INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses.

Background: As a major driver of lymphocyte proliferation and activation interleukin 2 (IL-2) is a crucial mediator for antitumor responses. Despite promising activity in a subset of patients, wider therapeutic utility of IL-2 (aldesleukin) has been hampered by severe dose-limiting toxicities, the expansion of immunosuppressive regulatory T cells and a poor pharmacokinetic (PK) profile. Recent engineering efforts, including non-α IL-2 variants, have lowered the toxicity profile, but have yet to induce meaningful antitumor activity in a wider patient population.

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in , and (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity.

RSK2 activity mediates glioblastoma invasiveness and is a potential target for new therapeutics.

In glioblastoma (GBM), infiltration of primary tumor cells into the normal tissue and dispersal throughout the brain is a central challenge to successful treatment that remains unmet. Indeed, patients respond poorly to the current therapies of tumor resection followed by chemotherapy with radiotherapy and have only a 16-month median survival. It is therefore imperative to develop novel therapies.

Synthesis of a stable and orally bioavailable englerin analogue.

Synthesis of analogues of englerin A with a reduced propensity for hydrolysis of the glycolate moiety led to a compound which possessed the renal cancer cell selectivity of the parent and was orally bioavailable in mice.

Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression.

Oxidized low-density lipoprotein (oxLDL) accumulates early in atherosclerosis and promotes endothelial nuclear factor κB (NF-κB) activation, proinflammatory gene expression and monocyte adhesion. Like for other atherogenic factors, oxLDL-induced proinflammatory responses requires integrin-dependent focal adhesion kinase (FAK, also known as PTK2) signaling; however, the mechanism by which FAK mediates oxLDL-dependent NF-κB signaling has yet to be revealed. We now show that oxLDL induces NF-κB activation and VCAM-1 expression through FAK-dependent IκB kinase β (IKKβ, also known as IKBKB) activation.

Neopetrocyclamines A and B, polycyclic diamine alkaloids from the sponge Neopetrosia cf exigua.

Two new polycyclic alkaloids, neopetrocyclamines A and B (1 and 2), along with the known metabolites papuamine (3) and haliclonadiamine (4), were isolated from the Indonesian sponge Neopetrosia cf exigua. Neopetrocyclamine A contains a formamidinium moiety, a rare functional group. While these compounds share the same basic biosynthetic building blocks, the size of the ring system differs in 1 and 2 because of the formamidinium moiety.

Organometallic Titanocene-Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties.

Early-late transition metal TiAu compounds [(η-CH)Ti{OC(O)CHPPhAuCl}] () and new [(η-CH)Ti{OC(O)-4-CHPPhAuCl}] () were evaluated as potential anticancer agents against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh}AuCl] (R = -CH- , -4-CH- ) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y.

FAK in cancer: mechanistic findings and clinical applications.

Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. FAK promotes tumour progression and metastasis through effects on cancer cells, as well as stromal cells of the tumour microenvironment. The kinase-dependent and kinase-independent functions of FAK control cell movement, invasion, survival, gene expression and cancer stem cell self-renewal.

FAK Inhibition disrupts a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth.

Ovarian cancer ascites fluid contains matrix proteins that can impact tumor growth via integrin receptor binding. In human ovarian tumor tissue arrays, we find that activation of the cytoplasmic focal adhesion (FAK) tyrosine kinase parallels increased tumor stage, β5 integrin, and osteopontin matrix staining. Elevated osteopontin, β5 integrin, and FAK mRNA levels are associated with decreased serous ovarian cancer patient survival.

Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer.

Objective: Focal adhesion kinase (FAK) is overexpressed in serous ovarian cancer. Loss of merlin, a product of the neurofibromatosis 2 tumor suppressor gene, is being evaluated as a biomarker for FAK inhibitor sensitivity in mesothelioma. Connections between merlin and FAK in ovarian cancer remain undefined.

RSK isoforms in cancer cell invasion and metastasis.

Metastasis, the spreading of cancer cells from a primary tumor to secondary sites throughout the body, is the primary cause of death for patients with cancer. New therapies that prevent invasion and metastasis in combination with current treatments could therefore significantly reduce cancer recurrence and morbidity. Metastasis is driven by altered signaling pathways that induce changes in cell-cell adhesion, the cytoskeleton, integrin function, protease expression, epithelial-to-mesenchymal transition and cell survival.

Englerin a selectively induces necrosis in human renal cancer cells.

The number of renal cancers has increased over the last ten years and patient survival in advanced stages remains very poor. Therefore, new therapeutic approaches for renal cancer are essential. Englerin A is a natural product with a very potent and selective cytotoxicity against renal cancer cells.

RSK2 protein suppresses integrin activation and fibronectin matrix assembly and promotes cell migration.

Modulation of integrin activation is important in many cellular functions including adhesion, migration, and assembly of the extracellular matrix. RSK2 functions downstream of Ras/Raf and promotes tumor cell motility and metastasis. We therefore investigated whether RSK2 affects integrin function.

PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma.

ERK and RSK2 drive proliferation and invasion of many cancers. Phosphoprotein enriched in astrocytes 15 (PEA15) binds ERK and RSK2 and high PEA15 levels can impair ERK- and RSK2-dependent transcription. PEA15 expression also inversely correlates with cell motility and invasiveness.

High dose of dietary resveratrol enhances insulin sensitivity in healthy rats but does not lead to metabolite concentrations effective for SIRT1 expression.

Scope: trans-Resveratrol has been shown to improve insulin sensitivity and to enhance cellular glucose uptake. Evidence from recent studies indicates that these effects depend on SIRT1-pathways.

Methods And Results: Since ingestion of resveratrol leads to the presence of resveratrol and resveratrol metabolites in the body, we aimed at investigating (i) whether a daily dose of 300 mg resveratrol/kg body weight in healthy male Wistar rats for a period of 8 wk affects the selected parameters of glucose and lipid metabolism and (ii) whether the resulting plasma concentrations of resveratrol metabolites were effective in modulating SIRT1 expression.

Stictamides A-C, MMP12 inhibitors containing 4-amino-3-hydroxy-5-phenylpentanoic acid subunits.

An extensive study of the secondary metabolites produced by a new Sticta sp. of lichen has led to the isolation of three new compounds containing the 4-amino-3-hydroxy-5-phenylpentanoic acid residue (Ahppa). The structures of stictamides A-C (1-3) were assigned by 2D NMR spectroscopic and chemical methods.

Bit-1 mediates integrin-dependent cell survival through activation of the NFkappaB pathway.

Loss of properly regulated cell death and cell survival pathways can contribute to the development of cancer and cancer metastasis. Cell survival signals are modulated by many different receptors, including integrins. Bit-1 is an effector of anoikis (cell death due to loss of attachment) in suspended cells.

The death effector domain protein PEA-15 negatively regulates T-cell receptor signaling.

PEA-15 is a death effector domain-containing phosphoprotein that binds ERK and restricts it to the cytoplasm. PEA-15 also binds to FADD and thereby blocks apoptosis induced by death receptors. Abnormal expression of PEA-15 is associated with type II diabetes and some cancers; however, its physiological function remains unclear.