Repurposing an old drug:Dichloroacetate’s potential to reduce acidification of the tumour microenvironment in melanoma

Recent advances in immunotherapy have shown unprecedented efficacy and improved survival of patients with metastatic melanoma. Nevertheless, still, a large population, estimated at around 50% of metastatic melanoma patients, do not benefit from immunotherapy. In the past decades, metabolism has become a hallmark in cancer. In melanoma specifically, it was linked to immunotherapy resistance. A high glucose uptake and lactate production is a commonly shared trait in melanoma. Lactate contributes greatly to the acidification of the tumour microenvironment (TME) and confers an immunosuppressive TME that leads to attenuated immunotherapy responses. Modulating metabolism to lower lactate production and thereby reverting the immunosuppressive TME might be a promising line of study to enhance the efficacy of immunotherapy in metastatic melanoma patients. As a proof-of-concept, a 13C-tracer-based clinical trial is planned with dichloroacetate (DCA) to repurpose and validate its use to lower lactate metabolism in melanoma patients. DCA redirects the lactate precursor into mitochondrial metabolism, thus preventing excessive lactate production. The analysis of 13C-tracer enrichment allows for direct insight into the active metabolic processes, contrary to the quantification of metabolite concentrations alone. It is important to realise that many challenges lie ahead for the implementation of DCA as a standard in melanoma therapy. Amongst these challenges is the unmet need for tools and markers to monitor and predict the response of melanoma metabolism to DCA, and more specifically to determine how patient-specific metabolic phenotypes affect this DCA response. In this thesis, I aimed to meet these challenges and present data and the developed methods that lay the groundwork for interpreting pre-clinical and clinical data, studying melanoma metabolism, and monitoring and predicting drug response in vivo in melanoma

Multifractality at the spin quantum Hall transition

Statistical properties of critical wave functions at the spin quantum Hall transition are studied both numerically and analytically (via mapping onto the classical percolation). It is shown that the index $\eta$ characterizing the decay of wave function correlations is equal to 1/4, at variance with the $r^{-1/2}$ decay of the diffusion propagator. The multifractality spectra of eigenfunctions and of two-point conductances are found to be close-to-parabolic, $\Delta_q\simeq q(1-q)/8$ and $X_q\simeq q(3-q)/4$.Comment: 4 pages, 3 figure

Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities

Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC50 values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2-to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3-to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs

Super Spin-Charge Separation for class A, C, and D disorder

We prove versions of super spin-charge separation for all three of the symmetry groups SU(N), Sp(2N), and SO(N) of disordered Dirac fermions in 2+1 dimensions, which involve the supercurrent-algebras gl (1|1)_{N}, osp(2|2)_{-2N}, and osp(2|2)_N respectively. For certain restricted classes of disordered potentials, the latter supercurrent algebra based conformal field theories can arise as non-trivial low energy fixed points. For all cases with such a fixed point, we compute the density of states exponents as a function of N.Comment: 10 pages; section 3 adde

Disordered O(n) Loop Model and Coupled Conformal Field Theories

A family of models for fluctuating loops in a two dimensional random background is analyzed. The models are formulated as O(n) spin models with quenched inhomogeneous interactions. Using the replica method, the models are mapped to the $M\to 0$ limits of $M$-layered O(n) models coupled each other via $\phi_{1,3}$ primary fields. The renormalization group flow is calculated in the vicinity of the decoupled critical point, by an epsilon expansion around the Ising point ($n=1$), varying $n$ as a continuous parameter. The one-loop beta function suggests the existence of a strongly coupled phase ($0<n<n_*$) near the self-avoiding walk point ($n=0$) and a line of infrared fixed points ($n_*<n<1$) near the Ising point. For the fixed points, the effective central charges are calculated. The scaling dimensions of the energy operator and the spin operator are obtained up to two-loop order. The relation to the random-bond $q$-state Potts model is briefly discussed.Comment: 48 pages, 12 figures, uses iopar

Simultaneous Quantification of the Concentration and Carbon Isotopologue Distribution of Polar Metabolites in a Single Analysis by Gas Chromatography and Mass Spectrometry

13C-isotope tracing is a frequently employed approach to study metabolic pathway activity. When combined with the subsequent quantification of absolute metabolite concentrations, this enables detailed characterization of the metabolome in biological specimens and facilitates computational time-resolved flux quantification. Classically, a 13C-isotopically labeled sample is required to quantify 13C-isotope enrichments and a second unlabeled sample for the quantification of metabolite concentrations. The rationale for a second unlabeled sample is that the current methods for metabolite quantification rely mostly on isotope dilution mass spectrometry (IDMS) and thus isotopically labeled internal standards are added to the unlabeled sample. This excludes the absolute quantification of metabolite concentrations in 13C-isotopically labeled samples. To address this issue, we have developed and validated a new strategy using an unlabeled internal standard to simultaneously quantify metabolite concentrations and 13C-isotope enrichments in a single 13C-labeled sample based on gas chromatography-mass spectrometry (GC/MS). The method was optimized for amino acids and citric acid cycle intermediates and was shown to have high analytical precision and accuracy. Metabolite concentrations could be quantified in small tissue samples (≥20 mg). Also, we applied the method on 13C-isotopically labeled mammalian cells treated with and without a metabolic inhibitor. We proved that we can quantify absolute metabolite concentrations and 13C-isotope enrichments in a single 13C-isotopically labeled sample. BT/Industrial Microbiolog

Non-chiral current algebras for deformed supergroup WZW models

We study deformed WZW models on supergroups with vanishing Killing form. The deformation is generated by the isotropic current-current perturbation which is exactly marginal under these assumptions. It breaks half of the global isometries of the original supergroup. The current corresponding to the remaining symmetry is conserved but its components are neither holomorphic nor anti-holomorphic. We obtain the exact two- and three-point functions of this current and a four-point function in the first two leading orders of a 1/k expansion but to all orders in the deformation parameter. We further study the operator product algebra of the currents, the equal time commutators and the quantum equations of motion. The form of the equations of motion suggests the existence of non-local charges which generate a Yangian. Possible applications to string theory on Anti-de Sitter spaces and to condensed matter problems are briefly discussed.Comment: 43 pages, Latex, one eps figure; v.2: minor corrections, a reference adde

Localization in the quantum Hall regime

The localization properties of electron states in the quantum Hall regime are reviewed. The random Landau model, the random matrix model, the tight-binding Peierls model, and the network model of Chalker and Coddington are introduced. Descriptions in terms of equivalent tight-binding Hamiltonians, and the 2D Dirac model, are outlined. Evidences for the universal critical behavior of the localization length are summarized. A short review of the supersymmetric critical field theory is provided. The interplay between edge states and bulk localization properties is investigated. For a system with finite width and with short-range randomness, a sudden breakdown of the two-point conductance from $ne^{2}/h$ to 0 ($n$ integer) is predicted if the localization length exceeds the distance between the edges.Comment: 16 pages, to be published in Physica E, Proceedings of the Symposium "Quantum Hall Effect: Past, Present and Future

Anderson Transitions

The physics of Anderson transitions between localized and metallic phases in disordered systems is reviewed. The term ``Anderson transition'' is understood in a broad sense, including both metal-insulator transitions and quantum-Hall-type transitions between phases with localized states. The emphasis is put on recent developments, which include: multifractality of critical wave functions, criticality in the power-law random banded matrix model, symmetry classification of disordered electronic systems, mechanisms of criticality in quasi-one-dimensional and two-dimensional systems and survey of corresponding critical theories, network models, and random Dirac Hamiltonians. Analytical approaches are complemented by advanced numerical simulations.Comment: 63 pages, 39 figures, submitted to Rev. Mod. Phy

SK channel-mediated metabolic escape to glycolysis inhibits ferroptosis and supports stress resistance in C. elegans

Metabolic flexibility is an essential characteristic of eukaryotic cells in order to adapt to physiological and environmental changes. Especially in mammalian cells, the metabolic switch from mitochondrial respiration to aerobic glycolysis provides flexibility to sustain cellular energy in pathophysiological conditions. For example, attenuation of mitochondrial respiration and/or metabolic shifts to glycolysis result in a metabolic rewiring that provide beneficial effects in neurodegenerative processes. Ferroptosis, a non-apoptotic form of cell death triggered by an impaired redox balance is gaining attention in the field of neurodegeneration. We showed recently that activation of small-conductance calcium-activated K+ (SK) channels modulated mitochondrial respiration and protected neuronal cells from oxidative death. Here, we investigated whether SK channel activation with CyPPA induces a glycolytic shift thereby increasing resilience of neuronal cells against ferroptosis, induced by erastin in vitro and in the nematode C. elegans exposed to mitochondrial poisons in vivo. High-resolution respirometry and extracellular flux analysis revealed that CyPPA, a positive modulator of SK channels, slightly reduced mitochondrial complex I activity, while increasing glycolysis and lactate production. Concomitantly, CyPPA rescued the neuronal cells from ferroptosis, while scavenging mitochondrial ROS and inhibiting glycolysis reduced its protection. Furthermore, SK channel activation increased survival of C. elegans challenged with mitochondrial toxins. Our findings shed light on metabolic mechanisms promoted through SK channel activation through mitohormesis, which enhances neuronal resilience against ferroptosis in vitro and promotes longevity in vivo