The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

/pdf/cancer-related-inflammation-ltml0xgfd3.pdf

Cancer-related inflammation.

http://aiocm.org/member/Immunity,%20Inflammation,%20and%20Cancer.pdf

Immunity, Inflammation, and Cancer

The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

mTOR Signaling in Growth Control and Disease

mTOR signaling in growth control and disease.

https://archive-ouverte.unige.ch/unige:18229/ATTACHMENT01

TOR signaling in growth and metabolism.

Immunological parameters have been evaluated both in vitro and in vivo in 20 Hodgkin's disease patients in continuous not maintained complete remission for at least 3 years. IgG, IgA and IgM levels were within the normal range. Delayed sensitivity, assayed by a battery of recall antigens, was normal too, in the majority of patients. The number of circulating lymphocytes was slightly inferior to normal controls. T cells, evaluated by the rosette E formation, seems to be diminished; on the contrary, B cells, evaluated by the membrane immunofluorescence, were increased in respect to normal controls. The differences are statistically significant. Timidine uptake of PHA stimulated lymphocytes was diminished too. It is concluded that even if these patients' clinical behaviour is like that of normal population, it is possible to find a disorder in vitro parameters, which could be attributable to long lasting effect of the therapy and/or to the persistence of serum factors acting as anti-T cells antibodies.

Immunological study of patients with Hodgkin's disease in long-lasting not-maintained complete remission.

Myc is one of the most highly activated oncogenes in human cancer, yet therapeutic approaches to directly target Myc are not currently available in the clinic. The evolutionarily conserved function of Myc in regulating ribosome biogenesis and protein synthesis is critical for the Myc oncogenic program. Indeed, deregulated control of mRNA translation leads to increased cellular proliferation, survival and genomic instability during Myc tumorigenesis. Therefore, inhibiting enhanced protein synthesis may represent an attractive strategy for the treatment of Myc-dependent cancers. To this end, we asked if specific components of the protein synthesis machinery could be effective therapeutic targets in Myc-driven cancers. We uncovered a novel functional link between Myc and increased mammalian Target of Rapamycin (mTOR) kinase-dependent phosphorylation of eukaryotic translation initiation factor 4E binding protein (4EBP1), a master regulator of protein synthesis. Specifically, we found in a transgenic model of Myc-driven lymphoma that oncogenic Myc activates mTOR-dependent phosphorylation of 4EBP1 prior to tumor formation while phosphorylation of other mTOR substrates is not increased. Employing a pharmacogenetic approach, we found that mTOR-dependent 4EBP1 phosphorylation is required for cellular survival during Myc-dependent tumor initiation and maintenance. Furthermore, we demonstrated the preclinical efficacy of a newly developed clinical mTOR active site inhibitor MLN0128, which is capable of fully blocking 4EBP1 phosphorylation, in Myc-driven hematologic malignancies. We found that MLN0128 significantly prolonged survival compared to treatment with vehicle or the allosteric mTOR inhibitor, RAD001, which was incapable of inhibiting 4EBP1 phosphorylation. Additionally, we extended the implications of our findings to human diffuse large B-cell lymphomas by demonstrating that high Myc expression correlated with increased phosphorylation of 4EBP1 in a large cohort of patients. Ongoing work will determine the specific translationally regulated mRNAs downstream of 4EBP1-eIF4E that are required for survival of Myc-overexpressing tumors and elucidate the mechanism by which Myc overexpression leads to increased mTOR-dependent phosphorylation of 4EBP1. Together, our findings reveal that an important mTOR substrate is found hyperactivated downstream of Myc oncogenic activity to promote tumor survival and confers synthetic lethality, thereby revealing a unique therapeutic approach to render Myc druggable in the clinic.

Citation Format: Michael Pourdehnad, Morgan L. Truitt, Imran N. Siddiqi, Gregory S. Ducker, Kevan M. Shokat, Davide Ruggero. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A46.

Abstract A46: Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

Ph1-positive chronic myeloid leukaemia presenting in blastic crisis: report of 12 cases.

Tailor Made Protein Synthesis for HSCs

Current therapies of chronic myeloid leukemia (CML) do not prevent the progression of the disease towards blastic metamorphosis, and have not resulted in a remarkable prolongation of survival. Splenectomy was proposed with the aim of removing a part of the tumor without cytotoxics and of removing a potentially privileged pool of malignant blast cells. Acute leukemia-like chemotherapy was proposed with the aim of eradicating or better controlling the highly malignant subclones that emerge during the chronic phase. A preliminary analysis of 2 clinical trials these therapeutic measures, suggests that splenectomy does not modify the rate of blastic transformation, during the first 2 to 3 years from diagnosis. Also the rate of blastic transformation is similar for patients receiving hydroxyurea at first, and arabinosyl cytosine (ARA-C), vincristine (VCR) and prednisone (P) thereafter, as for patients receiving from the clinical onset of CML a more intensive chemotherapy with ARA-C, thioguanine (TG) and daunomycin (DAUNO), but not VCR + P.

Davide Ruggero

Papers

Immunological study of patients with Hodgkin's disease in long-lasting not-maintained complete remission.

Abstract A46: Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

Ph1-positive chronic myeloid leukaemia presenting in blastic crisis: report of 12 cases.

Tailor Made Protein Synthesis for HSCs

Therapy of chronic myeloid leukemia (CML): interim report on protocols CML/73 and CML/74.