Project Details
Projekt
The heat shock protein/signaling interface as a therapeutic target in multiple myeloma and in Graft-versus-Host-Disease
Applicants
Dr. Manik Chatterjee; Professor Dr. Hermann Einsele
Subject Area
Hematology, Oncology
Term
from 2009 to 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 100308792
Allogeneic stem cell transplantation is currently the only proven treatment modality that is potentially curative for patients even with high-risk multiple myeloma (MM), as evidenced by recent results of our DSMM V clinical trial. However, achievement of a therapeutic Graftversus- MM effect is often limited by two major complications in the early phase upon transplantation: an overshooting immune response by massive proliferation and activation of alloreactive T cells (Graft-versus-Host-Disease; GvHD) and an MM relapse by proliferation of residual tumor cells. A dual therapeutic strategy that suppresses the growth of alloreactive T as well as MM cells is therefore highly warranted. Both MM and alloreactive T cells share crucial signaling pathways. These are stabilized by heat shock proteins (HSP), which act as molecular chaperones providing protection from cell death under acute or chronic cellular stress conditions. Therefore, we hypothesize that a functional HSP/signaling interface may be critical for both MM cell and T cell survival and proliferation, and thus represents a dual potential therapeutic target. Previously, we have shown that elevated HSP90 levels stabilize key signaling pathways regulating cell cycle or apoptosis in MM as well as in activated (including alloreactive) T cells. This finding indicates that pharmacological HSP90 inhibition could indeed serve as a reasonable dual therapeutic strategy to eradicate minimal residual disease while controlling GvHD. However, we observed that HSP90 inhibition is accompanied with strong induction of the heat shock transcription factor 1 (HSF1)/HSP70 system suggesting a potential salvage mechanism in MM as well as in activated T cells. We therefore aim to analyze the HSF1/HSP70/signaling regulatory circuit in order to develop effective HSP90 combination strategies. We found overexpression of HSF1, HSP72 and HSP73 in MM, and could demonstrate that a tight regulatory link between HSF1/HSP70 and HSP90 sustains chaperone function and appears to be instrumental for MM survival. Analyses of alloreactive T cells after pharmacological HSP72/HSP73 inhibition revealed increased induction of apoptosis. Importantly, blockade of HSP70 further enhanced the lethal effect of HSP90 inhibition in alloreactive T and MM cells. With TP7 we developed a novel class of allosteric HSP70 inhibitors that shows synergistic activity in combination with HSP90 inhibitors. Furthermore, we found that HSF1, and thus HSP70 expression, is co-regulated via the PI3K/Akt pathway in MM cells, and PI3K/Akt inhibition led to strong synergistic apoptotic effects in MM and T cells. In the next funding period, we will further extend our studies on the HSP/signaling interface. Thus, we will optimize novel HSP72/73 and HSF1 inhibitors (with TP7), specifically investigate the HSP70 isoforms HSPA5 and HSPA9 and plan to extend biological testing of potential HSP90 combination therapies in novel MM and GvHD mouse models (with Z1).
DFG Programme
Clinical Research Units
