9 research outputs found
A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma
Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups
Rhenium Complexes with Visible-Light-Induced Anticancer Activity
US National Institutes of Health [CA114046
Personalized pre-clinical trials in BRAF inhibitor resistant patient derived xenograft models identify second line combination therapies
Purpose: To test second-line personalized medicine combination therapies, based on
genomic and proteomic data, in patient-derived xenograft (PDX) models.
Methods: We established 12 PDX from BRAF inhibitor progressed melanoma patients.
Following expansion, PDX were analyzed using targeted sequencing and reverse phase
protein arrays (RPPA). By using multi-arm pre-clinical trial designs, we identified
efficacious precision medicine approaches.
Results: We identified alterations previously described as drivers of resistance: NRAS
mutations in 3 PDX, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and
aberrant PTEN in 7. At the protein level, re-activation of phospho MAPK predominated,
with parallel activation of PI3K in a subset. Second line efficacy of the pan-PI3K inhibitor
BKM120 with either BRAF (encorafenib) /MEK (binimetinib) inhibitor combination or the
ERK inhibitor VX-11e was confirmed in vivo. Amplification of MET was observed in 3
PDX models, a higher frequency than expected and a possible novel mechanism of
resistance. Importantly, MET amplification alone did not predict sensitivity to the MET
inhibitor capmatinib. In contrast, capmatinib as single agent resulted in significant but
transient tumor regression in a PDX with resistance to BRAF/MEK combination therapy
and high pMET. The triple combination capmatinib/ encorafenib/ binimetinib resulted in
complete and sustained tumor regression in all animals.
Conclusions: Genomic and proteomic data integration identifies dual core pathway
inhibition as well as MET as combinatorial targets. These studies provide evidence for
biomarker development to appropriately select patients’ personalized therapies and
avoid treatment failures
Personalized Preclinical Trials in BRAF Inhibitor–Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies
Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines
Summary: Tumor-sequencing studies have revealed the widespread genetic diversity of melanoma. Sequencing of 108 genes previously implicated in melanomagenesis was performed on 462 patient-derived xenografts (PDXs), cell lines, and tumors to identify mutational and copy number aberrations. Samples came from 371 unique individuals: 263 were naive to treatment, and 108 were previously treated with targeted therapy (34), immunotherapy (54), or both (20). Models of all previously reported major melanoma subtypes (BRAF, NRAS, NF1, KIT, and WT/WT/WT) were identified. Multiple minor melanoma subtypes were also recapitulated, including melanomas with multiple activating mutations in the MAPK-signaling pathway and chromatin-remodeling gene mutations. These well-characterized melanoma PDXs and cell lines can be used not only as reagents for a large array of biological studies but also as pre-clinical models to facilitate drug development. : Garman et al. have characterized melanoma PDXs and cell lines described in Krepler et al. (see the related paper in this issue of Cell Reports), identifying major and minor subtypes, some of which were previously not well defined, targeted and immunotherapy resistance, and tumor heterogeneity, creating a set of reagents for future drug discovery and biological studies. Keywords: melanoma, patient-derived xenografts, massively parallel sequencing, cell line
Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors
Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAF(V600E) melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi.ope
A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma
Summary: Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups. : Krepler et al. have established a collection of melanoma patient-derived xenografts (PDX). Melanoma is a very heterogeneous cancer, and this large collection includes even rare subtypes and genetic aberrations in sufficient numbers. Multiple PDX from therapy-resistant patients are characterized and tested in pre-clinical trials for second line therapies. Keywords: melanoma, patient-derived xenografts, targeted therapy, immune checkpoint blockade, melanoma brain metastasis, in vivo models, BRAF inhibitor resistance, ERK inhibitor, MDM2 inhibitor, PI3K beta inhibito