12 Dec 2016
Data has been presented on SY-1425, first-in-class selective retinoic acid receptor alpha (RARα) agonist, showing that SY-1425 inhibited tumour growth in multiple preclinical models of breast cancer driven by high levels of RARA gene expression.
In these studies, SY-1425 showed significant anti-proliferative activity both as a single agent and in combination with standard-of-care breast cancer therapies in in vitro and in vivo models of breast cancer, including those resistant to existing treatments.
These data were presented at the 39th Annual San Antonio Breast Cancer Symposium (SABCS).
SY-1425 is currently in a phase II clinical trial in genomically defined subsets of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients.
Using a gene control platform, researchers discovered subsets of AML, MDS and breast cancer patients whose tumours have the super-enhancer associated with the RARA gene, which codes for the RARα transcription factor.
The resulting over-expression of RARα locks the cells in an immature, undifferentiated and proliferative state.
Treatment with SY-1425 in cancer cells with this super-enhancer promotes differentiation of these cells.
SY-1425 is approved in Japan as Amnolake® (tamibarotene) to treat relapsed or refractory APL, a form of AML that is driven by a fusion of the RARA gene with other genes.
The data presented at SABCS show that subsets of breast cancer patients’ tumours have a highly specialised region of regulatory DNA, known as a super-enhancer, that is associated with the RARA gene and drives high levels of RARA gene expression.
In preclinical models of breast cancer, high RARA gene expression was shown to be predictive of response to treatment with SY-1425.
The data highlight that SY-142 inhibited tumour growth in breast cancer cell lines as well as cell line-derived xenograft and patient-derived xenograft models of breast cancer with high RARA gene expression, including models of HER2-positive breast cancer resistant to treatment with trastuzumab and ER-positive breast cancer resistant to hormonal therapies.
By contrast, SY-1425 did not inhibit tumour growth in models of breast cancer with low RARA gene expression.
Reduced the expression of genes responsible for tumor growth in HER2-positive and ER-positive breast cancer cells with high RARA expression.
Increased the anti-tumour effects of standard-of-care therapies, including tamoxifen and palbociclib in ER-positive breast cancer cells with high RARA expression and lapatinib in HER2-positive breast cancer cells with high RARA expression.
These data support the potential clinical development of SY-1425 in genomically defined subsets of breast cancer patients.
Source: SABCS 2016