Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas.

MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (-)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.

Bone tumors of the extremities or pelvis treated by microwave-induced hyperthermia.

From July 1992 through March 1999, 213 patients with malignant bone tumors of the extremities (176 patients) and pelvis (37 patients) were treated by microwave-induced hyperthermia. Osteosarcoma and chondrosarcoma were the most common diagnoses. The limb-salvage procedure was done as follows: After separating the tumor-bearing bone and the extraosseous mass from surrounding normal tissues with a proper margin, microwave energy was delivered into the tumor while the healthy tissues were protected carefully from overheating. Restrengthening of the devitalized bone was necessary in many cases. The eschar resulting from the heat necrosis was curettaged. Most patients can walk early with a partial weightbearing brace for support. The survival rate was 73.9%. Fracture, local recurrence, and infection were the main complications although the majority of complications occurred early in the study. Thermotherapy is a novel and effective way to treat bone tumors in selected patients.