Biomodulatory metronomic therapy in stage <scp>IV</scp> melanoma is well‐tolerated and may induce prolonged progression‐free survival, a phase <scp>I</scp> trial

Hart, Christina; Vogelhuber, Martin; Hafner, Christian; Landthaler, Míchael; Berneburg, Mark; Haferkamp, Sebastian; Herr, Wolfgang; Reichle, Albrecht

doi:10.1111/jdv.13391

Cited by 15 publications

(32 citation statements)

References 11 publications

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“…Controlling such inflammatory processes may aid in prolonging progression-free survival in patients with metastatic melanoma. Hart et al (2016) combined pioglitazone, etoricoxib, low-dose trofosfamide, and temsirolimus for stage IV melanoma, and concluded that the combined therapy could potentially prolong progression-free survival duration [299]. Independently, pioglitazone with rofecoxib in conjunction with low-dose chemotherapy in metastatic melanoma also reached a similar conclusion [300], suggesting that multi-modal therapy that includes PPARγ agonists benefits melanoma patients.…”

Section: Skin Cancermentioning

confidence: 98%

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Cheng

Tan

Low

et al. 2019

IJMS

164

152

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Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.

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Section: Skin Cancermentioning

confidence: 98%

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Cheng

Tan

Low

et al. 2019

IJMS

164

152

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“…The current study was designed to investigate melanomainduced functional changes at distant organ sites in patients with metastatic melanoma (17). Proteome profiling from blood serum samples was the method of choice for the screening of any kind of melanoma-associated reprogramming of organ functions at distant sites.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

Muqaku

Eisinger

Meier

et al. 2017

Molecular & Cellular Proteomics

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Pathophysiologies of cancer-associated syndromes such as cachexia are poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA, and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting of nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44, and C4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to alter levels of several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified Serum is the most important diagnostic sample type because of its minimal invasive access, a relatively high stability and its comprehensive representation of the physiological state of an individual. The latest technological development of mass spectrometric instruments, such as high resolution orbitrap instruments, improved substantially the quality and reliability of serum proteomics data (1). Shotgun proteomics analysis using the orbitrap technology is mainly applied for protein screening purposes (2). This method allows performing untargeted analyses, applicable for hypothesis-generating clinical applications. Targeted proteomics using triple-quadrupole mass spectrometric instruments, represents a complementary approach which is applied for protein quantification, hypotheses verification and validation (3). Enormous efforts have been invested in the last decades focusing on serum biomarker discovery (4). However, mass spectrometrybased proteomics analyses hardly managed to cope with biological variation. As a consequence, almost no clinically validated biomarker has emerged from these investigations yet, and a lot of questions about pathophysiological mechanisms remain unanswered.Using mass spectrometry-based proteomics, we have previously investigated melanoma and neighboring stroma cells, focusing on the identification of biomarkers associated with intrinsic and extrinsic drug resistance (5). In the present article, we followed the question how metastatic melanoma may reprogram distant organ functions, and how these...

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“…Agonistically active drugs, such as transcriptional modulators, contribute to the orchestrated restoration of apoptosis or differentiation competence (32, 41) at low, regulatory active dose levels and in a clinically relevant way (9, 81). Communication-guiding therapy aims to facilitate the reversing of tumor conditioning, also attenuation of aggressive tumor growth, as well as resolving tumorassociated conditions at distant organ sites, e.g., resolving cachexia (18,59).…”

Section: Targeting Tumor Systems With Master Modifiersmentioning

confidence: 99%

Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue—Going Beyond Apoptosis Induction

et al. 2019

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The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or "normalizing" such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia.

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Biomodulatory metronomic therapy in stage IV melanoma is well‐tolerated and may induce prolonged progression‐free survival, a phase I trial

Cited by 15 publications

References 11 publications

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue—Going Beyond Apoptosis Induction

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