• Therapeutic Targets

    If ACC patients are to benefit from targeted agents, it will be necessary to identify the molecular targets that drive the disease. Great progress has been made, but plenty of work remains. This section describes the evidence supporting the significance of various molecular targets in the development and progression of the disease.

    MYB

    The 2009 publication on the recurrent t(6;9) translocation in ACC that results in the MYB-NFIB fusion gene was pivotal in establishing the importance of MYB in ACC. Several studies (Mitani et. al., West et. al., Brill et. al., and a second Mitani et. al.) eventually established that approximately half of ACC tumors harbor the MYB-NFIB fusion gene, another 15% or so involve the fusion of MYB with another partner, and another 20% or so involve other translocations of chromosomes 6 and/or 9 (some involving NFIB). Although the precise mechanisms of these promiscuous translocations have yet to be worked out, the clear result is the over-expression of the myb protein (or at least its first few exons) in 90% or more of ACCs.

    Transgenic models with inducible over-expression of the MYB-NFIB fusion in the salivary gland compartment are in development. They will help determine whether the fusion is sufficient for tumorigenesis (myb over-expression in leukemia models has not been sufficient).

    The MYB gene is a transcription factor that is very difficult to target. ACCRF is supporting efforts to (i) identify drugs that suppress myb expression using high-throughput screening of zebrafish, (ii) pursue known downstream targets of myb, and (iii) identify new downstream targets of myb in ACC specimens using ChIP-sequencing.

    FGFR

    FGFR1 is over-expressed and phosphorylated in the vast majority of ACCs. Its ligand FGF2 is a known downstream target of MYB. And preclinical screening of an FGFR inhibitor in PDX models of ACC showed significant activity. Based on these findings, clinical trials of Dovitinib in ACC have been opened at the University of Virginia and at Seoul National University.

    HDAC

    HDAC inhibitors are cited in a review of MYB as differentiating agents of that
    can drive the down-regulation of MYB by inducing elongation arrest in the first intron. In a Phase I clinical trial of Vorinostat (SAHA), five ACC patients were enrolled; one had a partial response and four had stable disease. A Phase II study of Vorinostat in ACC has completed enrollment. One ACC patient had a partial response in a Phase I study of Chidamide, another HDAC inhibitor.

    IGF-1R

    IGF-1R is over-expressed and phosphorylated in a preponderance of ACCs. A recent ASCO abstract recounts how two ACC patients achieved partial responses in a Phase I study of Figitumumab (an IGF-1R inhibitor) and Dacomitinib (a HER family inhibitor), and how Figitumumab demonstrated good activity in ACCRF’s five PDX models of ACC. A case report of an ACC patient recounts how, following significant activity of an IGF-1R inhibitor in her associated patient-derived xenograft, she had a minor response during treatment with Figitumumab.

    Additional potential therapeutic targets are under investigation. ACCRF will update this list as new data becomes available.