sirolimus and Hodgkin-Disease

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.

Topics: Clinical Trials as Topic; Down-Regulation; Everolimus; Hodgkin Disease; Humans; Recurrence; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Hodgkin's lymphoma (HL) is diagnosed in 20,000 men and women annually in North America and Europe. Despite treatment advancements for HL resulting in an overall survival rate of 80%, patients with advanced stage disease continue to have suboptimal outcomes, with relapse rates of 30%-40%. An additional 10%-15% of patients present with primary refractory disease. For patients who relapse after initial treatment, salvage chemotherapy followed by autologous stem cell transplant in those with chemotherapy-sensitive disease is the standard of care. Patients who relapse after second-line therapy have a median survival time in the range of 6-36 months, and the optimal management of these patients remains unclear. Unfortunately, there have been no new agents approved for relapsed HL treatment since the 1970s. Consequently, clinical decision making in this population is difficult. Recently however, several agents have emerged that have shown clinical promise in this poor-risk population. This review discusses the management of these patients and also discusses several newer agents showing clinical promise in the treatment of HL.

Topics: Antibodies, Monoclonal, Murine-Derived; Boronic Acids; Bortezomib; Brentuximab Vedotin; Drug Therapy; Everolimus; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Immunoconjugates; Immunotherapy; Lenalidomide; Protease Inhibitors; Pyrazines; Recurrence; Rituximab; Secondary Prevention; Sirolimus; Thalidomide

Despite the success of modern therapy for Hodgkin lymphoma (HL), about 15 % of patients will fail both first-line and second-line therapy and treatment options for these patients are limited. New agents are needed to improve the outcome for relapsed or refractory HL and to improve the toxicity of current front-line regimens. Brentuximab vedotin (BV) was recently approved for HL and is likely to have a tremendous impact on the current treatment paradigm for HL. Additional agents that have demonstrated activity in HL include histone deacetylase inhibitors, such as panobinostat, entinostat, and mocetinostat, PI3-kinase/Akt/Mtor pathway inhibitors, such as everolimus, as well as lenalidomide and bendamustine. Studies evaluating these agents alone or in combination with either chemotherapy or other targeted agents are ongoing. Current challenges in HL research include identifying the most appropriate drug combinations of new and old drugs and identifying predictors of response to the new targeted agents.

Topics: Antineoplastic Agents; Bendamustine Hydrochloride; Brentuximab Vedotin; Everolimus; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Immunoconjugates; Lenalidomide; Nitrogen Mustard Compounds; Protein Kinase Inhibitors; Sirolimus; Thalidomide

The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of four (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of six prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic adverse events (AE) were common. Three grade 5 AE occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL (clinicaltrials gov. Identifier: NCT01076543).

Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lenalidomide; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Autologous; Treatment Outcome

Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma.. During the dose-escalation study (ClinicalTrials.gov number: NCT01087554) with the HDAC inhibitor vorinostat and the mTOR inhibitor sirolimus (V+S), a patient with Hodgkin lymphoma refractory to nine prior therapies demonstrated a partial response (PR) lasting for 18.5 months, which promoted additional enrollment of patients with Hodgkin lymphoma as well as exploration of an alternative combination of vorinostat and mTOR inhibitor everolimus (V+E).. Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Everolimus; Female; Hematopoietic Stem Cell Transplantation; Histone Deacetylase Inhibitors; Histone Deacetylases; Hodgkin Disease; Humans; Male; Middle Aged; Recurrence; Sirolimus; Stem Cell Transplantation; TOR Serine-Threonine Kinases; Vorinostat; Young Adult

To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity.. This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximum-tolerated dose. Exploratory analysis of serum cytokine levels was performed.. Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n = 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P = 0.013, and day 15, P = 0.021).. Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Everolimus; Female; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Hydroxamic Acids; Indoles; Interleukin-5; Lymphoma, Non-Hodgkin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Panobinostat; Sirolimus; TOR Serine-Threonine Kinases

Reduced-intensity conditioning (RIC) allo-SCT is a potentially curative treatment approach for patients with relapsed Hodgkin's or non-Hodgkin's lymphoma. In the present study, 37 patients underwent RIC allo-SCT after induction treatment with EPOCH-F(R) using a novel form of dual-agent immunosuppression for GVHD prophylaxis with CsA and sirolimus. With a median follow-up of 28 months among survivors, the probability for OS at 3 and 5 years was 56%. Treatment-related mortality was 16% at day +100 and 30% after 1 year of transplant. Acute GVHD grades II-IV developed in 38% of patients, suggesting that the regimen consisting of CsA and an ultra-short course of sirolimus is effective in the prevention of acute GVHD.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Middle Aged; Prednisolone; Rituximab; Sirolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Vincristine; Young Adult

Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin lymphoma (HL). The goal of this trial was to learn the antitumor activity and toxicity of everolimus in patients with relapsed/refractory HL. Patients were eligible if they had measurable disease, a platelet count >75,000, and an absolute neutrophil count >1,000. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Response was assessed after two and six cycles and then every three cycles until progression. Patients could remain on drug until progression or toxicity. Nineteen patients were enrolled. Median age was 37 years (range, 27-68). Patients had received a median of six prior therapies (range, 3-14) and 84% had undergone prior autologous stem cell transplant. The ORR was 47% (95% CI: 24-71%) with eight patients achieving a PR and one patient achieving a CR. The median TTP was 7.2 months. Four responders remained progression free at 12 months. Patients received a median of seven cycles of therapy. Of the 19 patients, one remains on therapy at 36 months; the others went off study because of progressive disease (16), toxicity (1), and death from infection (1). Four patients experienced a Grade 3 or higher pulmonary toxicity. Everolimus has single-agent activity in relapsed/refractory HL and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant.

Topics: Adult; Aged; Antineoplastic Agents; Disease-Free Survival; Drug Approval; Everolimus; Female; Hodgkin Disease; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Multiprotein Complexes; Neoplasm Recurrence, Local; Proteins; Salvage Therapy; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

Topics: Adolescent; Adult; Aged; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Remission Induction; Risk; Sirolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Triazoles; Young Adult

Growing evidence suggests that deregulation of signalling elements of Notch and mammalian target of rapamycin (mTOR) pathways contribute to tumorigenesis. These signals play important roles in cellular functions and malignancies. Their tumorigenic role in T-cell acute lymphoblastic leukaemia (T-ALL) is well known; however, their potential interactions and functions are poorly characterized in Hodgkin lymphoma (HL). The aim of our study was to characterize mTOR and Notch signalling elements in HL cell lines (DEV, L1236, KMH2) and human biopsies and to investigate their cross-talk in the tumorous process. High mTOR activity and constitutive NOTCH1 activation was confirmed in HL cell lines, without any known oncogenic mutations in key elements, including those common to both pathways. The anti-tumour effect of Notch inhibitors are well known from several preclinical models but resistance and side effects occur in many cases. Here, we tested mTOR and Notch inhibitors and their combinations in gamma-secretase inhibitor (GSI) resistant HL cells in vitro and in vivo. mTOR inhibitor alone or in combination was able to reduce tumour growth; furthermore, it was more effective in xenograft models in vivo. Based on these results, we suggest that constitutively activated NOTCH1 may be a potential target in HL therapy; furthermore, mTOR inhibitors may be effective for decreasing tumour growth if resistance to Notch inhibitors develop.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Proliferation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hodgkin Disease; Humans; Immunoenzyme Techniques; Leukemia; Mice; Mice, SCID; Real-Time Polymerase Chain Reaction; Receptor, Notch1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Although Hodgkin's lymphoma (HL) was one of the first human cancers to be cured by chemotherapy, no new agents other than brentuximab vedotin (Adcetris®, CD 30 directed antibody drug conjugate) have received US Food and Drug Administration (FDA) approval for HL since 1977. Subsets of young adult patients with HL continue to relapse, even after stem cell transplantation, warranting new approaches. Against this background, we report a dramatic response in a young patient with advanced HL refractory to the standard treatment who responded to the combination of a pan-histone deacetylase inhibitor (vorinostat, suberoylanilide hydroxamic acid, SAHA) and mammalian target of rapamycin (mTOR) inhibitor therapy (sirolimus,rapamume). In-depth immunohistochemical and morphoproteomic analyses of this exceptional responder to targeted therapy have yielded potential insights into the biology of advanced HL. The PI3K/AKT/mTOR pathway is a commonly activated pathway in multiple tumor types including HL. The patient was treated using therapy based on mechanistic in vitro data demonstrating that combined histone deacetylase (HDAC) and mTOR inhibition act together on this pathway, resulting in inhibition of reciprocal feedback networks, leading to better anti-proliferative activity. The in vivo response signature from this patient's tissue sample sheds light on immune dysregulation in HL. We describe the response signature achieved from targeting immune dysregulation in addition to targeting the key oncogenic PI3K/AKT/mTOR pathway. We also expand on the role of rapamycin analogs in oncology. This study supports a role for an immune-type pathogenesis that is amenable to immune modulating targeted therapy in refractory HL.. We report an exceptional responder to molecularly targeted and immune modulator therapy in advanced Hodgkin's lymphoma. The morphoproteomic/morphometric findings in this "unusual responder" patient's relapsed HL that correlate best, as a response signature with the subsequent clinical remission following rapamycin (sirolimus) and vorinostat (SAHA) therapies, center on an immune dysregulation involving an imbalance between effector and functional T regulatory cells in addition to targeting the mTOR pathway. This underscores the need for an approach illustrated in our study--namely of focusing on pathogenetic mechanisms and combinatorial therapies that target both the pathogenesis and adaptive responses to contemplated therapies.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Hodgkin Disease; Humans; Hydroxamic Acids; Immunologic Factors; Molecular Targeted Therapy; Phosphoinositide-3 Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Vorinostat

Neoplastic processes, tumor growth, and tumor cell proliferation and survival are often due to the altered activation of different signaling pathways. The increased activity of PI3K/AKT/mTOR signaling has been shown to be an important regulator of tumor growth in several solid tumors and in mantle cell lymphomas. The active form of mTOR kinase (mammalian target of rapamycin) is a key signaling molecule, and it exists in two different complexes, mTORC1 and mTORC2. In the present work, mTOR activity was investigated in different lymphoma types, in parallel with clinical data. We also examined in Hodgkin lymphomas (HL) the role of mTOR activity in survival mechanisms such as antiapoptotic protein expression and alterations in the microenvironment. We determined which lymphoma types display characteristic high mTOR activity in our TMA (tissue microarray) study. We observed that mTOR activity is increased in mitotic lymphoid cells compared to interphasic cells. The number of diffuse large B cell lymphoma (DLBCL) and HL cases was extended in a further set of TMA. We observed significantly higher mTOR activity in the non-centrum germinativum derived subtype of DLBCL than in the centrum germinativum derived subtype, which was a prognostic marker; 63% of mTOR active cases showed Rictor overexpression, indicating mTORC2 activity. High mTOR activity was also established in 92% of HL cases, which was linked to mTORC1. This finding was not a prognostic marker, however, it can be useful in targeted therapy. We observed the overexpression of the antiapoptotic protein BCL-xL and NFκB-p50 in the majority of mTOR active HLs. HLs showed high numbers of regulatory T cells in the microenvironment and high expression of galectin-1 in tumor cells and in the extracellular matrix, when compared to reactive lymph nodes. We confirmed that mTOR inhibition had significant antiproliferative and antiapoptotic effects in lymphoma cell lines and in lymphoma xenografts (HL, DLBCL, Burkitt lymphoma). We also showed that rapamycin was able to augment the effect of chemotherapeutic agents and TGF-β. Taken together, mTOR activity may be a potential therapeutic target in different lymphoma types. However, patient and inhibitor selection criteria must be carefully considered. The combination of mTOR inhibitors with other agents will probably offer the highest efficiency for achieving the best clinical response, and may also allow dose reduction in order to decrease late treatment toxicity in th. A neopláziás folyamatok kialakulása, a daganat növekedése, a daganatsejtek proliferációja és túlélése hátterében gyakran különbözõ jelutak magváltozott aktivitása áll. A PI3K/AKT/mTOR jelút fokozott aktivitása szolid daganatokban és köpenysejtes lymphomákban a daganatkialakulás és -növekedés fontos szabályozója. Az aktív mTOR (mammalian target of rapamycin) kináz két komplex (mTORC1, mTORC2) meghatározó eleme. Az mTOR-aktivitás szerepét vizsgáltuk különbözõ humán lymphomákban, összefüggéseket keresve a betegek klinikai adataival. Hodgkin-lymphomákban (HL) tanulmányoztuk, hogy a magas mTOR-aktivitás milyen, a daganat túlélésében fontos folyamatokban vesz részt (antiapoptotikus mechanizmusok és mikrokörnyezeti változások). Meghatároztuk azokat a humán lymphomatípusokat, amelyekre magas mTOR-aktivitás jellemzõ. Kimutattuk, hogy a mitotikus lymphoid sejtek mTOR-aktivitása magasabb, mint a nem osztódó sejteké. Nagyobb esetszámot tartalmazó TMA-blokkokon (tissue microarray) tovább vizsgáltuk a diffúz nagy B-sejtes lymphoma (DLBCL) és a HL eseteket. Szignifikáns összefüggést mutattunk ki DLBCL-s betegek altípusmegoszlása (csíraközpont-eredetû és nem csíraközpont-eredetû DLBCL-ek) és az mTOR-aktivitás között. DLBCL-ban a fokozott mTOR-aktivitás negatív prognosztikus markernek bizonyult. A HL-ek 92%-a magas mTOR-aktivitást mutatott (mTORC1-hez köthetõ), ami prognosztikus faktorként nem, viszont terápiás célpontként felhasználható. A HL-ek mikrokörnyezetének vizsgálata szerint a regulátor T-sejtek mennyisége a mikrokörnyezetben, valamint a galektin-1-expresszió a tumorsejtekben és az extracelluláris mátrixban emelkedett. A magas mTOR-aktivitás és a galektin-1-expresszió között kapcsolatot találtunk in vitro kísérleteinkben, ahol az mTOR gátlása transzlációs szinten csökkentette a galektin-1-expressziót. Az mTOR-gátlás jelentõségét – proliferációgátló és apoptotikus hatását – humán lymphoma xenograftokban (HL, DLBCL, Burkitt-lymphoma) bizonyítottuk. In vitro kombinációs kezelésekben a rapamycin apoptotikus hatást fokozó szerepét igazoltuk. Munkánkban meghatároztuk azokat a lymphomatípusokat, amelyekben az mTOR-gátlás célzott terápiaként alkalmazható lehet. Eredményeink alapján annak meghatározása, hogy melyik komplexhez köthetõ az mTOR-aktivitás, nagyon fontos a megfelelõ mTOR-gátló (klasszikus vagy kettõs gátlók) kiválasztásában. A jövõben a magas mTOR-aktivitást mutató lymphomákban várhatóan kombinációs kezelésben az mTOR-gátlók használata hozzájárulhatna a jobb t

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Burkitt Lymphoma; Cell Line; Drug Synergism; Galectin 1; Gene Expression Regulation, Neoplastic; Hodgkin Disease; Humans; Immunosuppressive Agents; Interphase; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mitosis; Multiprotein Complexes; NF-kappa B p50 Subunit; Signal Transduction; Sirolimus; T-Lymphocytes, Regulatory; Tissue Array Analysis; TOR Serine-Threonine Kinases; Transforming Growth Factor beta; Up-Regulation; Xenograft Model Antitumor Assays

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Proliferation; Child; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Hodgkin Disease; Humans; Immunohistochemistry; Male; Mice; Mice, SCID; Middle Aged; Signal Transduction; Sirolimus; Tissue Array Analysis; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays; Young Adult

The pan-deacetylase inhibitor panobinostat (LBH589) recently has been shown to have significant clinical activity in patients with relapsed Hodgkin lymphoma, but its mechanism of action in Hodgkin lymphoma remains unknown. In this study, we demonstrate that panobinostat has potent antiproliferative activity against Hodgkin lymphoma-derived cell lines. At the molecular level, panobinostat activated the caspase pathway, inhibited STAT5 and STAT6 phosphorylation, and down-regulated hypoxia-inducible factor 1 α and its downstream targets, glucose transporter 1 (GLUT1) and vascular endothelial growth factor. Paradoxically, panobinostat inhibited LKB1 and AMP-activated protein kinase, leading to activation of mammalian target of rapamycin (mTOR) that promotes survival. Combining panobinostat with the mTOR inhibitor everolimus (RAD001) inhibited panobinostat-induced mTOR activation and enhanced panobinostat antiproliferative effects. Collectively, our data demonstrate that panobinostat is a potent deacetylase inhibitor against Hodgkin lymphoma-derived cell lines, and provide a mechanistic rationale for combining panobinostat with mTOR inhibitors for treating Hodgkin lymphoma patients. Furthermore, the effect of panobinostat on GLUT1 expression suggests that panobinostat may modulate the results of clinical diagnostic imaging tests that depend of functional GLUT1, such as fluorodeoxyglucose positron emission tomography.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chemokines; Cytokines; Drug Synergism; Everolimus; Flow Cytometry; Glucose Transporter Type 1; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Hydroxamic Acids; Hypoxia-Inducible Factor 1; Immunosuppressive Agents; Indoles; Panobinostat; Phosphorylation; Protein Serine-Threonine Kinases; Sirolimus; STAT5 Transcription Factor; STAT6 Transcription Factor; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Topics: Adult; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Drug Approval; Everolimus; Hodgkin Disease; Humans; Intracellular Signaling Peptides and Proteins; Neoplasm Recurrence, Local; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

Topics: Adult; Brain Diseases; Female; Graft vs Host Disease; Hodgkin Disease; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Peripheral Blood Stem Cell Transplantation; Sirolimus; Syndrome

The molecular mechanisms underlying the pathogenesis of the malignant Hodgkin's/Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL) are largely unknown. This study investigates the contribution of phosphatidyl-inositide 3 kinase (PI3-kinase) and demonstrates that Akt, a substrate of PI3-kinase, is constitutively activated in HL-derived cell lines. Several downstream effectors of Akt signalling, including glycogen synthase kinase 3 (GSK-3) alpha and beta and mTOR substrates 4E-BP1 and p70 S6 kinase, were also phosphorylated in HL cells. The mTOR inhibitor, rapamycin, inhibited phosphorylation of these proteins. Furthermore, LY294002 inhibited phosphorylation of p70 S6 kinase and 4E-BP1, suggesting that the phosphorylation of p70 S6 kinase and 4E-BP1 in HL cells is PI3-kinase dependent. Importantly, HRS cells of primary tumour samples not only expressed high levels of activated Akt but also displayed phosphorylation of downstream targets of Akt activation including GSK-3, 4E-BP1, and p70 S6 Kinase. Inhibition of PI3-kinase and mTOR showed only modest effects on cell survival at the lower serum concentrations. However, rapamycin and doxorubicin acted synergistically to reduce HL cell survival. A combination of rapamycin and chemotherapy should be investigated in the treatment of HL.

Topics: Adaptor Proteins, Signal Transducing; Antibiotics, Antineoplastic; Carrier Proteins; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Chromones; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Hodgkin Disease; Humans; Immunohistochemistry; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases

The immunosuppressive macrolide rapamycin and its derivative everolimus (SDZ RAD, RAD) inhibit the mammalian target of rapamycin (mTOR) signaling pathway. In this study, we provide evidence that RAD has profound antiproliferative activity in vitro and in NOD/SCID mice in vivo against Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) cells. Moreover, we identified 2 molecular mechanisms that showed how RAD exerts antiproliferative effects in HL and ALCL cells. RAD down-regulated the truncated isoform of the transcription factor CCAAT enhancer binding protein beta (C/EBPbeta), which is known to disrupt terminal differentiation and induce a transformed phenotype. Furthermore, RAD inhibited constitutive nuclear factor kappaB (NF-kappaB) activity, which is a critical survival factor of HL cells. Pharmacologic inhibition of the mTOR pathway by RAD therefore interferes with essential proliferation and survival pathways in HL and ALCL cells and might serve as a novel treatment option.

Topics: Animals; CCAAT-Enhancer-Binding Protein-beta; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Everolimus; Hodgkin Disease; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Inbred NOD; Mice, SCID; NF-kappa B; Sirolimus; Transplantation, Heterologous