p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

Abstract

A number of drugs developed against cancer-specific molecular targets have been shown to offer survival benefits alone or in combination with standard treatments, especially for those cases where tumor pathogenesis is dominated by a single molecular abnormality. One example for such a tumor type is alveolar rhabdomyosarcoma (aRMS) which is characterized by a specific translocation creating the oncogenic PAX3/FKHR transcription factor, believed to be the molecular basis of the disease.Recently, we were able to demonstrate that the small molecule inhibitor PKC412 (midostaurin) exhibits strong antitumor activity against aRMS by reducing the transcriptional activity of PAX3/FKHR.Here, we screened for combination strategies that are superior to PKC412-only treatment and found that the combination of PKC412 with histone deacetylase (HDAC) inhibitors like valproic acid (VPA) synergistically induced apoptosis resulting in suppressed aRMS tumor growth in vivo.We provide evidence that the antitumor effect upon combination treatment is achieved by VPAinduced reactivation of p21 which is downregulated in aRMS cells via destabilization of the transcriptional regulator EGR1 by PAX3/FKHR. Our study highlights a possible mechanism behind the increased efficacy and indicates that different arms of PAX3/FKHR oncogenicity can be exploited therapeutically by the specific combination of drugs to increase their therapeutic potential.

Exosomes derived from embryonal and alveolar rhabdomyosarcoma carry differential miRNA cargo and promote invasion of recipient fibroblasts

“…Significantly represented networks featured proteins previously implicated in ARMS biology (GSK3b, MDM2, CDKN1A, CDKN2A, IGF1R)4344454647, proteins involved in immune evasion and tumor metastasis (CXCL8, CSF1, IFNAR1, CCR2, CASR)4849505152, stemness (SOX2, POU5F1)5354, tumor cell proliferation and invasion (YBX1)41, or have been associated with other tumor types with a possible role in tumor biology (PRKACA, MYO1C, BRINP3)555657. The finding of the miRNA networks targeting proteins involved in stemness, immune evasion and metastasis, enriched in ARMS but not ERMS exosomes, suggests that paracrine signaling via exosomes may have differential effects on mediating the known aggressive behavior of ARMS.…”

Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice

“…We evaluated the modulation of gene expression and protein levels of highly relevant RMS-correlated oncogenes, such as PAX3-FKHR, 2 PAX3, 2 MYCN, 6 MET, 5 and oncosuppressors such as p21, 19 DR5, and DR4 16 induced by SFN in rhabdomyosarcoma cells. Treatment with SFN in ERMS cells induced only MET mRNA decrease, and p21 mRNA increase (in two of the three cell lines) (Fig.…”

Valproic acid sensitizes pancreatic cancer cells to natural killer cell-mediated lysis by upregulating MICA and MICB via the PI3K/Akt signaling pathway

“…VPA, a histone deacetylase inhibitor which is used as an anti-epilepsy drug, was recently reported to exert anti-tumor effects by upregulating the expression of NKG2DLs, such as MICA/B and UL16-binding proteins (ULBPs), in a number of tumor types including hepatocarcinoma, myeloma, and myeloid leukemia [16,20,25-27]. These effects were linked to the activation of different signaling pathways in different tumor types, and were specific to malignant cells.…”