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
2014: ESMO Phase 1/2 of AT13387, HSP90 Inhibitor, in combo with abiraterone acetate and prednisone
Summary
Heat Shock Protein 90 (HSP90) is an ATP-dependent molecular chaperone that assists in correct folding Of a Wide variety Of ‘client’ proteins (Androgen Receptor (AR), AKT, HER2 and CDK4).
ATI 3387 (AT) is a fragment derived, second-generation novel potent non-ansamycin HSP90 inhibitor (Kd:O.71 nM)1 with good tissue distribution, excellent in vivo anti-tumor activity and long tumor half life in preclinical models (65-78 hours).
ATI 3387 demonstrated anti-tumor activity in preclinical castration-resistant prostate cancer (CRPC) models2 and ho ds promise as a therapeutic agent by simultaneously down-regulating multiple aberrant signalling pathways.
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2014: ESMO Phase 1/2 of AT13387, HSP90 Inhibitor, in combo with abiraterone acetate and prednisone
2014 AACR: AT13387 combined with erlotinib improves response in EGFR-driven xenograft models of NSCL
Summary
Epidermal Growth Factor Receptor (EGFR) can be activated by point mutations e.g L858R or by deletions in exon19. A subset of non-small cell lung cancer (NSCLC) have activated EGFR and can be successfully treated with EGFR inhibitors such as erlotinib. However, resistance frequently develops to these inhibitors, often due to acquisition of a further T790M mutation in EGFR leading to relapse. Methods to improve response and delay resistance are therefore of value.
Inhibition of the chaperone, HSP90, leads to the depletion of many client proteins, including EGFR, and has the capacity to simultaneously affect many signalling pathways, offering an alternative strategy for targeting EGFR-driven disease.
AT13387 is a potent, second generation HSP90 inhibitor currently being tested in Phase 2 clinical trials. Here we investigated the effects of combining AT13387 and erlotinib in models of EGFR- driven NSCLC.
2014 AACR: AT13387 combined with erlotinib improves response in EGFR-driven xenograft models of NSCL
2014 BACR: Characterisation of the Activity of Potent XIAP/cIAP1 Dual Antagonists in Melanoma Models
Summary
The inhibitor of apoptosis proteins (IAPs) are widely de-regulated in many tumours and contribute to cancer drug resistance. The targeted inhibition of IAPs can switch TNF-alpha
signaling in cancer cells from pro-survival to pro-apoptotic. Therefore, IAPs represent an attractive target for cancer therapy.
The IAP family member cellular IAP1 (cIAP1) is involved in the regulation of TNF-alpha signaling and X-linked IAP (XIAP) directly interacts with and inhibits caspases. IAP family members are
characterized by BIR (baculoviral IAP repeat) domains, to which the endogenous inhibitor of IAPs SMAC (second mitochondria derived activator of caspases) binds. Peptidomimetic compounds
based on the SMAC sequence have been developed, but they show high selectivity for cIAP1. We used our fragment based-drug discovery approach to generate a non-alanine, nonpeptidomimetic
IAP antagonist, which has dual potency for XIAP and cIAP1. Here we describe the characterization of this compound in in vitro and in vivo models of melanoma and breast cancer.
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2014 BACR: Characterisation of the Activity of Potent XIAP/cIAP1 Dual Antagonists in Melanoma Models
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