Small molecule and monoclonal antibody therapies in neurooncology

Department of Neurological Surgery, University of California, San Francisco, CA 94143-0350, USA.
Cancer control: journal of the Moffitt Cancer Center (Impact Factor: 3.5). 05/2005; 12(2):116-24.
Source: PubMed


The prognosis for most patients with primary brain tumors remains poor. Recent advances in molecular and cell biology have led to a greater understanding of molecular alterations in brain tumors. These advances are being translated into new therapies that will hopefully improve the prognosis for patients with brain tumors.
We reviewed the literature on small molecule targeted agents and monoclonal antibodies used in brain tumor research and brain tumor clinical trials for the past 20 years.
Brain tumors commonly express molecular abnormalities. These alterations can lead to the activation of cell pathways involved in cell proliferation. This knowledge has led to interest in novel anti-brain-tumor therapies targeting key components of these pathways. Many drugs and monoclonal antibodies have been developed that modulate these pathways and are in various stages of testing.
The use of targeted therapies against brain tumors promises to improve the prognosis for patients with brain tumors. However, as the molecular pathogenesis of brain tumors has not been linked to a single genetic defect or target, molecular agents may need to be used in combinations or in tandem with cytotoxic agents. Further study of these agents in well-designed cooperative clinical trials is needed.

Full-text preview

Available from:
  • Source
    • "Their large size, shape, affinity, and valency also limit favorable pharmacokinetics, antibody uptake by the tumor, and efficient penetration into the targeted tissue. In a recent study with murine xenograft models, mAbs directed against tumor-specific antigens remained largely in the blood, and no more than 20% of the administered dose interacted with the tumor (Beckman et al., 2007; Butowski and Chang, 2005). Administration of mAbs carries the risk of undesirable immune reactions, such as acute anaphylaxis, serum sickness, and production of neutralizing antibodies . "
    [Show abstract] [Hide abstract]
    ABSTRACT: A promising new era of cancer therapeutics with agents that inhibit specific growth stimulatory pathways is finding a new niche in our armamentarium in the war against cancer. Targeted cancer therapeutics, including humanized monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are amongst the major treatment options for cancer today together with cytotoxic chemotherapies. Targeted therapies are more selective for cancer cells and improve the quality of life for cancer patients undergoing treatment. Many of these drugs have been approved by the FDA, and several more are being studied in clinical trials. Although development of targeted therapeutics has improved cancer treatment significantly, the harsh reality is that the "War on Cancer" still exists. Major challenges still exist with the currently marketed inhibitors, including limitations associated with mAbs and TKIs drug types, acquired mechanisms of drug resistance that cause patient relapse, and tumor heterogeneity. Today, there is an urgent need for the development of novel anti-tumor agents that are cheaper, stable, can selectively target cancer dependent pathways without affecting normal cells, and most importantly, avoid development of resistance mechanisms. Peptide mimics have the potential benefits of being highly selective, stable, cheap, and non-toxic. The focus of this review is to discuss the disadvantages associated with the use of monoclonal antibodies and tyrosine kinase inhibitors. A special emphasis will be placed on efforts taken in our laboratory to 1) design peptide vaccines and therapeutics that target cancer dependent pathways and 2) use a combination approach that will shut down alternative mechanisms that lead to resistance.
    Full-text · Article · Mar 2013 · Discovery medicine
  • Source
    • "Targeted inhibition of EGFR activity can suppress signal transduction pathways which control tumor cell growth, proliferation, and resistance to apoptosis [25]. Small molecule tyrosine kinase inhibitors and monoclonal antibodies are among the most common EGFR targeting agents and have been used clinically for treating various malignancies [26]. Recently, it was reported that mutations in the tyrosine kinase domain of EGFR gene can predict the response to tyrosine kinase inhibitors [27]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oncogene addiction is a phenomenon that the survival of cancer cells depends on an activated oncogene or inactivation of tumor suppressor gene, and is regarded as the 'Achilles heel' of the successful molecular targeted therapies in cancer. However, the role of oncogene addiction in gliomas has not been elucidated systematically. In this review, we summarize the current experimental and clinical evidence for the concept of oncogene addiction and describe the mechanisms explaining oncogene addiction in gliomas. And the clinical implications for oncogene addiction in molecular targeted therapy are further emphasized. In addition, we discuss future direction for defining complex "oncogene addiction network" through the integrated analysis of multiple platforms in the flow of genetic information in gliomagenesis.
    Full-text · Article · May 2011 · Journal of Experimental & Clinical Cancer Research
  • Source
    • "The therapeutic monoclonal antibodies (MAb) targeting growth factor pathways are being developed. The purpose of antibody treatment of cancer is to induce the direct or indirect destruction of cancer cells, either by specifically targeting the tumor or the tumor vasculature (Butowski and Chang, 2005). Examples of therapeutic antibodies which are effective in treating cancer includes the humanized IgG antibody Herceptin for the treatment of breast cancer, Cetuximab, ABX-EGF, EMD 720000 and h-R3 directed at extracellular receptor domain that inhibits the ligand-receptor interactions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefly discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with over-expression of calcium-dependent potassium (K(Ca)) channels, and high grade glioma express specific K(Ca) channel gene (gBK) splice variants, and mutant epidermal growth factor receptors (EGFRvIII). These specific genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifically microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed.
    Full-text · Article · Aug 2007 · Drug Target Insights
Show more