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Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease--a
Ágnes Márk1, Melinda Hajdu, Zsófia Váradi
11st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest 1085, Hungary.
Background:
Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete.
Methods:
mTOR activity and the elements of mTOR complexes were investigated by immunohistochemistry on tissue microarrays representing different human non-Hodgkin-lymphomas (81 cases) and Hodgkin-lymphomas (87 cases). The expression of phospho-mTOR, phospho-4EBP1, phospho-p70S6K, phospho-S6, Rictor, Raptor and Bcl-2, Bcl-xL, Survivin and NF-kappaB-p50 were evaluated, and mTOR activity was statistically analyzed along with 5-year survival data. The in vitro and in vivo effect of the mTOR inhibitor rapamycin was also examined in human Hodgkin-lymphoma cell lines.
Results:
The majority (>50%) of mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, anaplastic large-cell lymphoma and Hodgkin-lymphoma cases showed higher mTOR activity compared to normal lymphoid tissues. Hodgkin-lymphoma was characterized by high mTOR activity in 93% of the cases, and Bcl-xL and NF-kappaB expression correlated with this mTOR activity. High mTOR activity was observed in the case of both favorable and unfavorable clinical response. Low mTOR activity was accompanied by complete remission and at least 5-year disease free survival in Hodgkin-lymphoma patients. However, statistical analysis did not identify correlation beetween mTOR activity and different clinical data of HL patients, such as survival. We also found that Rictor (mTORC2) was not overexpressed in Hodgkin-lymphoma biopsies and cell lines. Rapamycin inhibited proliferation and induced apoptosis in Hodgkin-lymphoma cells both in vitro and in vivo, moreover, it increased the apoptotic effect of chemotherapeutic agents.
Conclusions:
Targeting mTOR activity may be a potential therapeutic tool in lymphomas. The presence of mTOR activity probably indicates that the inclusion of mTOR inhibition in the therapy of Hodgkin-lymphomas may be feasible and beneficial, especially when standard protocols are ineffective, and it may also allow dose reduction in order to decrease late treatment toxicity. Most likely, the combination of mTOR inhibitors with other agents will offer the highest efficiency for achieving the best clinical response.
Insights
Targeting the PI3K/Akt/mTOR pathway shows promise for treating lymphomas. Inhibiting mTOR with rapamycin demonstrated significant anti-cancer effects in Hodgkin lymphoma cells, suggesting a potential new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling Pathways
Background:
- The PI3K/Akt/mTOR pathway is frequently activated in cancers, correlating with poorer survival rates.
- mTOR kinase inhibitors are used in treating certain lymphomas and other cancers, with ongoing clinical trials.
- The precise role and pathological characterization of mTOR activity in various lymphomas remain incompletely understood.
Purpose of the Study:
- To investigate the activity of the mTOR pathway and its complexes in different types of human lymphomas.
- To evaluate the correlation between mTOR activity, specific protein expression, and clinical outcomes in Hodgkin lymphoma (HL).
- To assess the therapeutic potential of the mTOR inhibitor rapamycin in Hodgkin lymphoma models.
Main Methods:
- Immunohistochemistry was used to assess mTOR activity and key protein expression (phospho-mTOR, Rictor, Raptor, etc.) in 81 non-Hodgkin lymphomas and 87 Hodgkin lymphomas.
- Expression of apoptosis-related proteins (Bcl-2, Bcl-xL, Survivin) and NF-kappaB was evaluated.
- Statistical analysis correlated mTOR activity with 5-year survival data, and in vitro/in vivo studies examined rapamycin's effects on HL cell lines.
Main Results:
- Elevated mTOR activity was observed in over 50% of evaluated lymphomas, including Hodgkin lymphoma (93% of cases).
- High mTOR activity correlated with Bcl-xL and NF-kappaB expression in HL, but not with survival outcomes.
- Rapamycin effectively inhibited proliferation and induced apoptosis in HL cells, potentiating the effects of chemotherapy.
Conclusions:
- Targeting mTOR activity presents a viable therapeutic strategy for lymphomas.
- mTOR inhibition may be beneficial in treating Hodgkin lymphomas, particularly when standard therapies fail or to reduce toxicity.
- Combination therapies involving mTOR inhibitors are likely to yield the best clinical responses in lymphoma treatment.
