TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The anti-tumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.

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On April, 14 2016. PharmaMar (MSE:PHM) reported four poster presentations at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, taking place in New Orleans, April 16-20th 2016 (Press release, PharmaMar, APR 14, 2016, View Source [SID:1234510832]). The presentations are based on the latest data obtained on the company’s compounds of marine origin, lurbinectedin, plitidepsin and PM184. Under the heading "Delivering Cures Through Cancer Science", oncologists and investigators from around the world will interchange knowhow and reinforce the links between research and the advancements in patient care.

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PharmaMar will present results from three molecules that are presently under clinical investigation in different types of solid and hematological tumors. Each one of these compounds has a very different mechanism of action. Apart from its direct activity on tumor cells, lurbinectedin (PM1183) also attacks the microenvironment, rendering tumor growth unfeasible. Plitidepsin (Aplidin), targets the eEF1A2 protein, and finally PM184 disrupts the tumor’s blood vessels, causing a reduction in the supply of both nutrients and oxygen to the tumor cells.

"At PharmaMar we have a commitment to the identification of new and novel mechanisms of action from marine compounds that can provide a step forward in the treatment of patients with cancer," explains Carmen Cuevas, Ph.D., R&D Director from the Oncology Business Unit at PharmaMar. "The results that we will present at scientific congresses such as the AACR (Free AACR Whitepaper) show that we are on right path and that we can count on a robust pipeline that will provide new methods for attacking tumor cells." 2
Presentation details are as follows:

PM1183 (lurbinectedin)
PM1183 is compound under clinical investigation, inhibitor of the RNA polymerase II enzyme. It is essential for the transcription process, inhibiting tumor growth, and resulting in tumor death. The antitumor efficacy of PM1183 is being investigated in various types of solid tumors.

Lurbinectedin reduces tumor-associated macrophages and the production of inflammatory cytokines, chemokines and angiogenic factors in preclinical models (abstract No 1284). Paola Allavena et al. Poster presentation, section 18, Monday April 18th, 8:00 am – 12:00 am.

This proves that part of lurbinectedin’s antitumor activity is due to its antiproliferative activity in monocytes and tumor associated macrophages, cells that are essential in the inflammatory microenvironment. Lurbinectedin inhibits transcription, therefore, the production of cytokines and angiogenic factors by these cells. Tumor growth is unfeasible, even when the tumor cells are resistant to the compound.

Lurbinectedin specifically targets transcription in cancer cells, triggering DNA breaks and degradation of phosphorylated Pol II (Abstract No 3039). Gema Santamaría-Nuñez et al. Poster presentation, section 17, Tuesday April 19th , 8:00 am-12:00 am.
Lurbinectedin (PM1183) binds to the DNA in the CG rich regions surrounding the promoter of genes, inhibiting transcription activity. The mechanism involves the ubiquitination and degradation by proteasome of the RNA polymerase II (pol II). The degradation of pol II is directly related to the appearance of DNA damage and the induction of cell death through apoptosis.

Plitidepsin (Aplidin)
Plitidepsin is an antitumor drug of marine origin, at the investigational phase for hematological tumors, including a phase Ib study in relapsed and refractory Multiple Myeloma, in triple combination with bortezomib and dexamethasone, along with a phase II study in Relapsed and Refractory Angioimmunoblastic T-cell Lymphoma. Recently, positive results have been seen in pivotal study in combination with dexamethasone in patients with Multiple Myeloma. 3

Plitidepsin targets the GTP-bound form of eEF1A2 in cancer cells (Abstract No 3015). Alejandro Losada et al. Poster presentation, section 17, Tuesday April 19th, 8:00am-12:00am.

This confirms that the protein eEF1A2 is Aplidin’s pharmacological target. This protein has numerous functions within the tumor cell, some of which have a marked oncogenic character. This assay delves into the peculiarities of the direct interaction of Aplidin with purified GTP bound eEF1A2.

PM184
PM184 is an inhibitor of tubulin polymerization. It is at the clinical development stage for solid tumors, including a Phase II trial in hormone-receptor positive, HER2-negative, locally advanced and/or metastatic breast cancer.

Anti-angiogenic properties of PM184 (Abstract No 3066). Carlos M. Galmarini et al. Poster presentation, section 25, Tuesday April 19th, 8:00am-12:00am.

The tumor cells rapidly growth, needing the supply of a large quantity of nutrients. One of the paths for the treatment of cancer at the moment is to disrupt the blood cells within the tumor, or to stop the development of new cells, cutting the supply of nutrients and oxygen to the tumor cells. Adding to its capacity to specifically eliminate tumor cells, PM184 has shown itself to have a strong intratumor vascular disrupting activity, inhibiting in this extraordinarily effective way, human transplanted tumors in mice.

Targeting protein-protein interacting sites for potential therapeutic applications is a challenge in the development of inhibitors, and this becomes more difficult when these interfaces are relatively planar, as in the eukaryotic translation initiation factor 4E (eIF4E) protein. eIF4E is an oncogene that is overexpressed in numerous forms of cancer, making it a prime target as a therapeutic molecule. We report here the presence of a cryptic pocket at the protein-binding interface of eIF4E, which opens transiently during molecular dynamics simulations of the protein in solvent water and is observed to be stable when solvent water is mixed with benzene molecules. This pocket can also be seen in the ensemble of structures available from the solution-state conformations of eIF4E. The accessibility of the pocket is gated by the side-chain transitions of an evolutionarily conserved tryptophan residue. It is found to be feasible for accommodating clusters of benzene molecules, which signify the plasticity and ligandability of the pocket. We also observe that the newly formed cavity provides a favorable binding environment for interaction of a well-recognized small molecule inhibitor of eIF4E. The occurrence of this transiently accessible cavity highlights the existence of a more pronounced binding groove in a region that has traditionally been considered to be planar. Together, the data suggest that an alternate binding cavity exists on eIF4E and could be exploited for the rational design and development of a new class of lead compounds against the protein.

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The definitive role of ganglioside GM2 in mediating tumor-induced growth and progression is still unknown. Here we report a novel role of ganglioside GM2 in mediating tumor cell migration and uncovered its mechanism. Data shows differential expression levels of GM2-synthase as well as GM2 in different human cancer cells. siRNA mediated knockdown of GM2-synthase in CCF52, A549 and SK-RC-26B cells resulted in significant inhibition of tumor cell migration as well as invasion in vitro without affecting cellular proliferation. Over-expression of GM2-synthase in low-GM2 expressing SK-RC-45 cells resulted in a consequent increase in migration thus confirming the potential role GM2 and its downstream partners play in tumor cell migration and motility. Further, treatment of SK-RC-45 cells with exogenous GM2 resulted in dramatic increase in migratory and invasive capacity with no change in proliferative capacity, thereby confirming the role of GM2 in tumorigenesis specifically by mediating tumor migration and invasion. Gene expression profiling of GM2-synthase silenced cells revealed altered expression of several genes involved in cell migration primarily those controlling the integrin mediated signaling. GM2-synthase knockdown resulted in decreased phosphorylation of FAK, Src as well as Erk, while over-expression and/or exogenous GM2 treatment caused increased FAK and Erk phosphorylation respectively. Again, GM2 mediated invasion and Erk phosphorylation is blocked in integrin knockdown SK-RC-45 cells, thus confirming that GM2 mediated migration and phosphorylation of Erk is integrin dependent. Finally, confocal microscopy suggested co-localization while co-immunoprecipitation and surface plasmon resonance (SPR) confirmed direct interaction of membrane bound ganglioside, GM2 with the integrin receptor.
Copyright © 2016. Published by Elsevier B.V.

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Phosphatase and tensin homologue (PTEN) reduces insulin sensitivity by inhibiting the phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt) pathway. This study investigated how a common single nucleotide polymorphism near PTEN, previously associated with fasting levels of plasma insulin and glucose, influences in vivo glucose metabolism and insulin signalling. The primary outcome measure was the gene variant’s association with peripheral glucose disposal rate and, secondarily, whether this association was explained by altered activities of PTEN targets PI3K and Akt.
A total of 183 normoglycaemic Danes, including 158 twins and 25 singletons, were genotyped for PTEN rs11202614, which is in complete linkage disequilibrium with rs2142136 and rs10788575, which have also been reported in association with glycaemic traits and type 2 diabetes (T2D). Hepatic and peripheral insulin sensitivity was measured using tracer and euglycaemic-hyperinsulinaemic clamp techniques; insulin secretion was assessed by intravenous glucose tolerance test; and muscle biopsies were taken during insulin infusion from 150 twins for measurement of PI3K and Akt activities.
The minor G allele of PTEN rs11202614 was associated with elevated fasting plasma insulin levels and a decreased peripheral glucose disposal rate, but not with the hepatic insulin resistance index or insulin secretion measured as the first-phase insulin response and disposition index. The single nucleotide polymorphism was not associated with either PI3K or Akt activities.
A common PTEN variation is associated with peripheral insulin resistance and subsequent risk of developing T2D. However, the association with insulin resistance is not explained by decreased proximal insulin signalling in skeletal muscle.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.

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