Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors.

Background: Autotaxin-lysophosphatidic acid (ATX-LPA) signaling has a predominant role in immunological and fibrotic processes, including cancer. Several ATX inhibitors and LPA receptor antagonists have been clinically evaluated, but none in patients with solid tumors. Many cancers are burdened with a high degree of fibrosis and an immune desert phenotype (so-called 'cold' tumors). In these cold tumors, the fibrotic stroma provides an intrinsic cancer-supporting mechanism. Furthermore, the stroma prevents penetration and limits the effectiveness of existing therapies. IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Materials and methods: In vitro and in vivo pharmacology studies have been carried out to elucidate the pharmaceutical properties and mechanism of action of IOA-289. A phase I clinical study in healthy volunteers was carried out to determine the pharmacokinetics and pharmacodynamics of IOA-289 following a single oral dose. Results: In vitro and in vivo studies showed that IOA-289 is a potent inhibitor of ATX and, as a monotherapy, is able to slow progression of lung fibrosis and tumor growth in mouse models. In a clinical study, IOA-289 showed a dose-dependent increase in plasma exposure levels and a corresponding decrease in circulating LPA. Conclusions: Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype.

Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment.

A lot of effort has been done to study how cancer cells react to low-oxygen tension, a condition known as hypoxia. Indeed, abnormal and dysfunctional blood vessels in the tumor are incapable to restore oxygenation, therefore perpetuating hypoxia, which, in turn, will fuel tumor progression, metastasis and resistance to antitumor therapies. Nevertheless, how stromal components including blood and lymphatic endothelial cells, pericytes and fibroblasts, as well as hematopoietic cells, respond to low-oxygen tension in comparison with their normoxic counterparts has been a matter of investigation in the last few years only and, to date, this field of research remains poorly understood. In general, opposing phenotypes can arise from the same stromal component when embedded in different tumor microenvironments, and, vice versa, different stromal components can have opposite reaction to the same tumor microenvironment. In this article, we will discuss the emerging link between tumor stroma and hypoxia, and how this complexity is translated at the molecular level.

Regulation of MDM4 (MDMX) function by p76(MDM2): a new facet in the control of p53 activity.

Under basal growth conditions, p53 function is tightly controlled by the members of MDM family, MDM2 and MDM4. The Mdm2 gene codes, in addition to the full-length p90(MDM2), for a short protein, p76(MDM2) that lacks the p53-binding domain. Despite this property and at variance with p90(MDM2), this protein acts positively toward p53, although the molecular mechanism remains elusive. Here, we report that p76(MDM2) antagonizes MDM4 inhibitory function. We show that p76(MDM2) possesses intrinsic ubiquitinating and degrading activity, and through these activities controls MDM4 levels. Furthermore, the presence of p76(MDM2) decreases the association of MDM4 with p53 and p90(MDM2), and antagonizes p53 degradation by the heterodimer MDM4/p90(MDM2). The p76(MDM2)-mediated regulation of MDM4 occurs in the cytoplasm, under basal growth conditions. Conversely, upon DNA damage, phosphorylation of MDM4Ser403 dissociates p76(MDM2) and prevents MDM4 degradation. The overall negative control of MDM4 by p76(MDM2) reflects on p53 function as p76(MDM2) impairs MDM4-mediated inhibition of p53 activity. In agreement with the positive role of p76(MDM2) toward p53, the p76(MDM2)/p90(MDM2) ratio significantly decreases in a group of thyroid tumor samples compared with normal counterparts. Overall, these findings reveal a new mechanism in the control of p53 basal activity that may account for the distinct sensitivity of tissues to stress signals depending on the balance among MDM proteins. Moreover, these data suggest an oncosuppressive function for a product of the Mdm2 gene.

Puzzling over MDM4-p53 network.

MDM4 (also called MDMX) has been initially identified as p53 inhibitor. Subsequent data have reinforced this role pointing to the requirement for MDM4 repressive activity on p53 for mouse embryo development. Molecular studies have shown that MDM4 exerts different activities by controlling both p53 transcriptional function and protein levels. On the basis of these data, therapeutic strategies aiming at releasing p53 from MDM4 inhibition are under development. However, recent studies suggest a more complex relationship between MDM4 and p53. These have evidenced heterogeneity of MDM4 function under different growth conditions and particularly positive activity exerted by MDM4 on stress-activated p53 levels and pro-apoptotic function. This review summarizes the different facets of MDM4-mediated regulation of p53 and the modifications able to modulate MDM4 localization and function.

MDM4 (MDMX) and its Transcript Variants.

MDM family proteins are crucial regulators of the oncosuppressor p53. Alterations of their gene status, mainly amplification events, have been frequently observed in human tumors.MDM4 is one of the two members of the MDM family. The human gene is located on chromosome 1 at q32-33 and codes for a protein of 490aa. In analogy to MDM2, besides the full-length mRNA several transcript variants of MDM4 have been identified. Almost all variants thus far described derive from a splicing process, both through canonical and aberrant splicing events. Some of these variants are expressed in normal tissues, others have been observed only in tumor samples. The presence of these variants may be considered a fine tuning of the function of the full-length protein, especially in normal cells. In tumor cells, some variants show oncogenic properties.This review summarizes all the different MDM4 splicing forms thus far described and their role in the regulation of the wild type protein function in normal and tumor cells. In addition, a description of the full-length protein structure with all known interacting proteins thus far identified and a comparison of the MDM4 variant structure with that of full-length protein are presented. Finally, a parallel between MDM4 and MDM2 variants is discussed.