Mechanism of Action: DNA methyltransferase (DNMT) inhibition
Indication: Solid tumors
How this therapy can help
Guadecitabine was rationally designed to be resistant to degradation by cytidine deaminase and prolong the exposure of tumor cells to the active metabolite, decitabine, ensuring greater uptake of decitabine into the DNA of rapidly dividing cancer cells.
As a next-generation DNA hypomethylating agent, guadecitabine inhibits DNMT to reverse aberrant DNA methylation, an epigenetic change characteristic of many cancer cells, restoring the expression of silenced tumor suppressor genes and tumor-associated antigens. Guadecitabine-mediated inhibition of DNA methylation upregulates tumor-associated antigens and may sensitize tumor cells to other anticancer agents, including immunotherapeutics, as well as resensitize resistant cancer cells to chemotherapeutics.
Guadecitabine is being tested in clinical trials for the treatment of solid tumors, including studies investigating combination with carboplatin in the treatment of platinum-resistant ovarian cancer, in hepatocellular (liver) cancer following failure of Nexavar (sorafenib), and in combination with irinotecan in the treatment of colorectal cancer.
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Astex is also developing guadecitabine (SGI-110) for hematologic malignancies including:
Treatment-Naïve Acute Myeloid Leukemia (TN-AML)
Relapsed/Refractory Acute Myeloid Leukemia (AML)
Relapsed/Refractory Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukaemia (CMML)