Sunday, November 26, 2017

HDAC inhibitors for melanoma....what are they again????

One of my first posts about HDAC inhibitors was back in 2016:  HDAC (Histone deacetylase) inhibitors for melanoma

Noting that researchers had hopes that in melanoma they could be used to try to overcome resistance to BRAF inhibitors, though at that time...not too much had come of them.

At ASCO this year, there was this:  ASCO 2017: Pembro plus Entinostat (histone deacetylase inhibitor - HDAC)

Where as the abstract discussed combining Pembro (now Keytruda) with entinostat, I noted:  "Existing evidence supports the hypothesis that HDAC inhibitors (HDACi) may sensitize melanoma cells to immunotherapy and targeted therapy and hence bear therapeutic potential concurrent with immune checkpoint blockade or BRAF and MEK inhibition."

Now, there's this:

HDAC inhibitors enhance the immunotherapy response of melanoma cells. Booth Robers, Polkepovic, et al.  Oncotarget. 2017 May 17. eCollection 2017 Oct 10.  
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney. Knock down of HDAC1, HDAC3, HDAC8 and HDAC10, but not HDAC6, recapitulated the effects of the HDAC inhibitors on the immunotherapy biomarkers. Using B16 mouse melanoma cells we discovered that pre-treatment with AR42 or sodium valproate enhanced the anti-tumor efficacy of an anti-PD-1 antibody and of an anti-CTLA4 antibody. In the B16 model, both AR42 and sodium valproate enhanced the anti-tumor efficacy of the multi-kinase inhibitor pazopanib. In plasma from animals exposed to [HDAC inhibitor + anti-PD-1], but not [HDAC inhibitor + anti-CTLA4], the levels of CCL2, CCL5, CXCL9 and CXCL2 were increased. The cytokine data from HDAC inhibitor plus anti-PD-1 exposed tumors correlated with increased activated T cell, M1 macrophage, neutrophil and NK cell infiltration. Collectively, our data support the use of pan-HDAC inhibitors in combination with kinase inhibitors or with checkpoint inhibitor antibodies as novel melanoma therapeutic strategies.
Here's hoping...again. - c

No comments:

Post a Comment