pyrimidinones and Bile-Duct-Neoplasms

Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second-line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non-competitive inhibitor of MEK1/MEK2. In this phase IIa open-label, single-arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine-based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12-week non-PD rate. Secondary assessments included safety, progression-free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non-PD rate at week 12 was 10% (95% confidence interval, 1.2-31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6-12.1) and 1-year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end-point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss-of-function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.

Topics: Administration, Oral; Aged; Aged, 80 and over; Ampulla of Vater; Bile Duct Neoplasms; Biliary Tract Neoplasms; DNA-Binding Proteins; Exome Sequencing; Female; Gallbladder Neoplasms; Humans; Male; Middle Aged; Neurofibromin 1; Nuclear Proteins; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Survival Analysis; Transcription Factors; Treatment Outcome

Intrahepatic cholangiocarcinoma (iCCA) accounts for a fraction of primary liver cancers but has a 5-year survival rate of only 10%. Immune checkpoint inhibitors are effective in treating many solid cancers, but immune checkpoint inhibitor monotherapy has no clear benefit in iCCA. Mitogen-activated kinase (MEK) inhibitors, such as trametinib, have shown promising results in preclinical studies for iCCA by inhibiting cell proliferation and modifying the tumor microenvironment. This study aimed to show the potential benefit of combining trametinib with anti-programmed cell death protein 1 (PD-1) therapy in different iCCA mouse models.. Here, we assessed the in vitro cytotoxicity of trametinib in mouse (SB1 and LD-1) and human (EGI-1) cholangiocarcinoma cell lines. We examined the efficacy of single-agent trametinib, anti-PD-1, and a combination of both in subcutaneous, orthotopic, and plasmid-induced iCCA mouse models. Flow cytometry analysis was used to elucidate changes in the tumor immune microenvironment upon treatment. Whole-exome sequencing (WES) was performed on the SB1 tumor cell line to correlate this preclinical model with iCCAs in patients.. Trametinib reduced tumor cell growth of SB1, LD-1, and EGI-1 tumor cells in vitro. Trametinib treatment led to up-regulation of major histocompatibility complex (MHC-I) and programmed cell death ligand 1 (PD-L-1) (programmed cell death ligand 1) on tumor cells in vitro. The combination of trametinib and anti-PD-1 reduced tumor burden in several iCCA tumor models and improved survival in SB1 tumor-bearing mice compared with either agent alone. Immunoprofiling of tumor-bearing mice showed an increase of hepatic effector memory CD8. Altogether, our study shows that trametinib improves the immunogenicity of tumor cells by up-regulating MHC-I surface expression. The combination with anti-PD-1 results in optimal treatment efficacy for iCCA. WES of SB1 cells suggests that KRAS wild-type iCCAs also respond to this combination therapy.

Topics: Animals; Bile Duct Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cholangiocarcinoma; Drug Synergism; Exome Sequencing; Female; High-Throughput Nucleotide Sequencing; Humans; Immune Checkpoint Inhibitors; Mice; Programmed Cell Death 1 Receptor; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

Although therapies for advanced melanoma have been greatly improved by the development of immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors, there are still many concerns about the administration of these novel drugs. Therefore, to combine these therapies sequentially at appropriate time points of the disease is important. In this report, we report two cases in which dabrafenib and trametinib therapy for advanced melanoma failed but were successfully controlled by nivolumab monotherapy, and investigated the sera sCD163, CCL22 and CXCL10 as biomarkers for tumor progression. Interestingly, the sera levels of sCD163, CXCL10 and CCL22, both of which are produced by activated tumor-associated macrophages, were increased in parallel with the tumor progression in each case. Because this report presents only two cases, further data will need to be accumulated to provide more fundamental insights into the usefulness of these biomarkers for predicting disease progression in melanoma.

Topics: Adult; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Disease Progression; Female; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Cholangiocarcinoma is an aggressive malignancy with limited therapeutic options. MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated. We evaluated the safety and efficacy of combination therapy with the oral VEGF receptor tyrosine kinase inhibitor pazopanib plus the MEK inhibitor trametinib in patients with advanced cholangiocarcinoma.. In this open-label, multicentre, single-arm trial, adults with advanced unresectable cholangiocarcinoma received pazopanib 800 mg daily and trametinib 2 mg daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) with secondary end points including overall survival (OS), response rate, and disease control rate (DCR).. A total of 25 patients were enrolled and had received a median of 2 prior systemic therapies (range 1-7). Median PFS was 3.6 months (95% CI: 2.7-5.1) and the 4-month PFS was 40% (95% CI: 24.7-64.6%). There was a trend towards increased 4-month PFS as compared with the prespecified null hypothesised 4-month PFS of 25%, but this difference did not reach statistical significance (P=0.063). The median survival was 6.4 months (95% CI: 4.3-10.2). The objective response rate was 5% (95% CI: 0.13-24.9%) and the DCR was 75% (95% CI: 51%, 91%). Grade 3/4 adverse events attributable to study drugs were observed in 14 (56%) and included thrombocytopenia, abnormal liver enzymes, rash, and hypertension.. Although the combination of pazopanib plus trametinib had acceptable toxicity with evidence of clinical activity, it did not achieve a statistically significant improvement in 4-month PFS over the prespecified null hypothesised 4-month PFS.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Cholangiocarcinoma; Disease Progression; Disease-Free Survival; Drug Eruptions; Exanthema; Female; Humans; Hypertension; Indazoles; Male; MAP Kinase Kinase Kinases; Middle Aged; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Pyrimidinones; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Survival Rate; Thrombocytopenia

Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.

Topics: Aniline Compounds; Animals; Anisoles; Antineoplastic Agents; Benzeneacetamides; beta Catenin; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cholangiocarcinoma; Clodronic Acid; Heterocyclic Compounds, 2-Ring; Humans; Keratins; Liposomes; Macrophages; Male; Mice, Nude; Pyridines; Pyrimidines; Pyrimidinones; Rats, Sprague-Dawley; Tamoxifen; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Cholangiocarcinoma is a relatively rare cancer of the biliary ducts that is highly refractory to treatment. The factors that drive cholangiocarcinoma are poorly understood, though chronic liver fluke infection is a risk factor for disease. In this issue of the JCI, Boulter and colleagues demonstrate that the WNT/β-catenin signaling pathway is upregulated in patients with sporadic cholangiocarcinoma. The authors determined that macrophages generate WNT ligands in cholangiocarcinomas and depletion or inhibition of this cell population in animal models of cholangiocarcinoma reduced tumor burden and proliferation. Moreover, pharmacological inhibition of WNT secretion or β-catenin activity was efficacious in animal models. Together the results of this study suggest that targeting WNT has potential as a therapeutic strategy for cholangiocarcinoma.

Topics: Animals; Antineoplastic Agents; Benzeneacetamides; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Bridged Bicyclo Compounds, Heterocyclic; Cholangiocarcinoma; Humans; Male; Pyridines; Pyrimidinones; Wnt Signaling Pathway

Topics: Animals; Antineoplastic Agents; Benzeneacetamides; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Bridged Bicyclo Compounds, Heterocyclic; Cholangiocarcinoma; Humans; Male; Pyridines; Pyrimidinones; Wnt Signaling Pathway