Targeted therapy in lymphoma

Discovery of new treatments for lymphoma that prolong survival and are less toxic than currently available agents represents an urgent unmet need. We now have a better understanding of the molecular pathogenesis of lymphoma, such as aberrant signal transduction pathways, which have led to the discovery and development of targeted therapeutics. The ubiquitin-proteasome and the Akt/mammalian target of rapamycin (mTOR) pathways are examples of pathological mechanisms that are being targeted in drug development efforts. Bortezomib (a small molecule protease inhibitor) and the mTOR inhibitors temsirolimus, everolimus, and ridaforolimus are some of the targeted therapies currently being studied in the treatment of aggressive, relapsed/refractory lymphoma. This review will discuss the rationale for and summarize the reported findings of initial and ongoing investigations of mTOR inhibitors and other small molecule targeted therapies in the treatment of lymphoma

Integrating precision medicine through evaluation of cell of origin in treatment planning for diffuse large B-cell lymphoma

Precision medicine is modernizing strategies for clinical study design to help improve diagnoses guiding individualized treatment based on genetic or phenotypic characteristics that discriminate between patients with similar clinical presentations. Methodology to personalize treatment choices is being increasingly employed in clinical trials, yielding favorable correlations with improved response rates and survival. In patients with diffuse large B-cell lymphoma (DLBCL), disease characteristics and outcomes may vary widely, underscoring the importance of patient classification through identification of sensitive prognostic features. The discovery of distinct DLBCL molecular subtypes based on cell of origin (COO) is redefining the prognosis and treatment of this heterogeneous cancer. Owing to significant molecular and clinical differences between activated B-cell-like (ABC)- and germinal center B-cell-like (GCB)-DLBCL subtypes, COO identification offers opportunities to optimize treatment selection. Widespread adoption of COO classification would greatly improve treatment and prognosis; however, limitations in interlaboratory concordance between immunohistochemistry techniques, cost, and availability of gene expression profiling tools undermine universal integration in the clinical setting. With advanced methodology to determine COO in a real-world clinical setting, therapies targeted to specific subtypes are under development. The focus here is to review applications of precision medicine exemplified by COO determination in DLBCL patients

Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma.

Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients

Net Charge Fluctuations in Au + Au Interactions at sqrt(s_NN) = 130 GeV

Data from Au + Au interactions at sqrt(s_NN) = 130 GeV, obtained with the PHENIX detector at RHIC, are used to investigate local net charge fluctuations among particles produced near mid-rapidity. According to recent suggestions, such fluctuations may carry information from the Quark Gluon Plasma. This analysis shows that the fluctuations are dominated by a stochastic distribution of particles, but are also sensitive to other effects, like global charge conservation and resonance decays.Comment: 6 pages, RevTeX 3, 3 figures, 307 authors, submitted to Phys. Rev. Lett. on 21 March, 2002. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (will be made) publicly available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm

Flow Measurements via Two-particle Azimuthal Correlations in Au + Au Collisions at sqrt(s_NN) = 130 GeV

Two particle azimuthal correlation functions are presented for charged hadrons produced in Au + Au collisions at RHIC sqrt(s_NN) = 130 GeV. The measurements permit determination of elliptic flow without event-by-event estimation of the reaction plane. The extracted elliptic flow values v_2 show significant sensitivity to both the collision centrality and the transverse momenta of emitted hadrons, suggesting rapid thermalization and relatively strong velocity fields. When scaled by the eccentricity of the collision zone, epsilon, the scaled elliptic flow shows little or no dependence on centrality for charged hadrons with relatively low p_T. A breakdown of this epsilon scaling is observed for charged hadrons with p_T > 1.0 GeV/c for the most central collisions.Comment: 6 pages, RevTeX 3, 4 figures, 307 authors, submitted to Phys. Rev. Lett. on 11 April 2002. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (will be made) publicly available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm

Measurement of the mid-rapidity transverse energy distribution from sNN=130\sqrt{s_{NN}}=130 GeV Au+Au collisions at RHIC

The first measurement of energy produced transverse to the beam direction at RHIC is presented. The mid-rapidity transverse energy density per participating nucleon rises steadily with the number of participants, closely paralleling the rise in charged-particle density, such that E_T / N_ch remains relatively constant as a function of centrality. The energy density calculated via Bjorken's prescription for the 2% most central Au+Au collisions at sqrt(s_NN)=130 GeV is at least epsilon_Bj = 4.6 GeV/fm^3 which is a factor of 1.6 larger than found at sqrt(s_NN)=17.2 GeV (Pb+Pb at CERN).Comment: 307 authors, 6 pages, 4 figures, 1 table, submitted to PRL 4/18/2001; revised version submitted to PRL 5/24/200

Centrality Dependence of Charged Particle Multiplicity in Au-Au Collisions at sqrt(s_NN)=130 GeV

We present results for the charged-particle multiplicity distribution at mid-rapidity in Au - Au collisions at sqrt(s_NN)=130 GeV measured with the PHENIX detector at RHIC. For the 5% most central collisions we find $dN_{ch}/d\eta_{|\eta=0} = 622 \pm 1 (stat) \pm 41 (syst)$. The results, analyzed as a function of centrality, show a steady rise of the particle density per participating nucleon with centrality.Comment: 307 authors, 43 institutions, 6 pages, 4 figures, 1 table Minor changes to figure labels and text to meet PRL requirements. One author added: M. Hibino of Waseda Universit

Event-by-event fluctuations in Mean pTp_T and Mean eTe_T in sqrt(s_NN) = 130 GeV Au+Au Collisions

Distributions of event-by-event fluctuations of the mean transverse momentum and mean transverse energy near mid-rapidity have been measured in Au+Au collisions at sqrt(s_NN) = 130 GeV at RHIC. By comparing the distributions to what is expected for statistically independent particle emission, the magnitude of non-statistical fluctuations in mean transverse momentum is determined to be consistent with zero. Also, no significant non-random fluctuations in mean transverse energy are observed. By constructing a fluctuation model with two event classes that preserve the mean and variance of the semi-inclusive p_T or e_T spectra, we exclude a region of fluctuations in sqrt(s_NN) = 130 GeV Au+Au collisions.Comment: 10 pages, RevTeX 3, 7 figures, 4 tables, 307 authors, submitted to Phys. Rev. C on 22 March 2002. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (will be made) publicly available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm

Centrality dependence of pi^[+/-], K^[+/-], p and p-bar production from sqrt(s_NN)=130 GeV Au + Au collisions at RHIC

Identified pi^[+/-] K^[+/-], p and p-bar transverse momentum spectra at mid-rapidity in sqrt(s_NN)=130 GeV Au-Au collisions were measured by the PHENIX experiment at RHIC as a function of collision centrality. Average transverse momenta increase with the number of participating nucleons in a similar way for all particle species. The multiplicity densities scale faster than the number of participating nucleons. Kaon and nucleon yields per participant increase faster than the pion yields. In central collisions at high transverse momenta (p_T greater than 2 GeV/c), anti-proton and proton yields are comparable to the pion yields.Comment: 6 pages, 3 figures, 1 table, 307 authors, accepted by Phys. Rev. Lett. on 9 April 2002. This version has minor changes made in response to referee Comments. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm