ASCO 2016 - Inhibitors that may overcome BRAFi resistance: Heat Shock Protein 90 (HSP90) and Ricolinostat (an HDAC6 inhibitor)

In this post, Webinar for melanoma - A look forward, Weber noted "Innovative Ideas for Targeted Therapy" - Overcoming BRAF resistance by combining with: Hsp90,   HDAC,   PI3 kinase/AKT,   ERK, and   ERBb3 inhibitors

Here are a couple of ASCO reports addressing some of those inhibitors:

Phase I study of vemurafenib and heat shock protein 90 (HSP90) inhibitor XL888 in metastatic BRAF V600 mutant melanoma.  ASCO 2016.  # 9544. J Clin Oncol 34, 2016.  Eroglu,Gibney, Weber, et al.

Background: BRAF inhibitors are clinically active in advanced BRAFV600 mutant melanoma patients, but resistance is common. Multiple resistance mechanisms involve HSP90 clients and preclinical data have shown abrogation of resistance using concurrent treatment with the HSP90 inhibitor XL888. Methods: The combination of vemurafenib (960 mg PO BID) with dose cohorts of XL888 (30, 45, 90 or 135 mg PO twice weekly [BIW]) was investigated in patients with advanced BRAFV600 mutant melanoma. A modified Ji dose escalation design was used. Primary endpoints were safety and determination of a recommended phase 2 dose (RP2D). Dose-limiting toxicity (DLT) was defined as treatment-related grade greater than or = to, 3 adverse event or inability to deliver 75% of planned XL888 dose in the first 8 weeks. Results: Nineteen patients (14 with M1C disease) were enrolled: cohorts 1 and 2 (n = 3 each), cohort 3 (n = 7), cohort 4 (n = 6). Two DLTs (diarrhea and pancreatitis) occurred in cohort 4, while a third patient received less than 75% of planned XL888. Therefore cohort 3 dose was determined to be RP2D: vemurafenib 960 mg BID + XL888 90 mg BIW. Most common grade 3 toxicities (in more than 1 patient) were hyperproliferative skin events (n = 5, 26%), diarrhea (n = 2, 11%), rash (n = 2) and headaches (n = 2) and one grade 4 lipase elevation. Skin toxicities were lower in cohorts 3/4. Objective responses were observed in 13 of 18 evaluable patients with 2 complete responses (CRs) and 11 partial responses (PR). Two patients with a PR who underwent surgical resection had a pathologic CR. Median PFS was 7.4 months; median overall survival was 33.1 months (5.75 – not reached). Targeted proteomics of patients’ baseline and day 8 PBMCs showed significant increases in HSP71 expression (a marker of HSP90 inhibition) in cohorts 2 through 4. Analysis of baseline and on-therapy tumor biopsies is ongoing. Conclusions: Promising clinical activity with an acceptable toxicity profile and evidence of HSP90 inhibition was observed with vemurafenib and XL888 in BRAF mutant melanoma patients. As HSP90 inhibitors also abrogate resistance to the combination of BRAF and MEK inhibitors in melanoma, clinical investigation of this approach is also planned. Clinical trial information: NCT01657591

In vitro and in vivo anti-melanoma activity of ricolinostat, a selective HDAC6 inhibitor with immunomodulatory properties.  ASCO 2016.  # e21075.  J Clin Oncol 34, 2016.  Cheng. Laino, Wang, Weber, et al.

Background: Previously, we have shown that pan-HDAC inhibitors induce apoptosis and changes in the immunogenicity of melanoma cells. Further studies identified HDAC6 playing a central role in regulating melanoma immunogenicity. Genetic knockdown (KD) of HDAC6 in murine and human melanoma cells increased the expression of MHCI and costimulatory molecules as well as melanoma associated antigens. In vivo studies demonstrated that the growth of melanoma cells lacking HDAC6 was significantly delayed as compared to wild-type cells. Methods: C57BL/6 mice were given melanoma cells sc. When mice developed a palpable mass they were treated with vehicle control, ricolinostat alone, or in combination with anti PD-1 or anti CTLA-4 antibodies. To assess the effects of ricolinostat upon T cells, murine T-cells were activated with anti-CD3/CD28 dynabeads in the presence -or not- of 1 uM ricolinostat for 24 hour. Then, cells were adoptively transferred into B16 bearing mice. T-cell subpopulations from the lymph nodes were analyzed ex vivo.Results: First, invivo treatment of melanoma bearing mice with ricolinostat resulted in a dose-dependent inhibition of tumor growth (p < 0.05). No toxicities were observed at the doses studied. Second, the antitumor effect exerted by ricolinostat was not observed when melanoma bearing SCID mice were treated with this compound, indicating that an intact adaptive immune system is required for the observed antitumor activity. In lieu of these previously unknown immunomodulatory properties of ricolinostat, we next assessed the effects of this compound upon T-cells in vivo. We show here that treatment of murine T-cells with ricolinostat resulted in a significant increase in central memory T-cells endowed with a strong anti-melanoma activity in vivo as compared to control-treated T-cells (p < 0.05). Finally, the addition of ricolinostat treatment to either anti-CTLA-4 or anti-PD-1 treatment was associated with an enhanced inhibition of melanoma tumor growth. Conclusions: Our results have identified HDAC6 as a novel target for melanoma immunotherapy and point to ricolinostat as an attractive agent to add to the immuno-oncology armamentarium.

Ratties....keeping it going! - c