Том 11, № 7 (2011)

Since its first description Focal Adhesion Kinase (FAK), a cytoplasmatic tyrosine kinase, has been implicated in the formation and progression of solid and liquid malignant tumors. Therefore orally available selective small molecule inhibitors of FAK have been developed, three of them (PF-562-271, PF-04554878 and GSK2256098) are already in clinical testing. This review discusses the recent data obtained from these Phase 1 trials. We also discuss available data on the mechanisms of action of these inhibitors in carcinogenesis and demonstrate that FAK plays an important role in neoangiogenesis which is a crucial step in cancer growth.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase which mediates integrin signaling from the sites of connection to the extracellular membrane known as focal adhesions. FAK mediates essential cellular processes including growth, proliferation, adhesion, migration, and survival through its functions as a molecular scaffold and as a kinase. FAK is frequently overexpressed and overactive in prostate cancer, which represents the second leading cause of cancer deaths in American men. Through the activation of major oncogenic pathways, FAK promotes the growth, survival, migration, metastasis, and androgen-independence of prostate tumors in vitro and in vivo. A full examination of FAK kinase function has never been completed despite many studies suggesting its importance and the development of kinase-specific therapeutic inhibitors. An expanded understanding of FAK kinase function is required to understand the role of FAK in prostate cancer progression, thereby aiding future development of novel inhibitory drugs and screening procedures.

Hyaluronan (HA) and hyaluronan synthases (HAS) have been implicated in cancer growth and progression. We previously have shown that HAS3 and HA mediate tumor growth in SW620 colon cancer cells, but the mechanism remains poorly understood. In addition, the effect of HAS3 inhibition on tumor growth with other cells lines has not been explored. We therefore hypothesized that inhibition of HAS3 in highly tumorigenic HCT116 colon cancer cells would decrease tumor growth and that the underlying mechanism would involve altering proliferation and/or apoptosis. HAS3 expression was inhibited by transfection with siRNA; a scrambled sequence served as a control. Stable transfectants were injected into the flanks of nude mice and tumor growth followed for 30 days. Proliferation and apoptosis were then assessed in the harvested tumors. Results were compared using the Students t-test and ANOVA where appropriate. siRNA transfection decreased HAS3 expression, protein production, and pericellular HA retention, and decreased in vivo tumor growth. Proliferation was unaffected in the HCT116 tumors, but increased slightly in the SW620 tumors. In contrast, HAS3 inhibition significantly increased apoptosis in all tumors. HAS3 inhibition decreases subcutaneous tumor growth by colon cancer cells and significantly increases apoptosis with less effect on proliferation. These data show that HAS3 and HA mediate colon cancer growth by inhibiting apoptosis.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase implicated in cancer progression, and plays a vital role in integrating environmental signals from growth factors, extracellular matrix and mechanical forces. As a scaffolding protein, FAK interacts and regulates the activity of many signaling kinases including Src, VEGFR-3, p53, PI3k and IGF-1R. In turn, FAK activity is modulated by a complex network of regulators that presents a number of therapeutic approaches to targeting FAK in cancer therapy. The ATP competitive inhibitors binds directly to FAK kinase domain to abrogate multiple downstream signaling pathways, and this class of agents lead the way in FAK inhibitor clinical development. CFAK-C4 and Y15 represents a novel class of non-ATP dependant, allosteric inhibitors that interrupt protein-protein interactions to achieve anti-cancer effects. The optimal approach to targeting FAK for cancer therapy is currently under investigation. Preliminary efficacy signals from early-phase trials suggest that FAK inhibitors may be best used in combination therapy. In addition to determining dosing schedules that is tolerable by patients, future clinical studies should include mechanistic-based pharmacodynamic studies to determine the biological active dose and explore potential predictive markers. In summary, a rich pipeline of FAK-targeting agents is entering clinical development and has the potential of improving the lives of cancer patients.

Drosophila modeling can be effectively used for comprehensive and refined analysis of tumorigenesis, including the discovery of therapeutic anti-cancer drugs and their testing [1]. The Drosophila lgl gene was the first animal tumor suppressor found and the first tumor-associated gene encoding cytoplasmic protein. We compared the gene ontology of two cancer – associated cytoplasmic proteins, Lgl and DFak56 (ortholog of human focal adhesion kinase, FAK). On the molecular level, both Lgl and FAK are involved in protein binding and the formation of macromolecular complexes mediated by phosphorylation in specific sites. On the cellular level, Lgl and FAK participate in cytoskeletal structure/dynamics, cell/ESM and cell to cell adhesion, and cell/tissue polarity. The biological processes of both genes comprise protein transport, cell signaling, cell motility and proliferation. Surprisingly, we found that diverse lgl*- null variants are widespread in lgl*-/lgl+ haplozygotic state in distant populations. To address this paradox, we found that under permanent thermal stress the developmental viability and the life span of lgl*-/lgl+ heterozygotes increased compared to the control flies. The stress-protective haplo-adaptive effect was maternally mediated and sex-specific, as males are more sensitive. The exposure of virgin haplozygotic females with one functional lgl allele to pulse thermal stress at successive stages of oogenesis showed that the germ line - early oocyte stage appeared most sensitive. Pulse heating of this stage in the parental females with one lgl dose resulted in a transgenerational haplo-adaptive effect on the viability and life span of the next generation animals. These data are important for a comprehensive knowledge of cancer-associated gene effects and evaluation of the aftermath of cancer therapy.

Cancer nanotherapeutics have shown promise in resolving some of the limitations of conventional drug delivery systems such as nonspecific biodistribution and targeting, lack of water solubility, low therapeutic indices, and poor oral bioavailability. Moreover, cancer nanotechnology has the potential of improving current approaches to cancer detection, diagnosis, and imaging. Recently, nanotechnology and molecular imaging have been combined to generate nanoparticles that simultaneously facilitate cancer therapy and diagnosis, the so called theragnostic nanoparticles. The aim of our review is to highlight recent developments within the context of the current knowledge of nanotechnology, to recall the experimental steps that have brought to the clinical development and application of nanoparticles, and explain the biological rationale for their use with oncologic patients. In particular, we summarize recent findings with respect to possible new applications for therapy and diagnosis, and their specific properties. Moreover, we report the more recent prospects in gene therapy, the possibility of using new drug delivery methods, the action of nanoparticles on the immune system and apoptosis, and the concrete possibility of detecting and characterizing circulating tumor cells or of developing new technologies in drug discovery.