Clusterin (CLU) has been implicated in various cell functions involved in carcinogenesis and tumour progression. There are two known CLU protein isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is proapoptotic, and a secretory form (sCLU) is prosurvival. CLU expression has been associated with tumorigenesis of various malignancies, including tumours of prostate, colon, and breast. Furthermore, CLU expression is modulated by many factors that are believed to regulate tumour growth and/or apoptosis, including 1,25-dihydroxyvitamin D 3 , transforming growth factor beta-1, ultraviolet radiation, and IR. sCLU upregulation appears to be a general molecular stress response. Presently, preliminary results indicate that therapeutic modalities targeting CLU may be effective in cancer treatment. However, such strategies should make sure that nCLU is not eliminated or reduced. This review summarizes our present understanding of the importance of CLU in various physiological functions including tumour growth, and discusses its relevance to future cancer therapy.

Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E 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.

Summary Therapy of advanced melanoma has been changing dramatically. Following mutational and biological sub-classification 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.

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 incomplete 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.

Metal complexes constitute an attractive class of compounds for applications in medicinal chemistry and chemical biology due to features such as unusual reactivities, tunable ligand exchange kinetics, stereochemical diversity, structural complexity, the availability of radioisotopes, and distinct physicochemical properties. [1] However, it is remarkable that although the discovery of the antiproliferative activity of cis-[PtCl 2 (NH 3) 2 ] dates back almost half a century, [2] cisplatin and its derivatives remain the most important metal-based anticancer drugs used in the clinic at the present day. [3] In the quest for a new generation of metal-containing anticancer agents we here wish to report a class of rhenium(I) complexes as highly potent visible-light-triggered anticancer organometallics. We discovered that rhenium(I) indolato complexes 1-3 provoke a strong light-induced antiproliferative activity in cancer cells (Figure 1). This is unexpected since the related class of rhenium(I) tricarbonyl polypyridine complexes (e.g. 4) are well-established nontoxic luminescent probes routinely applied for biological imaging. [4] Thus, replacing just the 2,2′bipyridine in 4 for 2-(2′-pyridyl)indolato and its derivatives (1-3) completely changes the physicochemical and biological properties of such rhenium(I) complexes by abolishing luminescence and instead causing light-induced anticancer activity. [5] Figure 2 displays the structure of a benzylated derivative of rhenium(I) complex 1 in which rhenium is coordinated in a bidentate fashion to a pyrido[2,3-a]pyrrolo

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 (PDX), cell lines and tumors to identify mutational and copy number aberrations. Samples came from 371 unique individuals; 263 were naïve 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 PDX and cell lines can be used not only as reagents for large array of biological studies, but also as pre-clinical models to facilitate drug development.

The glycoprotein clusterin (CLU), has two known isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is pro-apoptotic, while a secretory form (sCLU) is pro-survival. Both forms are implicated in various cell functions, including DNA repair, cell cycle regulation, and apoptotic cell death. CLU expression has been associated with tumorigenesis and the progression of various malignancies. In response to DNA damage, cell survival can be enhanced by activation of DNA repair mechanisms, while simultaneously stimulating energy-expensive cell cycle checkpoints that delay the cell cycle progression to allow more time for DNA repair. This review summarizes our current understanding of the role of clusterin in DNA repair, apoptosis, and cell cycle control and the relevance.

Melanoma is among the most aggressive and therapy-resistant human cancers. While great strides in therapy have generated enthusiasm, many challenges remain. Heterogeneity is the most pressing issue for all types of therapy. This chapter summarizes the clinical classification of melanoma, of which the research community now adds additional layers of classifications for better diagnosis and prediction of therapy response. As the search for new biomarkers increases, we expect that biomarker analyses will be essential for all clinical trials to better select patient populations for optimal therapy. While individualized therapy that is based on extensive biomarker analyses is an option, we expect in the future genetic and biologic biomarkers will allow grouping of melanomas in such a way that we can predict therapy outcome. At this time, tumor heterogeneity continues to be the major challenge leading inevitably to relapse. To address heterogeneity therapeutically, we need to develop complex therapies that eliminate the bulk of the tumor and, at the same time, the critical subpopulations.