XL888

Our ex vivo senolytic screening platform identified XL888, a HSP90 inhibitor, that cleared p16 Ink4a + cancer- associated fibroblasts in vivo . XL888 administration after establishment of advanced lung adenocarcinoma significantly reduced tumor burden concurrent with the loss of plastic tumor cells. Our study identified a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.

P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute

P1, N=49, Completed, Emory University | Active, not recruiting --> Completed

Combined vemurafenib and cobimetinib plus XL888 had significant toxicity, requiring frequent dose reductions, which may have contributed to the relatively low progression-free survival despite a high tumor response rate. Given overlapping toxicities, caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors.

P1, N=21, Completed, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Completed

P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2022 --> Dec 2023

P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Oct 2022 --> Oct 2023

P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Jul 2022 --> Dec 2022

P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Apr 2022 --> Oct 2022

P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2021 --> Apr 2022

Methods Based on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic cancer. As clinical data matures, changes in soluble and cellular biomarkers will be correlated with response to elucidate mechanisms of response or resistance to this combination therapy. Trial Registration This clinical trial is underway and registered with the ID NCT03095781

P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Jul 2021 --> Jul 2022

We implied that XL888 promoted apoptosis of HCC cells induced by heat via disrupting the binding of HSP90 and STAT3, providing theoretical basis for a novel combination strategy for HCC.

P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2020 --> Jul 2021

Tumors from mice treated with both XL888 and anti-PD-1 had a significantly increased CD8+ and CD4+ T cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly impacts PSC/CAF in vitro and enhances the efficacy of anti-PD-1 blockade in vivo.

P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Apr 2020 --> Dec 2020

Using the FDA-approved CDK4/6 inhibitors (palbociclib & abemaciclib), we observed that dual inhibition of CDK4 and HSP90 synergistically inhibits cancer viability in colorectal cancer cell lines (eg. HCT116, SW480, DLD1) under both normoxia and hypoxia. Multiple HSP90 inhibitors have been tested, including ganetespib, onalespib, XL888 and TAS116, which indicates such combinational inhibition as a class effect...Hypoxia sensitizes the Rb-deficient MDA-MB-468 breast cancer cell line to abemaciclib treatment. Our findings suggest a therapeutic potential for utilizing the combination of CDK4 and HSP90 inhibitors in cancer treatment.

P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Feb 2020 --> Oct 2019

P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2019 --> Apr 2020