Treatment of Kaposi Sarcoma-Associated Herpesvirus-Associated Cancers

Kaposi sarcoma (KS) is the most frequent AIDS-defining cancer worldwide. KS-associated herpesvirus (KSHV) is the etiological agent of KS, and the virus is also associated with two lymphoproliferative diseases. Both KS and KSHV-associated lymphomas, are cancers of unique molecular composition. They represent a challenge for cancer treatment and an opportunity to identify new mechanisms of transformation. Here, we review the current clinical insights into KSHV-associated cancers and discuss scientific insights into the pathobiology of KS, primary effusion lymphoma, and multicentric Castleman’s disease

Determinants of mTOR inhibitor therapy in AIDS-associated malignancies

Rapamycin/Sirolimus™ leads to the regression of transplant- associated Kaposi sarcoma (KS). It also leads to disease stabilization in HIV-associated KS. Case reports and a wealth of preclinical studies support rapamycin’s efficacy also in AIDS associated lymphoma, such as primary effusion lymphoma (PEL). Rapamycin inhibits the mammalian target of rapamycin (mTOR) and papamycin derivatives are approved for the treatment of mantle cell lymphoma and other cancers. It is not universally effective against all solid tumors. Even within this group of clinically responsive cancers, there are exceptions of cases or cell models in which this drug or its derivatives (rapalogs) fail

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Kaposi sarcoma–associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. This human gammaherpesvirus was discovered in 1994 by Drs. Yuan Chang and Patrick Moore. Today, there are over five thousand publications on KSHV and its associated malignancies. In this article, we review recent and ongoing developments in the KSHV field, including molecular mechanisms of KSHV pathogenesis, clinical aspects of KSHV-associated diseases, and current treatments for cancers associated with this virus

AKTivation of PI3K/AKT/mTOR signaling pathway by KSHV

As an obligate intracellular parasite, Kaposi sarcoma-associated herpesvirus (KSHV) relies on the host cell machinery to meet its needs for survival, viral replication, production, and dissemination of progeny virions. KSHV is a gammaherpesvirus that is associated with three different malignancies: Kaposi sarcoma (KS), and two B cell lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman’s disease. KSHV viral proteins modulate the cellular phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which is a ubiquitous pathway that also controls B lymphocyte proliferation and development. We review the mechanisms by which KSHV manipulates the PI3K/AKT/mTOR pathway, with a specific focus on B cells

AKTivation of PI3K/AKT/mTOR signaling pathway by KSHV

As an obligate intracellular parasite, Kaposi sarcoma-associated herpesvirus (KSHV) relies on the host cell machinery to meet its needs for survival, viral replication, production, and dissemination of progeny virions. KSHV is a gammaherpesvirus that is associated with three different malignancies: Kaposi sarcoma (KS), and two B cell lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman’s disease. KSHV viral proteins modulate the cellular phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which is a ubiquitous pathway that also controls B lymphocyte proliferation and development. We review the mechanisms by which KSHV manipulates the PI3K/AKT/mTOR pathway, with a specific focus on B cells

Kaposi sarcoma associated herpesvirus pathogenesis (KSHV)—an update

Kaposi sarcoma-associated herpesvirus (KSHV) is the etiological agent of several human malignancies. The virus is able to modulate pro-proliferative pathways to its advantage, while simultaneously inhibiting pro-apoptotic signaling pathways. These functions are carried out by multiple viral proteins acting in concert. The overall outcome is the survival and proliferation of the infected cell. Additionally, the virus also modulates innate immune pathways to allow for prolonged survival of the infected cell following primary infection, and during viral latency. Here we review the latest advances in our knowledge of KSHV pathogenesis

Modeling the Daily Activities of Breeding Colonial Seabirds: Dynamic Occupancy Patterns in Multiple Habitat Patches

We constructed differential equation models for the diurnal abundance and distribution of breeding glaucous-winged gulls (Larus glaucescens) as they moved among nesting and non-nesting habitat patches. We used time scale techniques to reduce the differential equations to algebraic equations and connected the models to field data. The models explained the data as a function of abiotic environmental variables with R2=0.57. A primary goal of this study is to demonstrate the utility of a methodology that can be used by ecologists and wildlife managers to understand and predict daily activity patterns in breeding seabirds

Habitat Patch Occupancy Dynamics of Glaucous-winged Gulls (larus glaucescens) ii: A Continuous-time Model

The diurnal distribution and abundance dynamics of loafing Glaucous-winged Gulls (Larus glaucescens) were examined at Protection Island National Wildlife Refuge, Strait of Juan de Fuca, Washington. Asynchronous movement of gulls among three habitat patches dedicated to loafing was modeled as a function of environmental variables using differential equations. Multiple time scale analysis led to the derivation of algebraic models for habitat patch occupancy dynamics. The models were parameterized with hourly census data collected from each habitat patch, and the resulting model predictions were compared with observed census data. A four-compartment model explained 41% of the variability in the data. Models that predict the dynamics of organism distribution and abundance enhance understanding of the temporal and spatial organization of ecological systems, as well as the decision-making process in natural resource management. © 2005 Rocky Mountain Mathematics Consortium

Combined Inhibition of Akt and mTOR Is Effective Against Non-Hodgkin Lymphomas

Non-Hodgkin lymphoma (NHL) are a diverse group of hematological malignancies comprised of over 60 subtypes. These subtypes range from indolent to aggressive. The PI3K/Akt/mTOR pathway has been shown to contribute to cell survival and proliferation and is constitutively active in most NHL. MK-7075 (miransertib) and MK-4440 are small molecules that effectively inhibit Akt and have entered clinical development. Using in vitro and in vivo models of NHL, we explored targeting the kinase Akt with miransertib and MK-4440 alone or in combination with the mTORC1 inhibitor, rapamycin (sirolimus). Both Akt inhibitors inhibited the pathway and NHL proliferation in a subtype-dependent manner. However, these compounds had a minimal effect on the viability of primary B-cells. Importantly, the combination of miransertib and sirolimus synergistically reduced cell proliferation in NHL, including in one indolent subtype, e.g., follicular lymphoma (FL), and two aggressive subtypes, e.g., diffuse large B-cell lymphoma (DLBCL) and primary effusion lymphoma (PEL). To establish in vivo efficacy, we used several xenograft models of FL, DLBCL, and PEL. The results obtained in vivo were consistent with the in vitro studies. The FL xenograft was highly sensitive to the inhibition of Akt alone; however, the tumor burden of PEL xenografts was only significantly reduced when both Akt and mTORC1 were targeted. These data suggest that targeting the PI3K/Akt/mTOR pathway with Akt inhibitors such as miransertib in combination with mTOR inhibitors serves as a broadly applicable therapeutic in NHL

Targeting the PI3K/AKT/MTOR pathway in KSHV-associated cancers

Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to three different human cancers: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). We have previously reported that the PI3K/Akt/mTOR pathway is critical for the survival of KSHV-infected endothelial cells and B cells, and have demonstrated that Rapamycin/Sirolimus, an inhibitor of mTOR, can induce PEL cell death in vitro and in vivo (Sin et al., Blood. 2007. 109(5):2165–73). We have now extended these findings and demonstrate that therapeutic targeting of other members of the PI3K/Akt/mTOR signal transduction pathway can also induce cell death in PEL in vitro and inhibit tumor growth in murine xenograft models. Importantly, some of these novel drug candidates have passed clinical trials for other indications and can therefore be tested for efficacy against KS and AIDS-associated lymphomas