Recent Patents on Anti-Cancer Drug Discovery - Volume 9, Issue 1, 2014

In the last decade, the molecular chaperone HSP90 has emerged as an important target in cancer therapeutics and has subsequently become the focus of several drug discovery and development efforts. The first-in-class HSP90 inhibitor 17-AAG entered into Phase I clinical trial in 1999. Today 13 HSP90 inhibitors representing multiple drug classes, with different modes of action, are undergoing clinical evaluation. The present review will highlight the involvement of HSP90 in regulating and maintaining the transformed phenotype, provide an overview on current HSP90 inhibitors and further update on the most relevant patents which have recently appeared in the literature.

Gastrointestinal cancers remain one of the main causes of death in developed countries. The main obstacles to combating these diseases are the limitations of current diagnostic techniques and the low stability, availability, and/or specificity of pharmacological treatment. In recent years, nanotechnology has revolutionized many fields of medicine, including oncology. The association of chemotherapeutic agents with nanoparticles offers improvement in the solubility and stability of antitumor agents, avoidance of drug degradation, and reductions in therapeutic dose and toxicity, increasing drug levels in tumor tissue and decreasing them in healthy tissue. The use of specific molecules that drive nanoparticles to the tumor tissue represents a major advance in therapeutic specificity. In addition, the use of nanotechnology in contrast agents has yielded improvements in the diagnosis and the follow-up of tumors. These nanotechnologies have all been applied in gastrointestinal cancer treatment, first in vitro, and subsequently in vivo, with promising results reported in some clinical trials. A large number of patents have been generated by nanotechnology research over recent years. The objective of this paper is to review patents on the clinical use of nanoparticles for gastrointestinal cancer diagnosis and therapy and to offer an overview of the impact of nanotechnology on the management of this disease.

Antibody-delivered drugs and toxins are poised to become important classes of cancer therapeutics. These biopharmaceuticals have potential in this field, as they can selectively direct highly potent cytotoxic agents to cancer cells that present tumor-associated surface markers, thereby minimizing systemic toxicity. The activity of some conjugates is of particular interest receiving increasing attention, thanks to very promising clinical trial results in hematologic cancers. Over twenty antibody-drug conjugates and eight immunotoxins in clinical trials as well as some recently approved drugs, support the maturity of this approach. This review focuses on recent advances in the development of these two classes of biopharmaceuticals: conventional toxins and anticancer drugs, together with their mechanisms of action. The processes of conjugation and purification, as reported in the literature and in several patents, are discussed and the most relevant results in clinical trials are listed. Innovative technologies and preliminary results on novel drugs and toxins, as reported in the literature and in recently-published patents (up to February 2013) are lastly examined.

A variety of clinical trials for vaccines against cancer have provided evidence that DNA vaccines are well tolerated and have an excellent safety profile. DNA vaccines require much improvement to make them sufficiently effective against cancer in the clinic. Nowadays, it is clear that an increased antigen expression correlates with improved immunogenicity and it is critical to vaccine performance in large animals and humans. Similarly, additional strategies are required to activate effective immunity against poorly immunogenic tumour antigens. This review discusses very recent scientific references focused on the development of sophisticated DNA vaccines against cancer. We report a selection of novel and relevant patents employed to improve their immunogenicity through several strategies such as the use of tissue-specific transcriptional elements, nuclear localisation signalling, codon-optimisation and by targeting antigenic proteins to secretory pathway. Recent patents validating portions or splice variants of tumour antigens as candidates for cancer DNA vaccines with improved specificity, such as mesothelin and hTERT, are also discussed. Lastly, we review novel patents on the use of genetic immunomodulators, such as “universal” T helper epitopes derived from tetanus toxin, E. coli heat labile enterotoxin and vegetable proteins, as well as cytokines, chemokines or costimulatory molecules such as IL-6, IL-15, IL- 21 to amplify immunity against cancer.

One of the greatest challenges in cancer drug therapy is to maximize the effectiveness of the active agent while reducing its systemic adverse effects. To add more, many widely-used chemoterapeutic agents present unfavorable physicochemical properties (e.g. low solubility, lack of chemical or biological stability) that hamper or limit their therapeutic applications. All these issues may be overcome by designing adequate drug delivery systems; nanocarriers are particularly suitable for this purpose. Nanosystems can be used for targeted-drug release, treatment, diagnostic imaging and therapy monitoring. They allow the formulation of drug delivery systems with user-defined characteristics regarding solubility, biodegradability, particle size, release kinetics and active targeting, among others. This review (Part I) focuses on recent patents published between 2008 and the present day, related to nanospheres, nanocapsules and nanogels applied to anticancer drug therapy. Other nanosystems is covered in a second article (Part II).

The great efforts of many researchers have brought down some of the barriers that exist to turn a good in vitro compound into a potential in vivo drug. The advent of pharmaceutical nanotechnology has allowed an arsenal of drugs with poor stability, low solubility, high off-target toxicity and other disadvantageous features, to be accessible as pharmaceutical products that could be administered to a patient. Nanotechnology was introduced in drug delivery very long ago, but has flourished with unprecedented intensity during the last twenty years and now a diversity of nano-based preparations are at clinical stage of development or already available in the market. Undoubtedly, nanotechnology plays a key role in future pharmaceutical development and pharmacotherapy. In the first part of this review, we have already discussed recent (2008-2012) patents on linear polymer-based nanosystems (nanogels, nanospheres and nanocapsules) applications to cancer therapy. Here, we have expanded such analysis to branched polymers (dendrimers), self-assembling nanomicelles and lipid-based nanocarriers.

Bevacizumab, one of the best-known patents of VEGF inhibitor, has demonstrated significant radiosensitive effects on various preclinical tumor models and clinical trials recently. The radiosensitive effects of this novel patent have achieved satisfactory efficacy through the following mechanisms: normalization of the tumor vasculature, overcoming resistance to radiation, inhibition of repopulation after radiation, and blockade of radiation-induced increased VEGF expression. The combination of bevacizumab with radiotherapy in the treatment of malignant tumors was an inevitable path for the further clinical development of bevacizumab and a very good opportunity for improving the curative effect of radiotherapy. However, many questions such as those regarding the bevacizumab administration dosage and schedule, radio sensitivity efficacy evaluation and multi-target radiosensitive therapy need further research. The advent of bevacizumab combined with radiation has left physicians to encounter multiple challenges as well as opportunities for improving anti-cancer drug treatments.