sirolimus and enzastaurin

Results of treatment for patients with non-Hodgkin's lymphomas have significantly improved over the last decade, especially following the discovery that anti-CD20 antibody therapy can significantly change the outlook for patients with both aggressive and indolent lymphomas. Although investigators have previously attempted to prevent relapses by intensifying chemotherapy programs for patients with poor-risk disease, further improvements in treatment will require development of biologic agents that can be added to current programs and exploitation of currently available drugs that can prevent recurrence of these diseases with good tolerability. This review analyzes currently available plans that can be used to maintain responses or "consolidate" initial responses to therapy, programs that may prevent relapse and potentially cure more patients with lymphomas, with a review of current ongoing trials designed along these lines.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Everolimus; Hematopoietic Stem Cell Transplantation; Humans; Indoles; Lenalidomide; Lymphoma, Non-Hodgkin; Protein-Tyrosine Kinases; Radioimmunotherapy; Randomized Controlled Trials as Topic; Risk Factors; Rituximab; Secondary Prevention; Signal Transduction; Sirolimus; Survival Rate; Thalidomide; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Gene Targeting; Hematopoietic Stem Cell Transplantation; Humans; Indoles; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Nitrogen Mustard Compounds; Prednisone; Prognosis; Purine Nucleosides; Pyrimidinones; Risk; Rituximab; Salvage Therapy; Sirolimus; Transplantation, Autologous; Vincristine

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Brentuximab Vedotin; Diphtheria Toxin; Drug Discovery; Everolimus; Humans; Hydroxamic Acids; Immunoconjugates; Indoles; Inotuzumab Ozogamicin; Interleukin-2; Lenalidomide; Lymphoma; Lymphoma, B-Cell; Nitrogen Mustard Compounds; Purine Nucleosides; Pyrazines; Pyrimidinones; Recombinant Fusion Proteins; Sirolimus; Thalidomide; Vorinostat

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma; the complete response rate for standard therapies in use today is 85 - 90%. NVP-BEZ235 inhibits the PI3K/Akt/mTOR signaling axis at the level of both PI3K and mTOR. In this study, we analyzed the inhibitory effects of NVP-BEZ235 on mantle cell lines and its effects in combination with enzastaurin, everolimus and perifosine.. The effects of NVP-BEZ235 on cell proliferation and apoptosis were evaluated using MTT assay and flow cytometry analysis. The cell cycle analysis was performed applying BrdU incorporation. Western blot analysis was utilized for phosphorylation status evaluation of protein kinases. The interaction between NVP-BEZ235 and enzastaurin, everolimus and perifosine was examined by Chou-Talalay method.. NVP-BEZ235 induced significant increase of apoptosis, both via intrinsic and extrinsic pathways. We found that NVP-BEZ235 inhibited mantle cells growth by induction of G1 arrest. NVP-BEZ235 exerts its antitumor activity even when mantle cells were in contact with bone marrow microenvironment. Enzastaurin, everolimus and perifosine enhanced the cytotoxicity triggered by NVP-BEZ235.. The above results encourage clinical development of NVP-BEZ235 in combination and the possible inclusion of patients with mantle lymphoma in Phase I/II clinical trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Bone Marrow; Cell Line, Tumor; Cell Proliferation; Everolimus; Flow Cytometry; G1 Phase Cell Cycle Checkpoints; Humans; Imidazoles; Indoles; Lymphoma, Mantle-Cell; Phosphorylation; Phosphorylcholine; Protein Kinases; Quinolines; Sirolimus

Rapamycin is an mTOR inhibitor with preclinical efficacy in squamous cell carcinoma of the head and neck (SCCHN). However, mTOR inhibitors also increase Akt activity in SCCHN cell lines, which would promote survival and oncogenesis. Enzastaurin is an AGC kinase inhibitor with nanomolar inhibitory concentrations for Akt and protein kinase C (PKC). Moreover, Akt and PKC inhibitors have demonstrated efficacy in SCCHN.. We hypothesized that the combination of rapamycin and enzastaurin would be more effective than either agent alone.. Rapamycin and enzastaurin generally inhibited putative targets in SCCHN cell lines in culture. In mice xenografted with CAL27 cells, rapamycin and enzastaurin produced growth delay. In contrast, the combination of rapamycin and enzastaurin caused regression of CAL27 tumors with evidence of inhibition of putative targets, survival, angiogenesis and proliferation.. These data demonstrate that the combination of rapamycin and enzastaurin disrupts critical oncogenic pathways in SCCHN and has efficacy in preclinical models.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Head and Neck Neoplasms; In Situ Nick-End Labeling; Indoles; MAP Kinase Signaling System; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Protein Kinase Inhibitors; Sirolimus; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Angiogenesis has generated interest in oncology because of its important role in cancer growth and progression, particularly when combined with cytotoxic therapies, such as radiotherapy. Among the numerous pathways influencing vascular growth and stability, inhibition of protein kinase B(Akt) or protein kinase C(PKC) can influence tumor blood vessels within tumor microvasculature. Therefore, we wanted to determine whether PKC inhibition could sensitize lung tumors to radiation.. The combination of the selective PKCbeta inhibitor Enzastaurin (ENZ, LY317615) and ionizing radiation were used in cell culture and a mouse model of lung cancer. Lung cancer cell lines and human umbilical vascular endothelial cells (HUVEC) were examined using immunoblotting, cytotoxic assays including cell proliferation and clonogenic assays, and Matrigel endothelial tubule formation. In vivo, H460 lung cancer xenografts were examined for tumor vasculature and proliferation using immunohistochemistry.. ENZ effectively radiosensitizes HUVEC within in vitro models. Furthermore, concurrent ENZ treatment of lung cancer xenografts enhanced radiation-induced destruction of tumor vasculature and proliferation by IHC. However, tumor growth delay was not enhanced with combination treatment compared with either treatment alone. Analysis of downstream effectors revealed that HUVEC and the lung cancer cell lines differed in their response to ENZ and radiation such that only HUVEC demonstrate phosphorylated S6 suppression, which is downstream of mTOR. When ENZ was combined with the mTOR inhibitor, rapamycin, in H460 lung cancer cells, radiosensitization was observed.. PKC appears to be crucial for angiogenesis, and its inhibition by ENZ has potential to enhance radiotherapy in vivo.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Combined Modality Therapy; Endothelium, Vascular; Humans; Indoles; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Mice; Neovascularization, Pathologic; Protein Kinase C; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Radiation Tolerance; Radiation-Sensitizing Agents; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Central Nervous System Neoplasms; Combined Modality Therapy; Drug Therapy, Combination; ErbB Receptors; Gefitinib; Glioma; Humans; Indoles; Protein Kinase C; Protein Kinase Inhibitors; Protein Kinases; Quinazolines; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases