sirolimus and Lymphoma--Primary-Effusion

Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Benzoxazoles; Cell Cycle Checkpoints; Cell Line, Tumor; Disease Models, Animal; Enzyme Inhibitors; Heterografts; Humans; Inhibitory Concentration 50; Lymphoma, Primary Effusion; Mice; Neoplasm Transplantation; Pyrimidines; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Primary effusion lymphoma (PEL) is a fatal malignancy, which typically presents as a lymphomatous effusion that later disseminates. Rapamycin (Rapa), which targets mTOR (mammalian target of Rapa), is currently evaluated as a treatment for PEL, but the recent development of PEL in Rapa-treated post-transplant recipients questions the drug's use in PEL. Here, we used a murine model of PEL effusion that mimics the human disease to investigate the anti-PEL activity of Rapa. We found that Rapa reduces ascites accumulation and extends mouse survival. Initially, Rapa reduced PEL load compared with control mice, but most mice rapidly showed PEL progression. Levels of VEGF, which promotes vascular permeability contributing to effusion formation, were significantly reduced in ascites of Rapa-treated mice compared with controls. Expression of IL-10, the principal autocrine growth factor for PEL, was initially reduced in PEL from Rapa-treated mice but rapidly increased despite treatment. We found that the hypoxic environment of ascites and Rapa cooperate in stimulating IL-10 expression in PEL, which likely contributes to the emergence of drug resistance. These results identify Rapa an effective drug to reduce PEL effusions but illustrate the rapid development of drug resistance, which likely limits the efficacy of Rapa in PEL.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Female; Humans; Hypoxia; Immunoblotting; Immunoenzyme Techniques; Immunosuppressive Agents; Interleukin-10; Interleukin-6; Lymphoma, Primary Effusion; Mice; Mice, Inbred NOD; Mice, SCID; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factors

Topics: Antibiotics, Antineoplastic; Castleman Disease; Herpesvirus 8, Human; Humans; Liver Transplantation; Lymphoma, Primary Effusion; Protein Kinases; Sarcoma, Kaposi; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases; Transplantation Immunology

The Akt/mammalian target of rapamycin (mTOR) signaling cascade has been demonstrated to be constitutively activated in several malignancies, including Kaposi sarcoma (KS) and human herpesvirus-8 (HHV-8)-associated primary effusion lymphoma (PEL). In organ transplant recipients, therapeutic change from cyclosporin to the mTOR inhibitor rapamycin can lead to regression of KS lesions. Recent experiments using PEL cell lines and murine xenograft PEL models suggested that rapamycin could inhibit the growth of PEL cells. In the present report, we describe the cases of two HIV-1-negative males of African origin who underwent renal transplantation and developed PEL while receiving rapamycin as immunosuppressive treatment. Both patients were retrospectively found to be HHV-8 seropositive before renal transplantation. The present case report suggests that rapamycin may not protect HHV-8-infected renal transplant recipients from occurrence of PEL or progression of pre-existing PEL.

Topics: Fatal Outcome; Herpesviridae Infections; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoma, Primary Effusion; Male; Middle Aged; Sirolimus; Treatment Failure