Recent Patents on Anti-Cancer Drug Discovery - Volume 5, Issue 3, 2010

Temozolomide (TMZ) is a monofunctional methylating agent which is spontaneously activated in aqueous solution into the dacarbazine metabolite 5-(3-methyl-1-triazeno)imidazole-4-carboxamide. This drug has been approved for the treatment of metastatic melanoma and glioblastoma multiforme, the latter in combination with radiotherapy. Furthermore, clinical trials have been performed to assess the activity of TMZ, alone or in combination, on brain metastatic solid tumors and leukaemias. This review will report clinical evidence on the use of TMZ for the treatment of different types of cancer; it also considers current knowledge on TMZ's molecular mechanisms of action of and discusses relevant patents relating to the same drug.

Cancer, a leading cause of death, can be prevented by different nutrients, in accordance to epidemiological and experimental data. Cancer chemoprevention might involve different dietary substances, which can counteract genetic damage and modulate the acquisition of a neoplastic phenotype. Critical to this process is redox cellular homeostasis, with antioxidants and essential biomolecules being the most promising functional compounds of the diet. Nutritional interventions require accurate biomarkers in order to evaluate their appropriateness. Such parameters may be biological targets involved in the oncogenetic process, and biochemical changes deriving from the organic response to tumours, which can be considered as endpoints of dietary interventions. This review will thus focus on patents on recent progress in the development of redox-related anticancer nutritional interventions involving lipophilic compounds, and of biological markers for evaluating them, with their scientific basis being reviewed.

Recently, the field of oncology has witnessed the introduction of several effective chemotherapeutic agents. Still, not all cancers respond to the use of conventional chemotherapy and thus combination therapy is an emerging weapon in the battle against cancer. There is emerging evidence in support of the use of Monoclonal antibodies (MoAbs) in cancer therapy. The mechanisms behind their efficacy are multi-faceted; they can kill tumor cells through antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis as well as target ligands or growth factor receptors favoring tumor growth. The interaction of the Fc domains of antibodies with the Fcγ (gamma) receptors is an essential checkpoint in ADCC. This interaction is strongly regulated and is largely dependent upon receptor conformation and number. It is accepted that germ-line single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) have the potential to predict the outcome of therapy. The possibility of predicting patients response to monoclonal antibody therapy is of particular importance, as response rates are moderate, with the risk of serious side effects all at a high financial cost. This patent review provides an insight into the role of Fcγ receptors (FcγRs) genetic variation in Monoclonal Antibody-based anti-cancer therapy.

Many studies have demonstrated that most cancers are clonal and are maintained by a cancer stem cell. Cancer stem cells have been identified in blood, breast, brain, lungs, gastrointestinal, prostate and ovarian cancer. Under normal homeostasis tissue specific stem cell division would be under strict control. When proliferation becomes independent of normal cellular controls, cancer develops. Studies indicate that cancer stem cells maintain their ability to differentiate, which explains the variety of cell types observed in tumors. Most therapies are directed at the fast growing tumor mass but not the slow dividing cancer stem cells and therefore the cancer is not eradicated. Understanding the process of transformation from a highly regulated stem cell to a cancer stem cell requires an understanding of genetic and epigenetic processes as well as having an understanding of the stem cell niche and the interaction of the stem cells with supportive cells in the niche. Current research is helping us to understand stem cells and stem cell regulation and in turn this will help to develop novel therapies to eliminate cancer and the initiating cancer stem cell. The relevant patents on the stem cell regulation and cancer therapy by stem cells are discussed.

The Aurora Kinases are highly related serine-threonine kinases, essential for accurate and equal segregation of genomic material during mitosis. A large number of studies have linked the aberrant expression of Aurora kinases to cancer, leading to the development of specific Aurora kinases inhibitors. Several small molecules inhibit with a similar efficacy both Aurora A and Aurora B, however, in most cases the effects resemble Aurora B disruption by genetic methods, indicating that Aurora B represents an effective therapeutic target. These drugs are currently under preclinical or clinical evaluation and are reviewed in this article. The relevant patents are discussed.

Renal cell cancer is fastly growing in incidence worldwide. No adjuvant therapy has been unarguably proven feasible so far, although an autologous vaccine has achieved a significant benefit. An effective agent in adjuvant therapy against renal cell cancer must achieve several goals. It should be relatively non toxic, have estabilished efficacy in the metastatic setting, and have demonstrated efficacy against the standard of care in randomized phase III trials. The development of adjuvant therapy requires the properly identification of patients at highest risk of relapse, as potential benefactors of adjuvant therapy development. Our ability to predict when and where patients will recur has much room for improvement. Therefore several models and nomograms including the most important prognostic and predictive factors have been developed. Nevertheless, during the past few years, major advances have been made concerning the metastatic setting of the disease with the arrival of new drug classes such as tyrosine kinase inhibitors and monoclonal antibodies, strongly improving overall and progression free survivals, renewing hopes on activity regarding the adjuvant therapy. Several trials are today in progress to evaluate the effectiveness of antiangiogenic agents in this area. An overall review of the completed and upcoming trials and patents shall be discussed here.

Drug discovery in the ovarian cancer arena has led to the activation of several important clinical trials. Many biologic agents have come down the pipeline and are being studied in phase II trials for recurrent disease. These agents include antivascular compounds that disrupt angiogenesis through a variety of mechanisms (e.g., prevention of ligandbinding to the vascular endothelial growth factor receptor-2 (VEGF-R2), high-affinity VEGF blockade, oral inhibitors of tyrosine kinases stimulated by VEGF, inhibition of α5ß1 integrin, neutralization of angioproteins, etc.). Other novel drugs include oral platinum compounds as well as those that antagonize the tumor proliferation genes in the Hedgehog pathway, and that target folic acid receptors which are expressed by ovarian cancer cells. In addition, studies are underway with oral agents that inhibit the tyrosine kinase activity associated with two oncogenes (epidermal growth factor receptor (EGFR) and HER-2/neu). Finally, emerging technologies in clinical trials include nanotechnology to enhance delivery of chemotherapy to ovarian tumors, drug resistance/sensitivity assays to guide therapy, and agents that mobilize and induce proliferation of hematopoetic progenitor cells to aid in red blood cell, white blood cell, and platelet recovery following chemotherapy. The relevant patents in drug discovery of ovarian cancer are discussed.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets and therapeutic agents related to anti-cancer drug discovery.