Current Cancer Therapy Reviews - Volume 9, Issue 1, 2013

Anthracyclines show anti myeloma effects, being part of active regimens like infusional vincristine/ doxorubicin/ pulsed dexamethasone (VAD) in the past and recently of bortezomib/doxorubicin/pulsed dexamethasone (PAD) for the treatment of multiple myeloma. The recent introduction of pegylated liposomal doxorubicin has led to the development of newer anthracycline-containing regimens with improved toxicity profiles. In vitro, anthracyclines are able of suppressing bortezomib-mediated induction of some stress response proteins with a large synergic effect. Clinical trials have shown impressive activity of pegylated liposomal doxorubicin and conventional doxorubicin in combination with bortezomib in patients with relapsed/refractory myeloma. Herein, we review the clinical data supporting the use of pegylated liposomal doxorubicin combined to active agents in salvage regimens for relapsed/ refractory multiple myeloma patients.

2011 was a landmark year in the therapy for metastatic melanoma as it was the year that both Ipilmumab and Vemurafenib were approved by the FDA. Preceding this lay many years of frustration with no improvement in survival rates for 40 years. The prior standard therapy consisted of two main options, dacarbazine a non classic alkylating agent approved in the 1970s on the basis of overall response rates but having no benefit on survival and high dose IL2, approved in 1998 on the basis of durable complete response in a minority of patients. Thus the survival rates of patients with metastatic melanoma had remained largely unchanged since the 1970s with a median overall survival of 6 to 9 months. Metastatic melanoma is responsible for more than 75% of deaths from all forms of skin cancer, yet only represents less than 5% of all skin cancer diagnosis [1]. It is the most aggressive form of skin cancer and it is estimated that 76, 250 patients will be diagnosed in the United States in 2012 with 9,180 deaths [2]. The fruition of immunological and molecular research Ipilimumab, a CTLA4 antibody and Vemurafenib, a BRAF inhibitor in patients with BRAF mutation, have shown significant improvements in overall survival. With more targeted therapy options on the horizon these are significant times of hope for a disease which has proved so elusive in the past and has grown dramatically in incidence and annual mortality during the last few decades [3, 4]. This review will describe these new advances in targeted molecular and immunological therapies on the background of older therapies and also look at potential future therapy targets.

DNA methylation is an epigenetic phenomenon, which has major effects on gene expression. Increased methylation generally inhibits transcription while hypomethylation is primarily associated with increased transcription. Hypermethylation of tumor suppressor genes occurs frequently in cancer leading to silencing of these growth inhibitory genes. Demethylating agents are a class of anti-cancer drugs which reduce cytosine methylation, promoting transcriptional activation of genes by virtue of reducing methylation in their promoter regions. Most compounds that inhibit methylation are inhibitors of DNA methyltransferases (DNMTs) that are responsible for methylating cytosine residues on DNA. Azacitidine and Decitabine are two such demethylating agents that are approved for use in myelodysplastic syndromes. In this review, we describe the pharmacology of demethylating agents and their use in recent clinical studies. The current literature describing the efficacy of combining these agents with other chemotherapeutics in various types of cancer is also reviewed.

Extracts of Scutellaria species have been used in Eastern traditional medicine as well in the Americas for the treatment of several human ailments, including cancer. Crude extracts or flavonoids derived from Scutellaria have been scientifically studied for potential anti-cancer activity using in vitro as well as animal models of various cancers, including breast cancer, prostate cancer, ovarian cancer and malignant gliomas. Phase I clinical studies have also been conducted to study the toxicity/efficacy of Scutellaria extract in patients with metastatic breast cancer. This article is a succinct review of pertinent research articles on the anti-tumor efficacy and associated molecular mechanisms of Scutellaria extracts, particularly those containing the flavonoid wogonin. The potential significance of Scutellaria flavonoids as an adjuvant therapy for malignant tumors is discussed.

In recent years, a clear trend has been observed for taxanes to be used earlier in the course of breast cancer, with a large proportion of patients previously treated with anthracyclines and/or taxanes in the (neo)adjuvant setting. In addition, tolerability issues associated with taxane use in elderly patients and patients with substantial comorbidity, means that taxane use is frequently compromised in a substantial proportion of patients with metastatic breast cancer (MBC). Retreatment with taxanes yields variable results, and alternative cytotoxic agents with good activity in patients with anthracycline- and taxane-pretreated MBC are required. Large studies and meta-analyses have helped to establish the role of anthracycline- and taxane-based adjuvant therapy for early breast cancer (EBC). Addition of further cytotoxic agents has generally met with little success, thus the focus has moved towards optimization of adjuvant therapy through scheduling and patient selection. This review considers recent and ongoing developments in the chemotherapeutic management of EBC and MBC.

Osteosarcoma (OS) is the most common non-hematologic malignant tumor of bone in adults and children. As sarcomas are more common in adolescents and young adults than most other forms of cancer, there are a significant number of years of life lost secondary to these malignancies. OS is associated with a poor prognosis secondary to a high grade at presentation, resistance to chemotherapy and a propensity to metastasize to the lungs. Current OS management involves both chemotherapy and surgery. The incorporation of cytotoxic chemotherapy into therapeutic regimens escalated cure rates from <20% to current levels of 65-75%. Furthermore, limb-salvage surgery is now offered to the majority of OS patients. Despite advances in chemotherapy and surgical techniques over the past three decades, there has been stagnation in patient survival outcome improvement, especially in patients with metastatic OS. Thus, there is a critical need to identify novel and directed therapy for OS. Several Phase I trials for sarcoma therapies currently ongoing or recently completed have shown objective responses in OS. Novel drug delivery mechanisms are currently under phase II and III clinical trials. Furthermore, there is an abundance of preclinical research which holds great promise in the development of future OSdirected therapeutics. Our continuously improving knowledge of the molecular and cell-signaling pathways involved in OS will translate into more effective therapies for OS and ultimately improved patient survival. The present review will provide an overview of current therapies, ongoing clinical trials and therapeutic targets under investigation for OS.

Interdependent genetic and epigenetic events control the initiation and progression of tumors. Genetic amplification and overexpression of the GASC1 (gene amplified in squamous cell carcinoma 1) gene has been found in various tumor types and this upregulation correlates with a poor prognosis for cancer patients. Gain- and loss-of –function approaches demonstrate the importance of GASC1 for the maintenance of cancer phenotypes. The GASC1 gene encodes a Jumonji C domain-containing protein, a newly identified histone lysine demethylase, that mainly catalyzes demethylation of tri- and di-methylated forms of histone H3 lysine 9 (H3K9me3/me2) epigenetic repressive marks. Recent studies indicated that over-production of GASC1 may induce alterations in epigenetic histone methylation and affects the expression of key genes that are implicated in carcinogenesis and stem cell properties in human cancer. Furthermore, histone demethylases, such as GASC1, represent highly promising anti-cancer therapeutic targets; a number of GASC1 inhibitors have been identified and reported. This review provides an overview of the current findings on genetic alterations and the biological function of GASC1 in cancer, together with a summary of recent advances in GASC1 inhibitor discovery.