PMC3960191_01
FDG PET/CT scans showing metabolic response to therapy. Response in the 26 year old female with classic Hodgkin's lymphoma with sirolimus and vorinostat after 6 lines of therapy. Pre-treatment scans show extensive lymphoma. Scans after 3 cycles of therapy show an exceptional response and decreased SUV activity.
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F1
Positron emission tomography and computed tomography (PET/CT) scans were done (Figure 1 A), which showed increasing lymphoma involving lymph nodes, liver, spleen and bones. A restaging PET/CT after 3 cycles of therapy noted a dramatic metabolic response to therapy (Figure 1 B).
Patient biopsy specimen containing lesional R-S/H cells and companionate lymphocytes. H&E stained section (Frame A; inset shows CD30 positivity); plasmalemmal expression of insulin-like growth factor (IGF)-1 receptor[Tyr1165/1166] (Frame B); p-Akt [Ser 473] detected on the plasmalemmal-cytoplasmic aspect and in occasional nuclei (Frame C); Sirt1 expression in the majority of the nuclei (Frame D); Foxp3 showing nuclear expression in companionate lymphocytes (Frame E); and CD8 expression(Frame F) on the plasmalemmal aspect of companionate lymphocytes (TIA-1 and p-mTOR [Ser 2448], not depicted; DAB brown chromogenic signal; original magnifications x600 for Frames A and B and x400 for Frames C-F).
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F2
The hematoxylin-eosin stained section of the patient's HL revealed R-S/H cells and companionate lymphocytes (Figure 2, Frame A). Morphoproteomic analysis demonstrated the following: CD30 immunopositivity on the plasmalemmal aspect of R-S/H cells (Figure 2, Frame A with inset); the insulinlike growth factor(IGF) pathway as evidenced by the expression (up to 2+ on a scale of 0 to 3+) of IGF-1R (Tyr1165/1166) on the plasmalemmal aspect of R-S/H cells and companionate lymphocytes (Figure 2, Frame B); correlative expression and activation of the downstream pathway of convergence in IGF signaling in the form of mTOR, phosphorylated on serine 2448 with up to 3+ nuclear and 1+ cytoplasmic expression scores and p-Akt (Ser 473) at up to 1+ in the cytoplasmic-plasmalemmal compartment and occasionally up to 3+ in the nuclear compartment, supporting activation of the mTORC2 pathway (see Figure 2, Frame C).Sirt 1, an NAD+ histone deacetylase and an immune modulating protein was noted up to 3+ in the nuclei of the R-S/H cells and in the vast majority of the companionate lymphocytes (Figure 2, FrameD). The numbers of Foxp3+, T regulatory cells and CD8+ and TIA-1+ effector cells were as many as 150, 130 and 70 cells, respectively, per high power field (Figure 2, Frames E, and F).
Key interactions modulated by sirolimus and vorinostat in Hodgkin's Lymphoma. Dashed lines: indirect interactions. Red coloration/t-bar: downregulation: Green coloration/arrow: upregulation. The rationale for combinatorial therapy with vorinostat and sirolimus (rapamycin) is refected in the potential for both the blunting of adaptive responses of the lymphoma process to rapamycin alone and also the beneft of combinatorial therapy to effect functional and expanded T regulatory cells to address an immune dysregulation. For example, rapamycin can, in the short term, result in increased phosphorylative activation of p-Akt on serine 473 by removing the feedback inhibition of IGF-1R pathways signaling through mTORC2. This is countered by vorinostat through the activation of protein phosphatase (PP); the action of the latter leads to dephosphorylation of Akt, including on serine 473. Additionally, rapamycin has been shown to upregulate Sirt1 expression and activity and this would be moderated by the inhibitory effect of vorinostat on Sirt1 at both the genomic and functional level. Moreover, because the actions of rapamycin and vorinostat result in the expansion and function of Foxp3 T regulatory cells, their use in combination should converge on righting any immune dysregulation.
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F3
In order to focus on our attempt to increase T regulatory (Foxp3) function, the network model evoked from Ingenuity Pathway Analysis (IPA, www.ingenuity.com) and additional MEDLINE sources was edited to emphasize the companionate lymphocyte reaction in HL and not the R-S/H cells (see Figure 3).