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kinase complexes 1and 2regulate translation of important proteinspositioned at the nodal points CX-4945 of several pathways throughout cell growthand proliferation. They are downstream effectors of PI3KAkt and keyregulators of translational initiation by phosphorylation of p70 S6kinase and 4E binding protein1. Targeting of mTORC in BNHL issignificant, and several smallmolecule rapalogs according to the prototyperapamycinwith much less immunosuppression have been evaluated. Onephase II study23 evaluated temsirolimus in patients with treatmentrefractoryBNHL, with an ORR of approximately 40% inFL, CLLSLL, and DLBCL and an RR of approximately 14% inDLBCL. Three patients with FL achieved CR.23 In patients withtreatmentrefractory MCL, treatment with temsirolimusresulted in anORRof38%and a duration of responseof 6.9 months.
24 One more study25 of MCLevaluated a lessmyelosuppressive dose, with anORRof41%. A phase III study26 of MCLcomparing temsirolimuswith physician selection demonstrated ORRs of 22% and 2%,respectively, with a 3month survival advantage. A phase II study oftemsirolimus plus rituximab in MCL is ongoing. A phase II study27evaluating everolimus in aggressive BNHLshowed a 32% ORR. An evaluation of deforolimus CX-4945 inpatients with hematologic malignanciesshowed three ofnine patients with MCL achieving PR.28 mTORC SMIs are active inBNHL, but resistance develops due to interference of a negativefeedback loop that commonly turns off this pathway. In malignancy,blocking of mTORC interferes with this inhibitory feedback loop,resulting in paradoxic enhanced PI3KAkt signaling.
Resistance perhaps overcome with a dual PI3KmTORC SMI or combination of anmTORC SMI with a PI3K, Syk, or Btk SMI.2. Enhancing Tumor Suppressor ActivityA program of gene silencing of tumor suppressors by epigeneticmodification of DNA andor histones is established in human malignancies.Numerous enzymes that epigenetically modify the nucleosomehave been validated as anticancer axitinib targets; of these, DNA methyltransferaseand histone deacetylasehave resulted inapproved drugs for hematologic malignancies.45HDAC inhibitors. The reversible acetylation of histones catalyzedby histone acetyltransferasesandHDACswithin the nucleosomestructure modulates DNA repair and gene expression. In tumors,HDACsdrive the equilibrium of this reaction in favor of deacetylationand tightening of histones, top to epigenetic silencing.
45 DNAmethylation and histone deacetylation work in concert in gene silencingas a result of direct binding interactions in between DNMTs andHDACs. HDAC inhibitorsinduce cellcycle arrest, promote differentiation, NSCLC and hyperacetylateBCL646 and HSP90 and its client proteins.The latter effect seems to achieve a disruption of BCL6 and HSP90function equivalent to that produced by HSP90 inhibitors.45Vorinostat, an oral panHDAC inhibitor approved forcutaneous Tcell lymphoma, has been evaluated in aggressive BNHL.Among 12 patients with DLBCL, three responses had been observed.29 In a second study30 of patients with relapsed DLBCLtreated at 300mgtwice each day, only a single patient achieved CR. In a third study31, no responses had been seen in MCL, whereas activity was seen in FL.
MGCD0103, an oral classIHDACinhibitor, was evaluated inside a phase II study32 axitinib of patients withrelapsed or refractory DLBCLand FL. Amongpatients with DLBCL, a 15% RRwas observed, andof the evaluable patients, 60% had tumor reduction by RECIST. OtherHDACinhibitorsin early phase clinical trials in BNHL are romidepsin, panabinostat, and belinostat.47,48 Because of modest singleagentactivity, CX-4945 combination studies have been initiated with DNMT inhibitors, and bortezomib.47,483. Targeting AntiapoptosisBalanced processes of cell division and programmed cell deathmaintain cellular homeostasis. Extrinsicand intrinsicapoptosispromotingsignaling pathways play a pivotal role in malignant progression andresponse to therapy. Therapeutic targeting of dysregulated antiapoptosisand autophagy gives a rationale to develop agents that promoteNHL apoptosis.
BCL2MCL1 inhibitors. Malignant cells highjack the BCL2 familyof 25 proand antiapoptotic proteins to mainly axitinib inhibit apoptosisby overexpression of antiapoptotic members and sequestration andgene deletion of proapoptotic members.45 In most FL and in someDLBCLcases, BCL2 is juxtaposed with the Ig heavychainlocus, resulting inside a ttranslocation, aberrant overexpression,and resistance to apoptosis.49 ABT263, a BH3mimetic oral SMI ofBCL2, BCLXL, and BCLW, binds with high affinity and inhibits BCL2family proteins. A phase I study evaluated ABT263 in patients withrelapsed or refractoryNHLat doses of 10, 20, 40, 80, 160, 225,and 315 mg inside a 21day cycle with a schedule of 14 days on7 days off.PR was observed in CLLand natural killerTNHL,and minor responses had been observed in FL.33 Simply because ABT263has no activity against MCL1, drug resistance may well be overcome inphase II combination studies with rituximab, bortezomib, or HDACinhibitors. One more approach to overcoming drug resistance utilizesthe broadspectrum B