Mutations as Actionable Targets: A Paradigm Shift in the Management of Colorectal Cancer and Novel Avenues.

mutations in colorectal cancer have been studied over the past several decades. V600E mutation, a class I mutation, is the most common oncogenic alteration in colorectal cancer. Until recently, the V600E mutation was not among actionable genes for colorectal cancer.

Precision medicine for metastatic colorectal cancer: an evolving era.

: Metastatic colorectal cancer (CRC) remains a dilemma for cancer researchers with an increasing incidence in the younger patient population. Until the last decade, limited therapeutic options were available for metastatic CRC patients leading to relatively poor clinical outcomes.: With advances in genome sequencing technology and reductions in the cost of next-generation sequencing, molecular profiling has become more accessible for cancer researchers and clinical investigators, which has furthered our understanding of the molecular behavior of CRC.

Magnetic resonance imaging contrast enhancement in vitro and in vivo by octanuclear iron-oxo cluster-based agents.

A water-soluble octanuclear cluster, [Fe], was studied with regard to its properties as a potential contrast enhancing agent in magnetic resonance imaging (MRI) in magnetic fields of 1.3, 7.2 and 11.

TRIB2 contributes to cisplatin resistance in small cell lung cancer.

Small cell lung cancer (SCLC) is the most aggressive lung-cancer subtype and so far, no favorable therapeutic strategy has been established for chemo-resistant SCLC. Cisplatin is one of the most important components among all standard poly-chemotherapeutic regimens for SCLC; therefore, this study focused on revealing Cisplatin-resistance mechanism(s) in this disease. Cisplatin-resistant SCLC cells were generated in the NCI-H69 xenograft model in nude mice by continuous intravenous administration of Cisplatin; Cisplatin resistance of the tumor cells was confirmed by and tests, and the gene expression profile of the resistant cells was determined using microarray analysis.

CD44 as a drug delivery target in human cancers: where are we now?

In the treatment of cancers, the dual goals of drug targeting are to deliver therapeutic agents more selectively to tumor tissue and to minimize exposure of normal tissues and organs to those agents, the latter causing toxicities that limit treatment and thereby attenuate clinical efficacy. CD44, a transmembrane proteoglycan, has been considered as a targetable candidate to generate a cancer-specific drug delivery axis. Although numerous preclinical studies showed promising results exploiting CD44 as such a target, results of two clinical trials, including a Phase III registration trial, have been very disappointing.

Targeting SH2 domains in breast cancer.

Breast cancer is among the most commonly diagnosed cancer types in women worldwide and is the second leading cause of cancer-related disease in the USA. SH2 domains recruit signaling proteins to phosphotyrosine residues on aberrantly activated growth factor and cytokine receptors and contribute to cancer cell cycling, metastasis, angiogenesis and so on. Herein we review phosphopeptide mimetic and small-molecule approaches targeting the SH2 domains of Grb2, Grb7 and STAT3 that inhibit their targets and reduce proliferation in in vitro breast cancer models.

The consequences of selective inhibition of signal transducer and activator of transcription 3 (STAT3) tyrosine705 phosphorylation by phosphopeptide mimetic prodrugs targeting the Src homology 2 (SH2) domain.

Herein we review our progress on the development of phosphopeptide-based prodrugs targeting the SH2 domain of STAT3 to prevent recruitment to cytokine and growth factor receptors, activation, nuclear translocation and transcription of genes involved in cancer. We developed high affinity phosphopeptides (K I = 46-200 nM). Corresponding prodrugs inhibited constitutive and IL-6 induced Tyr705 phosphorylation at 0.

A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis.

Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a number of human cancers and cancer cell lines. Via its Src homology 2 (SH2) domain, Stat3 is recruited to phosphotyrosine residues on intracellular domains of cytokine and growth factor receptors, whereupon it is phosphorylated on Tyr705, dimerizes, translocates to the nucleus and is reported to participate in the expression of genes related to angiogenesis, metastasis, growth and survival. To block this process, we are developing cell-permeable, phosphatase-stable phosphopeptide mimics, targeted to the SH2 domain of Stat3, that inhibit the phosphorylation of Tyr705 of Stat3 in cultured tumor cells (Mandal et al.

Metronomic activity of CD44-targeted hyaluronic acid-paclitaxel in ovarian carcinoma.

Purpose: Most primary human ovarian tumors and peritoneal implants, as well as tumor vascular endothelial cells, express the CD44 family of cell surface proteoglycans, the natural ligand for which is hyaluronic acid. Metronomic dosing, the frequent administration of chemotherapeutics at substantially lower than maximum tolerated doses (MTD), has been shown to result in reduced normal tissue toxicity and to minimize "off-treatment" exposure resulting in an improved therapeutic ratio.

Experimental Design: We tested the hypothesis that hyaluronic acid (HA) conjugates of paclitaxel (TXL; HA-TXL) would exert strong antitumor effects with metronomic (MET) dosing and induce antiangiogenic effects superior to those achieved with MTD administration or with free TXL.

Magnetic nanovectors for drug delivery.

Nanotechnology holds the promise of novel and more effective treatments for vexing human health issues. Among these are the use of nanoparticle platforms for site-specific delivery of therapeutics to tumors, both by passive and active mechanisms; the latter includes magnetic vectoring of magnetically responsive nanoparticles (MNP) that are functionalized to carry a drug payload that is released at the tumor. The conceptual basis, which actually dates back a number of decades, resides in physical (magnetic) enhancement, with magnetic field gradients aligned non-parallel to the direction of flow in the tumor vasculature, of existing passive mechanisms for extravasation and accumulation of MNP in the tumor interstitial fluid, followed by MNP internalization.

CD44: a validated target for improved delivery of cancer therapeutics.

Introduction: Advances in cancer therapeutics, namely more effective and less toxic treatments, will occur with targeting strategies that enhance the tumor biodistribution and thwart normal tissue exposure of the drug. This review focuses on cancer drug targeting approaches that exploit the expression of the cell-surface proteoglycan family, CD44, on the tumor cell surface followed by some form of ligand binding and induced CD44 internalization and intracellular drug release: in effect using this as a 'Trojan Horse' to more selectively access tumor cells.

Areas Covered: This review defines the origins of evidence for a linkage between CD44 expression and malignancy, and invokes contemporary views of the importance of putative CD44(+) cancer stem cells in disease resistance.

Magnetic nanovectors for drug delivery.

Nanotechnology holds the promise of novel and more effective treatments for vexing human health issues. Among these are the use of nanoparticle platforms for site-specific delivery of therapeutics to tumors, both by passive and active mechanisms; the latter includes magnetic vectoring of magnetically responsive nanoparticles (MNP) that are functionalized to carry a drug payload that is released at the tumor. The conceptual basis, which actually dates back a number of decades, resides in physical (magnetic) enhancement, with magnetic field gradients aligned non-parallel to the direction of flow in the tumor vasculature, of existing passive mechanisms for extravasation and accumulation of MNP in the tumor interstitial fluid, followed by MNP internalization.

Magnetically vectored platforms for the targeted delivery of therapeutics to tumors: history and current status.

Superparamagnetic iron oxide nanoparticles (SPIONs) are being developed as vehicles for the selective targeting of therapeutics and bioactive compounds. Presented herein is a brief review of the history of approaches to magnetic-based drug delivery platforms, leading to current concepts of magnetically vectored therapeutics via functionalized SPION-prodrugs. With this background, recent experimental results are discussed that demonstrate the use of shaped external magnetic field gradients, generated by designed configurations of permanent magnets, to drive the concentration/accumulation of modified SPION-prodrug constructs at a tumor site, followed by tumor extravasation and activation of the prodrug within the tumor microenvironment.

Drug-tolerant cancer cells show reduced tumor-initiating capacity: depletion of CD44 cells and evidence for epigenetic mechanisms.

Cancer stem cells (CSCs) possess high tumor-initiating capacity and have been reported to be resistant to therapeutics. Vice versa, therapy-resistant cancer cells seem to manifest CSC phenotypes and properties. It has been generally assumed that drug-resistant cancer cells may all be CSCs although the generality of this assumption is unknown.

Hyaluronic acid-paclitaxel conjugate inhibits growth of human squamous cell carcinomas of the head and neck via a hyaluronic acid-mediated mechanism.

Chemotherapeutic regimens incorporating taxanes significantly improve outcomes for patients with squamous cell carcinomas of the head and neck (SCCHN). However, treatment with taxanes is limited by toxicities, including bone marrow suppression and peripheral neuropathies. We proposed that conjugating taxanes to targeting carrier molecules would increase antitumor efficacy and decrease toxicity.

Combinatorial selection of DNA thioaptamers targeted to the HA binding domain of human CD44.

CD44, the primary receptor for hyaluronic acid, plays an important role in tumor growth and metastasis. CD44-hyaluronic acid interactions can be exploited for targeted delivery of anticancer agents specifically to cancer cells. Although various splicing variants of CD44 are expressed on the plasma membrane of cancer cells, the hyaluronic acid binding domain (HABD) is highly conserved among the CD44 splicing variants.

Current and future applications of magnetic resonance imaging (MRI) to breast and ovarian cancer patient management.

Magnetic resonance imaging (MRI) is occupying an increasing niche in the clinical diagnostic workup of several cancers, including breast cancers. Despite the high level of implementation of mammography, it has become apparent that MRI can play at least a complementary role in the imaging and diagnosis of primary breast cancers, including ductal carcinoma in situ, the earliest stage of breast cancer that is associated with an increased risk of invasive breast cancer. This can also be said of inflammatory breast cancer, of low incidence but with high impact on overall breast cancer mortality rates, and for which mammography is not ideal due to the typically diffused nature of this disease.

N,N-Dimethylsphingosine conjugates of poly-L-glutamic acid: synthesis, characterization, and initial biological evaluation.

Poly-L-glutamic acid (PGA) has previously been demonstrated to be an effective backbone for creating a hydrophilic prodrug of the established anti-tumor agent, paclitaxel, the active agent in Taxol; this approach has obviated the need for the toxic Cremophor excipient, used to enhance the solubility of paclitaxel in the clinical formulation. In order to form hydrophilic prodrugs of the hydrophobic pro-apoptotic sphingolipid, N,N-dimethylsphingosine (DMSP), PGA was condensed with DMSP, previously modified with coumarin to allow spectroscopic detection during conjugate synthesis, to yield PGA-DMSP. Conjugates with different loadings of DMSP were prepared and evaluated for in vitro cytotoxicity against two human breast adenocarcinoma cell lines.

Hyaluronic acid-paclitaxel: antitumor efficacy against CD44(+) human ovarian carcinoma xenografts.

Numerous human tumor types, including ovarian cancer, display a significant expression of the CD44 family of cell surface proteoglycans. To develop tumor-targeted drugs, we have initially evaluated whether the CD44 ligand hyaluronic acid (HA) could serve as a backbone for paclitaxel (TXL) prodrugs. HA-TXL was prepared by modification of previous techniques.

N,N-dimethylsphingosine-coumarin: synthesis, chemical characterization, and biological evaluation.

Coumarin derivatives of N,N-dimethylsphingosine (DMSP) were prepared and chemically characterized. They were apparently biologically equivalent to DMSP in terms of tumor cell cytotoxicity and were used to establish the rapid mitochondrial localization of this sphingolipid in tumor cells, followed closely by its marked reduction of mitochondrial membrane potential.

Antitumor activity of hydrophilic Paclitaxel copolymer prodrug using locoregional delivery in human orthotopic non-small cell lung cancer xenograft models.

Paclitaxel (Taxol) has demonstrated clinical activity in non-small-cell lung cancer (NSCLC), but its use has not led to marked improvements in survival. This ineffectiveness can in part be attributed to inadequate delivery of effective drug levels to the lung via systemic administration and to drug resistance mechanisms. Locoregional drug administration and the use of drug copolymers are possible approaches to address these issues.

Distinct stress and cell destruction pathways are engaged by TNF and ceramide during apoptosis of MCF-7 cells.

Ceramide has been proposed to be an important signaling intermediate in tumor necrosis factor (TNF)-induced apoptosis in human MCF-7 breast adenocarcinoma cells. We compared cell death and signal transduction pathways induced by TNF and ceramide in TNF-sensitive, parental MCF-7 cells to those in TNF-resistant, MCF-7 cells (3E9). TNF caused proteolysis of the caspase substrate, polyADP-ribose polymerase (PARP) in parental cells, but not in 3E9 cells.

Superior therapeutic profile of poly-L-glutamic acid-paclitaxel copolymer compared with taxol in xenogeneic compartmental models of human ovarian carcinoma.

Previous preclinical studies with ectopic tumor models have demonstrated remarkable improvements in the therapeutic profile of paclitaxel, formulated as a copolymer with poly-L-glutamic acid, compared with paclitaxel in the clinical formulation, Taxol. In this study, we evaluated these formulations in two human ovarian carcinoma xenograft models, NMP-1 and HEY, in nude mice. i.

Effective cytotoxicity against human leukemias and chemotherapy-resistant leukemia cell lines by N-N-dimethylsphingosine.

We evaluated the cytotoxicity of dimethylsphingosine (DMS) against four human leukemia cell lines: two acute (HL60 and a multi-drug resistance MDR-positive derivative HL60-dox) and two blast crisis chronic myelogenous leukemias (JFP1, from a treatment refractory patient and K562), and against blasts isolated from 11 leukemia patients. Cell line viability decreased proportionally to DMS concentration and treatment time (P<0.001).

Ceramide does not act as a general second messenger for ultraviolet-induced apoptosis.

Ceramide has been proposed as a second messenger for stress-induced apoptosis. By characterization of murine melanoma cells and their E1A transfectants, we found several lines of evidences against the role of ceramide as a second messenger for ultraviolet (UV)-induced apoptosis. First, although E1A transfected melanoma cells were more sensitive to UV-induced apoptosis than parental cells, the relative endogenous ceramide elevation induced by UV was greater in parental cells than in E1A transfectants.