2015: AACR PD and PK Results of SGI-110 in Patients with HCC after Progression on Sorafenib

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Summary

  • Hepatocellular Carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer death worldwide (1)
  • Sorafenib treatment improves survival in advanced disease, but no therapy has demonstrated significant activity after progression on sorafenib (2)
  • SGI-110, a dinucleotide of decitabine and deoxyguanosine (Fig 1), affords increased in vivo exposure of decitabine by protecting it from deamination due to slow release upon SQ injection
  • In Phase 1 AML/MDS studies, SGI-110 provides longer exposure and more potent hypomethylation compared to decitabine (3)
  •  Preclinical studies demonstrated:
    • In vitro, SGI-110 induced significant hypomethylation of tumor suppressor genes RASSF1A, SOCS1 and DAB2IP in human HCC cell lines HuH7 an HepG2 and resulted in a potent reduction in colony formation at low nanomolar concentrations of SGI-110 (4)
    • SGI-110 efficiently sensitizes HCC cells and xenografts to oxaliplatin by inhibiting distinct signaling pathways, allowing for high antitumor activity without systemic toxicity (Kuang et al., AACR 2015, Abst 2533)
    • Numerous epigenetic alterations accumulate during hepatocarcinogenesis, leading to activation of oncogenes or loss of tumor suppressor genes in HCC. Specifically, increased methylation of genes implicated in HCC tumorigenesis has been associated with pathogenesis and poor outcome
  • In this study, we evaluated therapeutic and biologic effects of SGI-110, a hypomethylating agent (HMA)in patients with HCC. PK and PD results of this open-label, phase 2 study in patients with HCC are presented here

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2015: AACR PD and PK Results of SGI-110 in Patients with HCC after Progression on Sorafenib