2014:ASH Identification of Methylation Biomarkers to Predict Clinical Response to SGI-110 in AML pts
Summary
SGI-110 is a second generation hypomethylating agent (HMA) formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine that prolongs the in vivo exposure of decitabine by protecting it from deamination. It gets injected subcutaneously as a small volume, allowing longer half-life and more extended decitabine exposure than DAC IV infusion. SGI-110’s differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in a phase 1 trial (Kantarjian H et al. 2012).
Here, we have identified novel DNA-methylation biomarker candidates that may be predictive of response to SGI-110 using Differential Methylation Hybridisation (DMH) profiling of the NCI-60 cell line panel (Fassbender A et al, 2010). Cell lines were stratified based on SGI-110 EC50 values from Colony Forming Assays and the degree of LINE-1 (Long Interspersed Nucleotide Elements) demethylation post-SGI-110 treatment. Both stratification data sets were used to classify cell lines into either SGI-110 sensitive or resistant, and to generate 249 genomic methylation sites as candidate biomarkers of response to SGI-110. Fifty genomic fragments that characterized sensitivity and resistance to SGI-110 in cancer cell lines were selected for further validation. These candidate markers were tested in DNA samples from whole blood from 44 treatment naïve and relapsed/refractory AML patients that were classified into responders and non-responders following treatment with SGI-110 in our phase 2 clinical study.
We have identified DNA methylation patterns associated with sensitivity and resistance to SGI-110 in vitro. The validated methylation biomarker discovery process based on DMH and DBS approaches may help to identify and characterise specific subgroups of AML patients that could preferentially respond to SGI-110.
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2014:ASH Identification of Methylation Biomarkers to Predict Clinical Response to SGI-110 in AML pts
2014 EORTC: Epigenetic immunomodulation by SGI-110 combined with immune check-point blockade
Summary
Background: SGI-110 is a dinucleo- SGI-110 tide of decitabine (DAC) and deoxyguanosine formulated as a small volume SQ injection that extends DAC exposure compared to DAC IV. Our in
vitro and in vivo evidence identified a strong immunomodulatory activity of SGI-110 on human cancer cells of different histotype and on human melanoma xenografts. We also showed a remarkable anti-tumor effect once combined with anti-CTLA-4 mAb in a syngeneic mouse model. In this study we evaluated the contribution of antitumor immune responses in the reduction of tumor growth achieved by this therapeutic combination.
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2014 EORTC: Epigenetic immunomodulation by SGI-110 combined with immune check-point blockade
2014 ASCO: First results of a Phase 2 study using a 10-day SC regimen of the HMA SGI-110 for r/r AML
Summary
- Relapsed/refractory AML (r/r AML) is often drug-resistant with high mortality
- Hypomethylating agents (HMAs) such as decitabine and azacitidine have shown some clinical activity in r/r AML
- SGI-110 is next generation hypomethylating agent (HMA) given as a small volume subcutaneous (SC) administration
- We previously presented phase 2 data of SGI-110 in heavily pretreated r/r AML using a standard 5-day regimen Q 28 days showing an overall Complete Remission (CR+CRp+CRi) rate of 16% (Kantarjian et al, ASH, 2013)
- Here we present the first phase 2 results of SGI-110 given SC in a 10-day regimen Q 28 days
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2014 ASCO: First results of a Phase 2 study using a 10-day SC regimen of the HMA SGI-110 for r/r AML
2014 AACR: SGI-110 SQ provides superior disposition profile for active metabolite decitabine
Summary
- SGI‐110 is a 2nd generation hypomethylating agent. It is a dinucleotide of decitabine (DAC) and deoxyguanosine; is resistant to deamination by cytidine deaminase and is in clinical evelopment for hematologic malignancies and solid tumors
- Clinical PK data for SGI‐110 show lasting exposures (8 hr+) in parent form
- Due to the slow release from SGI‐110 after SQ injection, exposure window for the active metabolite decitabine is prolonged compared to IV DAC, which is the proposed basis for the improved clinical activity emerging from early clinical trials with SGI‐110
- The objective of this study was to characterize the mass balance and tissue distribution of [14C]SGI‐110 compared to IV [14C]DAC and evaluate the potential uptake into cells of SGI‐110 in parent form prior to conversion to active metabolite DAC
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2014 AACR: SGI-110 SQ provides superior disposition profile for active metabolite decitabine
2014 AACR: Clinical epigenetic resensitization of platinum-resistant recurrent ovarian cancer
Summary
- In the past 20 years there has been little change in the 1‐, 3‐, and 5‐ year survival rates for patients with
ovarian cancer - 5‐year survival is ~25% for patients diagnosed with advanced stage disease
- Recurrence is common and patients develop resistance to chemotherapy
- Platinum resistant ovarian cancer is uniformly fatal and epigenetic changes have been implicated in the development of platinum resistance
- Previous experience with decitabine, a hypomethylating agent, in combination with carboplatin demonstrated activity in recurrent platinum resistant ovarian cancer patients (Matei et al. Cancer Research 2012)
- SGI‐110 is a dinucleotide of decitabine and deoxyguanosine, affords increased in vivo exposure of decitabine by protecting it from deamination due to slow release upon SQ injection
- In Phase 1 studies, SGI‐110 provides longer exposure and more potent hypomethylation compared to decitabine. Combining SGI‐110 with carboplatin in this population may improve upon the encouraging preliminary results
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2014 AACR: Clinical epigenetic resensitization of platinum-resistant recurrent ovarian cancer
2014 Clinical Epigenetics International Meeting. Identification of Novel Biomarker Candidates
Summary
SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine designed to be more stable than decitabine to deamination by cytidine deaminase, thus offering a promising alternative to current approved HMAs. In our preclinical experiments, SGI-110 affected the clonogenic survival of malignant cells in various cancers, induced gene-specific as well as global LINE-1 (Long Interspersed Nucleotide Element 1) DNA hypomethylation in cell lines and xenograft models.
Here, we have identified novel predictive DNA-methylation biomarker candidates using an approach based on DMH profiling data of the NCI-60 cell line (Fassbender A et al, Methods Mol Biol 2010). Cell line stratification was based on EC50 values from Colony Forming Assays and LINE-1Methylation measurements.
Both data sets were used to classify the cell lines into SGI-110 sensitive and resistant groups and then used to generate three marker candidate sets with 249 genomic marker candidate sites in total that may be used for further assessment and classification, and might serve as a first step towards a predictive test.
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2014 Clinical Epigenetics International Meeting. Identification of Novel Biomarker Candidates
2014 AACR: SGI-110 DNA HMA SGI-110 reverses Platinum resistance of ovarian cancer models
Summary
- Patients with advanced stage ovarian cancer (OC) have a 5-year survival rate of less than 25%. The most common treatment strategy comprises debulking surgery followed by platinum-based chemotherapy. Patients commonly respond to first-line chemotherapy, but >70% relapse, developing platinum-resistance.
- There is evidence that the acquisition of platinum resistance is associated with the epigenetic silencing of specific genes by DNA methylation.
- SGI110 is a novel second generation DNA hypomethylating agent, which is currently in a Phase II clinical trial in combination with carboplatin, in platinumresistant recurrent ovarian cancer patients (NCT01696032).
- SGI110 is a dinucleotide of decitabine and deoxyguanosine, which is resistant to modification by cytidine deaminase: a common pathway of decitabine metabolism and deactivation.
- Here we demonstrate that SGI110 reverses the cisplatin-resistance of the A2780 OC model, by abrogating the epigenetic silencing of MLH1. We demonstrate SGI110 activity in a panel of OC cell lines. We suggest that epigenetic silencing of ZIC1 is a mechanism of cisplatin resistance in the OAW28 and Ovcar8 cells and demonstrate that it is reversed by SGI110.
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2014 AACR: SGI-110 DNA HMA SGI-110 reverses Platinum resistance of ovarian cancer models
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