Components Of Most Influential Components

One of them is Gleevec (Imatinib mesylate), a tyrosine kinase inhibitor, was called a “magical bullet”. This was the first targeted therapy drug used to treat cancer. It was invented in the late 1990’s, to treat “chronic myeloid leukemia and gastrointestinal stromal growth”. Imatinib is tyrosine kinase inhibitors. Tyrosine kinase is a protein that cells use to signal to each other to grow (Iqbal and Iqbal, 2014, p.1). It works by preventing a tyrosine kinase enzyme and therefore inhibits growth factor-induced receptor phosphorylation and blocks the PDGF/PDGFR and P13-k/Akt pathway (Kheradmand, et.al.2016, p.83). According to Richardson (2010, p.679), the drug Velcade was also known as “Bortezomib” is useful in the treatment of multiple myelomas. The main goal of this drug is to lower the tumor growth significantly. The American cancer society (2013, para.20) studies show Bortezomib is a “proteasome inhibitor”. It works by blocking or slowing down the action of proteosome is to break down protein in both healthy and cancerous cells. When proteosome activity is blocked, proteins in the cells accumulate. This accumulation may cause cells to stop growing and multiplying, and cause them to die and Sutent (Sunitinib) is a drug used to treat metastatic renal cell carcinoma. It is currently approved as a second-line treatment of MRCC. Sunitinib inhibits the vascular endothelial growth factor receptor and stops the growth of tumors (Kolesar, et.al. 2008, pp.123 131). It is considered as a multi- targeted kinase inhibitor because it is a type of VEGF inhibitor, an angiogenesis inhibitor, and it blocks an enzyme called tyrosine kinase. By doing all of this, it slows cancer growth and keeps tumors from making their own blood vessels to help them grow and spread (American

Dominant (D) – Described as demanding, vocal, adventurous and competitive, people with dominant personalities often make the first move in social situations and take the lead at work. They are often project leaders, pioneers in their field, and innovators. People with this personality type may seem rude as they are often in a hurry and tend to interrupt other people as they are speaking. Most people would consider them blunt, opinionated and not up for open discussion.

Significance: understanding the mechanism of drug resistance in cancer leads to developing more potent drugs.

Optimal management of NSCLC now requires that tumours be screened for a certain range of predictive and prognostic biomarkers that help to predict sensitivity to targeted therapy and estimate prognosis respectively . For NSCLC, much of the work in the past years has been focussed on mutations of the epidermal growth factor receptor (EGFR) and on the abnormal fusion of the anaplastic lymphoma kinase (ALK) being inhibited successfully with EGFR tyrosine kinase inhibitors (TKI) and crizotinib respectively. Targeted agents are now being rationally designed to inhibit particular mutations leading to a more streamlined clinical trial process. In this review, we will examine the major subtypes of driver mutations that have been identified in NSCLC and relevant targeted therapies available both now, and in the foreseeable future.

Cancer cells displayed marked alterations in pro-growth signaling pathways and key metabolic pathways relative to non-tumorigenic differentiated cells, often due to loss of tumor suppressor genes and oncogenic driver mutations. The remodeled signaling and metabolic profiles of cancer cells support not only their aberrant proliferation, but also their survival. Further factors such as intra-tumoral heterogeneity, altered redox status, and epigenetic modifications all contribute to the ability of certain tumors to develop drug resistance and persist under standard treatments.

Crizotinib (PF-02341066) is a potent inhibitor of c-Met and ALK. Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) is a molecular subtype of NSCLC with at least 27 ALK-fusion variants identified. c-Met is the prototypic member of RTKs, which is the only known high-affinity receptor for hepatocyte growth factor (HGF). Binding of HGF to the c-Met results in receptor multimerization and phosphorylation of multiple tyrosine residues at the intracellular region.

The main focus of this article was to Crizotinib as an inhibitor for ALK-rearragements in the Non-Small Cell Lung Cancer (NSCLC). The drug was first developed because of the ability for a diagnostic fluorescent in situ hybridization assay to be used to detect ALK-rearranged NSCLC. Pfizer has developed this drug to inhibit ALK and MET in many cancers that are associated with mutations in these specific genes. It has recently been shown to have an effect against ROS1-rearragements in NSCLC. This article provided better insight on the heterogeneity between ALK and ROS1 rearrangements in different subtypes of NSCLC. There is also information in the research article that sheds light into the future developments for crizotinib for ALK-rearrangements and some diagnostic assays that can detect NSCLC. This drug is important to the future of cancer therapies because it targets a subtype to NSCLC and defines a molecular target for its effectiveness. It can broaden a field which involves personalized therapies

Mutations (for most cancers) must appear in both tumour suppressing genes and oncogenes for cancers to form. The tumour suppressing genes and oncogenes act in complementary fashion to one another; one pulls forward, and the other pushes back ensuring that the cell cycle occurs in a controlled manner (Sherr, 2004).

A large body of literature has documented hyperactivated AKT signaling in human solid tumors and hematological malignancies[34]. The PI3K/AKT/mTOR signaling pathway plays an important role in HCC and is activated in 30%–50% of HCC[35]. Sorafenib does not target this pathway. AKT/mTOR is critical for regulating growth and proliferation in any cell type. Data from HCC clinical trials have revealed that AKT/mTOR pathway is upregulated upon treatment and therefore the cancer acquires resistance to therapy. Cyclin D1 is a downstream target of AKT, which directly regulates cell cycle progression. Of the three highly conserved AKT isoforms, AKT1 is involved in regulating cell proliferation[36]. Accumulating research suggests that PI3K/AKT activation after sorafenib treatment plays a pivotal role in tumor progression in HCC. p-AKT levels increase in HCC cell lines after treating them with sorafenib [11, 37]. Targeting AKT1 will also suppress the activity of its downstream effector pathway

that can play a role in tumor development." These 300 altered genes could or could not change

In the past, most of the cancer drugs were developed to hinder the growth of tumors. The main strategy was so called “targeted therapies, which interfere with genetic signals that act like accelerators, causing tumors to grow.”1 However, because there are too many pathways and signals that can act as an accelerator of the cancer growth, a single drug was usually not enough to suppress the cancer.

Advance downstream, changes in the tumor silencers TSC1 and TSC2 hyper initiate motioning by mTORC1 (Laplante and Sabatini 2012). This is a critical focus of P13K-Aktsignaling. Additionally, the Ras-ERK pathway is enacted by transformations in Ras, or its downstream target Raf, that reason constitutive initiation of these proteins or by inactivation of GTPase-actuating proteins (Holes, for example, NF1, that empower the hydrolysis of GTP bound to Ras, which prompt its inactivation (Cichowski,2001).

The epidermal growth factor receptor (EGFR) is the cell-surface receptor for extracellular protein ligands. EGFR family has four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu, Her 3 and Her 4. Mutations affecting EGFR expression or activity could lead to cancer.

BYL719 is a specific PI3Kα inhibitor. The PI3K pathway deregulation occurs in more than 50% of breast cancers. Mutations in PIK3CA, the gene encoding the p110alpha subunit of PI3K has been reported to contribute to resistance to endocrine and anti-HER2 therapies.

Dysregulation of the phosphoinositide 3-kinase (PI3K) pathway is one of the common factors observed in approximately 30% of human cancers [10]. In human cancer, PTEN loss or PIK3CA mutation occurs frequently which results in deregulation of the PI3K signaling pathway leading to resistance to antitumor therapies [11]. These pathways are also found to be involved in maintaining the transformed tumor state and metastasized mesothelioma [12-14]. In a recent study, the MET inhibitor PHA-665752 was shown to exert anti-proliferative effects in mesothelioma cell lines by inhibiting MET-dependent PI3K/AKT and RAF/MAPK [15, 16]. Several PI3K/AKT dual inhibitors have been currently studied in clinical trials which have been effective in mutant cancers. One such recently introduced dual PI3K/mTOR inhibitor, PF-04691502 (PF0) has shown potent anti-tumor activity against U87, SKOV3 (PIK3CA mutation), as well as gefitinib- and erlotinib-resistant non–small cell lung carcinoma xenografts indicating it has a broad anti-tumor activity [11]. In this study, we aim to develop and evaluate the potential of this dual inhibitor PF0 encapsulated targeted hybrid nanocarriers for the treatment of MM. In our understanding this is the first study to evaluate the