2015 AACR Novel Combination Therapy of SGI-110 and BMN-673 for BRCA-Proficient Ovarian Cancer

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Summary

  • Ovarian cancer (OC) is initially chemoresponsive but the majority of patients relapse after first line platinum-, taxane-based chemotherapy.
  • Recurrence has been shown to be associated with increased DNA damage response (DDR) mediated by poly-(ADP)-ribose polymerase 1/2 (PARP1/2), which can be therapeutically targeted by PARP inhibitors (PARPi). Although PARPi are indicated for platinum-responsive, BRCA-mutated OC, most OC patients have BRCA-proficient disease.
  • Based on our previous studies supporting a role for DNA methylation in chemoresistant OC, mediated by the enzyme DNA methyltransferase 1 (DNMT1), and reports on a functional role for DNMT1 in DNA double strand break repair mediated by BRCA1/2, we hypothesize that combining the DNMTi SGI-110 and the PARPi talazoparib (BMN673) will impair BRCA-mediated DDR, resulting in cytotoxicity. CONCLUSION: Combination SGI-110 + talazoparib treatment significantly reduced cancer cell colony formation. Regardless of BRCA and platinum sensitivity status, co-administration of SGI-110 and talazoparib reduced cell survival, albeit %survival was dependent on drug dose and cancer cell line.

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2015 AACR Novel Combination Therapy of SGI-110 and BMN-673 for BRCA-Proficient Ovarian Cancer

2015 AACR: Determinants of hypomethylation and clinical response in r/r AML pts treated with SGI-110

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Summary

SGI-110 (guadecitabine) is a dinucleotide of decitabine and deoxyguanosine and a novel subcutaneous (SQ) hypomethylating agent. In a previous Phase 1 (dose escalation) study, we found in relapsed/refractory (r/r) AML patients who were treated with SGI-110 (36 mg/m2-125 mg/m2) subcutaneously (SQ) daily for 5 days a correlation between low LINE-1 demethylation induction, a three gene expression classifier score (low CDA, low P15 and high DNMT3B) and resistance to SGI-110. Here, we analyzed r/r AML patients (n=122) from Phase 1/2 studies treated at pharmacologically effective doses of SGI-110 looking for determinants of hypomethylation and response. Phase 1 patients with r/r AML (n=27) who were treated at a therapeutic dose range of SGI-110 (36 mg/m2 – 125 mg/m2) by SQ daily for 5 days. Phase 2 study r/r AML patients received 60 mg/m2 SQ daily for 5 days (n=22), 90 mg/m2 SQ daily for 5 days (n=25) and 60
mg/m2 SQ daily for 10 days (n=48). Global DNA methylation at pre/post treatment was estimated by bisulfite-pyrosequencing for the LINE-1 repetitive
sequence. We also examined expression of a panel of genes (CDA, P15, P21, DNMT3B, DNMT3A, DNMT1, and CTCF) at baseline by quantitative RT-PCR.
We analyzed samples from 122 patients with r/r AML. Median age was 59.6 (range, 23–86), 75 were males (61.5%). Overall, peak LINE-1 demethylation generally occurred on day 8 after daily x 5 treatment, or on day 8 or 15 after daily x 10 treatment(Fig.1). In individual patients, peak LINE-1 demethylation ranged from +4.9% to -56.3%. In 122 r/r AML patients, 28 showed overall remission (23.0 %, 15 CR and 13 CRi/CRp). Unsupervised clustering by expression of a panel of genes at baseline grouped the patients into two clusters: A (N=95, response rate = 29.5 %) and B (N=27, response rate = 0 %).
Cluster B is characterized by high DNMT3b expression, low P15 expression, low CDA expression (average Z-score 1.44 ± 0.26 in cluster B compared to -1.26 ± 0.14 in clusters A, p<0.0001) and reduced demethylation (demethylation average -14.2 ± 1.90 % in cluster B compared to -26.1 ± 1.38 % in clusters A, p<0.0001)(Fig. 2). Peak LINE-1 demethylation was significantly higher in
responders than non-responders (average demethylation -32.33 ± 1.91 % in responders compared to -21.25 ± 1.42 % in non-responders, p=0.0001). (Fig.3) A three gene classifier score (low CDA, low P15 and high DNMT3B) was associated with low LINE-1 demethylation (R=0.27, p=0.0034) as well as resistance to SGI-110 (mean Z-score -0.75 in non-responders compared to -1.67
in responders, p=0.014)(Fig.4).
In a phase 1/2 study of SGI-110, we identified in r/r AML patients a gene expression signature (high DNMT3B, low P15, and low CDA) associated with reduced demethylation and resistance to SGI-110 and we found strong trends for associations between demethylation and response.

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2015 AACR: Determinants of hypomethylation and clinical response in r/r AML pts treated with SGI-110

2015 Keystone Conf: DNA Methylome Alterations in Platinum Resistant Ovarian Cancer Tumors

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Summary

Epigenetic changes, particularly DNA methylation aberrations have been implicated in acquired resistance to platinum in ovarian cancer. An ongoing phase I/II multi-institutional clinical trial uses the novel DNA methyl transferase (DNMT) inhibitor SGI-110 to resensitize recurrent platinum resistant ovarian cancer to carboplatin.

Tumor biopsies or malignant ascites were collected at baseline and after two cycles of SGI-110 administered daily for 5 days in low dose (30mg/m2). The goal of the current study was to analyze
global DNA methylation profiles of platinum resistant tumors and compare them to the methylome of untreated, platinum-sensitive ovarian tumors. LINE1 methylation and promoter methylation of
selected genes (MAGE-A2, MAGE-A3, MAGE-A11, NY-ESO, RASSF1, MLH1, and HOXA11) were quantified by pyrosequencing before and after SGI-110 treatment (n=12 paired samples).

Epigenetic profiling using the Infinium HumanMethylation450 BeadChip (HM450) revealed extensive methylation changes when comparing recurrent platinum resistant ovarian tumors (n=42) to
primary, untreated ovarian cancer specimens analyzed as part of the TCGA project (n=10). Six hundred and four promoters were significantly differentially methylated (adjusted p<0.05, absolute methylation changes β>0.2), among which, 498 and 106 were hypermethylated or hypomethylated respectively in recurrent platinum resistant ovarian tumors. DNMT1, 3A, and 3B mRNA levels in the tumors were highly variable (n=19). Analysis of a limited number of paired samples (n=7) revealed no significant changes in global methylation or in DNMT expression levels induced by  treatment with SGI-110 (adjusted p>0.05). However, the DNMT inhibitor induced significant methylome alterations in selected patients. Significant hypomethylation of MAGE-A3 and
MAGE–A11 promoters (p<0.05) was detected. Correlations between methylation changes and clinical outcomes are being explored.

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2015 Keystone Conf: DNA Methylome Alterations in Platinum Resistant Ovarian Cancer Tumors

2015 ASCPT: Systems Pharmacology Modeling of Decitabine and SGI-110

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Summary

Acute myeloid leukemia (AML) is a tumor associated with myeloid line of blood cells, characterized by the abnormal rapid proliferation of white blood cells in the bone marrow. The most common approach for AML treatment is the reduction of abnormal cell proliferation rate which can be achieved by targeting the key stages of the cell cycle.

Decitabine is a well characterized hypomethylating agent (HMA), which is incorporated into DNA during the S-phase of cell cycle, inhibits methylation of antitumor genes and induces G2/M arrest. However, it has a very short half-life (15-35 min) after IV infusion due to rapid degradation by cytidine deaminase. SGI-110, a 2nd generation HMA was designed to increase the in vivo xposure/potential efficacy of its active metabolite decitabine. The aim of this effort was to explore how changes in exposure window of decitabine affect DNA demethylation and tumor cell proliferation in AML patients.

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2015 ASCPT: Systems Pharmacology Modeling of Decitabine and SGI-110

2015 TAT: Combination of onalespib (AT13387) with crizotinib to treat or delay resistance in NSCLC

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2015 TAT: Combination of onalespib (AT13387) with crizotinib to treat or delay resistance in NSCLC

2014: ASH First clinical results of P2 study of SGI-110 in intermediate or high risk MDS or CMML

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2014: ASH First clinical results of P2 study of SGI-110 in intermediate or high risk MDS or CMML

2014: ESMO Study of HSP90 Inhibitor AT13387 alone and combo w/ Crizotinib in the treatment of NSCLC

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Summary

  • Hsp90 is required for proper ALK function
  • AT13387 is a second generation Hsp90 inhibitor
  • AT13387 in ALK-driven pre-clinical models:
    • Displays potent antitumor activity
    • Delays the onset of resistance
  • In the clinic, AT133872
    • Has a safety profile consistent with the class
    • (diarrhea, mild transient visual changes)
      • PK & PD results support weekly dosing
      • Has antitumor activity (PR) at a dose of 220 mg/m2
        (D1,8,15 of 28 Day cycle)
  • Crizotinib (CZT) has demonstrated clinical activity in ALK-pos NSCLC3
  • AT13387-05 is a 3-part, Phase 1-2, randomized study

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2014: ESMO Study of HSP90 Inhibitor AT13387 alone and combo w/ Crizotinib in the treatment of NSCLC

2014 EORTC: Induction of apoptosis with a novel dual cIAP1/XIAP antagonist in models of melanoma

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Summary

Inhibitor of apoptosis (IAP) antagonists are being tested in the clinic for the treatment of cancer as they can switch cancer cell TNFα signalling from being pro-survival to being pro-apoptotic, and
relieve the block on effector caspase activation (1,2). Astex has used fragment based-drug discovery to develop a first-in-class, dual XIAP/cIAP1 antagonist (ASTX660), which is non-peptidomimetic,
does not contain an alanine as a warhead and demonstrates prolonged antagonism of both XIAP and cIAP1 in vivo.

Melanoma is a highly aggressive malignancy with an exceptional ability to develop resistance to targeted therapies. Targeting IAP proteins in melanoma is a promising strategy to overcome this
resistance (3), and ASTX660 represents a novel approach because of the enhanced potency against XIAP (4).

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2014 EORTC: Induction of apoptosis with a novel dual cIAP1/XIAP antagonist in models of melanoma

2014:ASH Identification of Methylation Biomarkers to Predict Clinical Response to SGI-110 in AML pts

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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

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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