A Phase I dose-escalation study of the BRAF inhibitor vemurafenib in combination with the MTOR inhibitor everolimus in subjects with advanced cancer

Vemurafenib has been approved in the United States for the treatment of relapsed or refractory BRAF mutation positive malignant melanoma and is being investigated in various other malignancies. The RAS/RAF/MEK/ERK (MAPK) pathway is critical to cell proliferation in many human cancers. The mTOR inhibitors are well known to exert profound anticancer effects across malignancies through inhibition of the PTEN/PI3K/AKT/mTOR (mTOR) pathway. We hypothesize that the toxicity profile of the combination of vemurafenib and everolimus will be well tolerated. The primary objective is to find the maximum tolerated dose (MTD) and the toxicity of the combination of vemurafenib and everolimus following a standard 3 + 3 design. The most common diagnosis was melanoma in 5 out of 10 patients (50%). Male patients in 7 out of 10 patients (70%). The average age was 63.5 years. Two out of 10 patients (20%) had partial responses and an additional 2 out of 10 patients (20%) had stable disease

Melanoma Brain Metastases in the Era of Target Therapies: An Overview

Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed

Targeting the Hsp90 Molecular Chaperone and Resistant Pathways in BRAF-mutant Melanoma

Melanoma remains the most aggressive and fatal type of skin cancer. In greater than 50% of cases, patients present with an activating BRAF mutation (BRAF+), leading to upregulated mitogen-activated protein kinase (MAPK) pathway signaling. Of these patients, 80-90% have a missense mutation at codon 600 (e.g., BRAFV600E), making the mutant form of the protein an attractive and druggable target. In 2011, the FDA approved combination therapy of BRAF+ and MEK inhibitors (BRAFi/MEKi), like vemurafenib and cobimetinib (Ve/Cb), for use in unresectable late-stage melanoma patients, drastically changing treatment options and initial outcomes. Still, the majority of patients become refractory to BRAFi/MEKi within the first year of treatment. The lack of treatment durability underscores the need for novel therapeutic strategies and drug candidate development, such as the utilization of molecular chaperone inhibitors. The 90-kDa heat shock protein (Hsp90) is a molecular chaperone and responsible for stabilizing the protein folding of “client” proteins that interact with the heterochaperone complex that Hsp90 forms with the 70-kDa heat shock protein (Hsp70) and other co-chaperones. These clients are involved in several cellular signaling pathways and processes, highlighting the significance of chaperone function in eukaryotic cells. Interestingly, Hsp90 expression increases several-fold in cancer cells to compensate for cellular stress and client protein dependence on chaperone function. To-date 18 small molecule Hsp90 inhibitors (Hsp90i) entered clinical trials, of which 94.4% target the N-terminus (NT-Hsp90i) but failed to get FDA approval. The NT-Hsp90i are effective and xvi potent, but pan-inhibitors of all four Hsp90 isoforms. In clinical trials, patients require dose-escalation of NT-Hsp90i to reach a therapeutic effect, ultimately leading to dose-limiting toxicities (DTL). Studies suggest a link between DTLs and the activation of the heat shock response (HSR), especially the cytoprotective role of Hsp70. Previously, our lab, with collaborators, developed novel C-terminal Hsp90i (CT-Hsp90i) and showed efficacy in several cancer models in vitro and in vivo while mitigating the HSR, suggesting a decreased toxicity profile compared to NT-Hsp90i. For this dissertation, I researched therapeutic resistance mechanisms in BRAF+ melanoma through various preclinical in vitro studies that targeted Hsp90. Specifically, I tested the hypothesis that several resistance-promoting processes require Hsp90 function and, therefore, could be targeted with an Hsp90i to simultaneously knockdown resistance pathways and oncogenic processes. First, I showed effective melanoma cell death using the CT-Hsp90i KU758 at potent micromolar concentrations (e.g., IC50 = 0.36 – 0.43 micromolar). Next, I demonstrated robust synergy (e.g., CI<0.5) of KU758 when combined with either a BRAFi or MEKi to target two resistance pathways effectively (e.g., MAPK/Erk and PI3K/Akt), significantly mitigate melanocyte migration, and downregulate key Hsps involved in HSR activation. Finally, I accessed publicly available genomic data via the National Cancer Institute and The Cancer Genome Atlas (TCGA) program to identify additional genes of interest in BRAF+ melanomas. Using a clustered heatmap of RNA expression data, I distinguished genes of interest based on common expression alterations amongst a subset of BRAF+ melanoma patients to provide a genetic perspective in the context of Hsp90i use in melanoma patients. Collectively, this work reviews the use of and development of several small xvii molecule inhibitors in melanomas (e.g., BRAFi/MEKi and Hsp90i), identifies a novel and effective KU758-combination approach in BRAF+ melanomas, and gives insight into future therapeutic directions based on various translational and genetic signatures in these difficult-to-treat tumors.PHDPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163262/1/jaquesan_1.pd

Novel treatments for advanced thyroid cancer and elucidation of biomarkers

In this thesis we describe the latest developments in the field of advanced thyroid cancer. Several clinical trials with sorafenib and everolimus were performed. The relation between clinical outcome and mutational status was analyzed. Furthermore, the pharmacokinetics of everolimus in patients with advanced thyroid cancer was described. LUMC / Geneeskund