taverna, Steven A. Belinsky. SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 679. doi:10.1158/1538-7445.AM2013-679