Molecular targeted therapy: A new avenue in glioblastoma treatment.

Glioblastoma, also referred to as glioblastoma multiforme (GBM), is grade IV astrocytoma characterized by being fast-growing and the most aggressive brain tumor. In adults, it is the most prevalent type of malignant brain tumor. Despite the advancements in both diagnosis tools and therapeutic treatments, GBM is still associated with poor survival rate without any statistically significant improvement in the past three decades. Patient's genome signature is one of the key factors causing the development of this tumor, in addition to previous radiation exposure and other environmental factors. Researchers have identified genomic and subsequent molecular alterations affecting core pathways that trigger the malignant phenotype of this tumor. Targeting intrinsically altered molecules and pathways is seen as a novel avenue in GBM treatment. The present review shed light on signaling pathways and intrinsically altered molecules implicated in GBM development. It discussed the main challenges impeding successful GBM treatment, such as the blood brain barrier and tumor microenvironment (TME), the plasticity and heterogeneity of both GBM and TME and the glioblastoma stem cells. The present review also presented current advancements in GBM molecular targeted therapy in clinical trials. Profound and comprehensive understanding of molecular participants opens doors for innovative, more targeted and personalized GBM therapeutic modalities.

Role of the tumor microenvironment in cancer hallmarks and targeted therapy (Review).

Genetic alterations drive tumor onset and progression. However, the cross­talk between tumor cells and the benign components of the surrounding stroma can also promote the initiation, progression and metastasis of solid tumors. These cellular and non­cellular stromal components form the tumor microenvironment (TME), which co­evolves with tumor cells. Their dynamic and mutualistic interactions are currently considered to be among the distinctive hallmarks of cancer. Biochemical and physical cues from the TME serve an essential role in regulating tumor onset and progression. They are also associated with resistance to treatment and poor prognosis in patients with cancer. Therefore, a deep understanding of the TME is vital for developing potent anticancer therapeutics and improving patient outcomes. The present review aims to review the biology of both cellular and non­cellular constituents of the TME and novel findings regarding their contribution to core as well as emerging cancer hallmarks. The present review also describes key TME markers that are either targeted in interventional clinical trials or serve as promising potential anticancer therapies. Understanding TME components and their intercellular interactions is key toward identifying the mechanisms of progression and treatment resistance. Such understanding is of utmost significance for personalized and effective cancer therapy strategies.

A guide through conventional and modern cancer treatment modalities: A specific focus on glioblastoma cancer therapy (Review).

Cancer still ranks as one of the top causes of morbidity and mortality despite recent improvements in standard chemotherapy, radiotherapy, and surgery. This underlines some of the difficulties in creating successful therapeutic strategies, but it also highlights the shortcomings of conventional methods. In order to enhance the standard treatment of cancer patients, biology­driven therapies are emerging towards more specific and effective clinical options. In the present review, both conventional and novel methods for cancer treatment were addressed, with a particular focus on Glioblastoma multiforme (GBM) therapies. GBM is one of the most challenging cancers for conventional treatments, and survival rates of patients remain very low. In the present review, focus was addressed on employed chemo­ and radiotherapies along with developing novel targeted and immunotherapies assessed in clinical trials on patients with GBM or yet to be evaluated clinically. It was aimed to evaluate efficiency of treatments in suppressing GBMs, roadblocks and challenges. A brief discussion of a few promising delivery methods for targeted drug and gene therapy for cancer was also provided. Increment advancements in this field emphasizes the significance of combining different treatment strategies for improved survival and quality of patients' lives.

Proteome-level assessment of origin, prevalence and function of leucine-aspartic acid (LD) motifs.

MOTIVATION: Leucine-aspartic acid (LD) motifs are short linear interaction motifs (SLiMs) that link paxillin family proteins to factors controlling cell adhesion, motility and survival. The existence and importance of LD motifs beyond the paxillin family is poorly understood. RESULTS: To enable a proteome-wide assessment of LD motifs, we developed an active learning based framework (LD motif finder; LDMF) that iteratively integrates computational predictions with experimental validation. Our analysis of the human proteome revealed a dozen new proteins containing LD motifs. We found that LD motif signalling evolved in unicellular eukaryotes more than 800 Myr ago, with paxillin and vinculin as core constituents, and nuclear export signal as a likely source of de novo LD motifs. We show that LD motif proteins form a functionally homogenous group, all being involved in cell morphogenesis and adhesion. This functional focus is recapitulated in cells by GFP-fused LD motifs, suggesting that it is intrinsic to the LD motif sequence, possibly through their effect on binding partners. Our approach elucidated the origin and dynamic adaptations of an ancestral SLiM, and can serve as a guide for the identification of other SLiMs for which only few representatives are known. AVAILABILITY AND IMPLEMENTATION: LDMF is freely available online at www.cbrc.kaust.edu.sa/ldmf; Source code is available at https://github.com/tanviralambd/LD/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Endogenous Control Mechanisms of FAK and PYK2 and Their Relevance to Cancer Development.

Focal adhesion kinase (FAK) and its close paralogue, proline-rich tyrosine kinase 2 (PYK2), are key regulators of aggressive spreading and metastasis of cancer cells. While targeted small-molecule inhibitors of FAK and PYK2 have been found to have promising antitumor activity, their clinical long-term efficacy may be undermined by the strong capacity of cancer cells to evade anti-kinase drugs. In healthy cells, the expression and/or function of FAK and PYK2 is tightly controlled via modulation of gene expression, competing alternatively spliced forms, non-coding RNAs, and proteins that directly or indirectly affect kinase activation or protein stability. The molecular factors involved in this control are frequently deregulated in cancer cells. Here, we review the endogenous mechanisms controlling FAK and PYK2, and with particular focus on how these mechanisms could inspire or improve anticancer therapies.

Role of the Retinoblastoma protein, Rb, during adult neurogenesis in the olfactory bulb.

Adult neural stem cells (aNSCs) are relatively quiescent populations that give rise to distinct neuronal subtypes throughout life, yet, at a very low rate and restricted differentiation potential. Thus, identifying the molecular mechanisms that control their cellular expansion is critical for regeneration after brain injury. Loss of the Retinoblastoma protein, Rb, leads to several defects in cell cycle as well as neuronal differentiation and migration during brain development. Here, we investigated the role of Rb during adult neurogenesis in the olfactory bulb (OB) by inducing its temporal deletion in aNSCs and progenitors. Loss of Rb was associated with increased proliferation of adult progenitors in the subventricular zone (SVZ) and the rostral migratory stream (RMS) but did not alter self-renewal of aNSCs or neuroblasts subsequent migration and terminal differentiation. Hence, one month after their birth, Rb-null neuroblasts were able to differentiate into distinct subtypes of GABAergic OB interneurons but were gradually lost after 3 months. Similarly, Rb controlled aNSCs/progenitors proliferation in vitro without affecting their differentiation capacity. This enhanced SVZ/OB neurogenesis associated with loss of Rb was only transient and negatively affected by increased apoptosis indicating a critical requirement for Rb in the long-term survival of adult-born OB interneurons.