Recent Patents on Anti-Cancer Drug Discovery - Volume 6, Issue 1, 2011

Cancer is a class of diseases with an uncontrolled growth of cells (usually derived from a single cell) beyond the normal limits. The growths often invade adjacent tissues and, sometimes, migrate to other locations of the body (metastasis) via lymph or blood, and promote the growth of new blood vessels from which the cells derive nutrients. Cancerous (malignant) cells can develop from any tissue within the body. These malignant properties of cancers differentiate them from benign tumors, which are self-limited, and do not invade or metastasize [1, 2]. TYPES OF CANCER Cancerous tissues (malignancies) can be divided into those of the blood and blood-forming tissues and cells of the immune system (leukemias and lymphomas) and “solid” tumors, often termed cancer. Cancers can be carcinomas (tumor derived from epithelial tissue) or sarcomas (tumor arising from cells that form muscles and connective tissue) [2]. COSTS OF CANCER The National Institutes of Health in United States estimated overall costs of cancer in 2010 at $263.8 billion: $102.8 billion for direct medical costs (total of all health expenditures); $20.9 billion for indirect morbidity costs (cost of lost productivity due to illness); and $140.1 billion for indirect mortality costs (cost of lost productivity due to premature death) [3, 4]. STATISTICS One in eight deaths worldwide are due to cancer, it is the second and third leading cause of death in economically developed and developing countries, respectively. Cancer affects 1 in 3 of us in our lifetime. It also affects people at all ages with the risk for most types increasing with age. Over 70% of cancers happen to people who are over the age of 60 [5]. Lung cancer, the most common cause of cancer-related death in men and women, is responsible for 1.3 million deaths worldwide annually [1]. In 2007, cancer caused about 13% of all human deaths (7.6 million) in the world. In 2010, according to National Institutes of Health, about 569,490 Americans were expected to die of cancer, more than 1,500 people a day. Cancer is the second most common cause of death in the US, exceeded only by heart disease. In the US, cancer accounts for nearly 1 of every 4 deaths [1, 3, 4, 6-9]. CAUSES OF CANCER Cancer is caused by both external and internal factors. It is primarily an environmental disease with 90-95% of cases due to lifestyle and environmental factors and 5-10% due to genetics [10]. Common environmental factors leading to cancer death include: tobacco (25-30%), diet and obesity (30-35%), infections (15-20%), radiation, stress, lack of physical activity, environmental pollutants [10]. These environmental factors cause abnormalities in the genetic material of cells [11]. May be another important cause for this disease is the post-traumatic stress disorder (PTSD) which is an anxiety disorder associated with serious traumatic events (death of a beloved person, robbery, bankruptcy, financial lost, rape, assault, kidnapping, fighting in war, imprisonment, natural catastrophes and car, bus, train, airplane accidents, etc.) and is characterized by symptoms such as survivor guilt, reliving the trauma in dreams, numbness, lack of involvement with reality or recurrent thoughts and images, absence of optimism, and higher neuroticism [12, 13]. Studies demonstrated that patients with higher scores on the neuroticism test tended to have lower immune system responses [14, 15]. When the immune mechanism is slowed down or made ineffective, the malignant cells develop [16, 17]. Some studies of cancer survival have found significant associations between lower optimism and higher neuroticism with shorter survival. More mental distress and fatigue and poorer quality of life is significantly associated with higher neuroticism and lower optimism at cancer screening, diagnosis and primary treatment, short- and long-term follow-up and towards the end of life. Neuroticism is a strong predictor of PTSD triggered by cancer as a life-threatening experience eventually leading to negative personality changes [18, 19]. Recently, a study was conducted to determine the prevalence of PTSD in parents of children with cancer. The prevalence of PTSD was 34.6%. The statistically significant tendency to develop PTSD were found in the female gender, better educational status, death of a loved one, previous history of psychiatric disorder, having a child with poorer prognosis, and the presence of radiotherapy in child's treatment [20, 21]. . . . . .

Metabolism in tumors deviates significantly from that of normal tissues. Increasingly, the underlying aberrant metabolic pathways are being considered as novel targets for cancer therapy. Denoted “metabolic targeting”, small molecule drugs are under investigation for focused inhibition of key metabolic steps that are utilized by tumors, since such inhibitors should harbor minimal toxicity towards surrounding normal tissues. This review will examine the primary biochemical pathways that tumors harness to enhance their bioenergetic capacity, which in turn, help their rapid proliferation and metastasis within the host. It is hoped that “metabolite-mimetic” drugs can be utilized to interfere with metabolic flux pathways active within the tumor, and across tumor-microenvironment boundary. In fact, the major pathways of mammalian metabolism, i.e., the carbohydrate, amino-acid, and fatty-acid metabolic pathways have been examined as putative targets for drug development, with some drug candidates advancing to phase II/III stages. In this regard, glucose metabolism, i.e., the glycolytic pathway - that predominates the bio-energetic flux in tumors, and the associated mitochondrial metabolism have received the most attention as suitable “druggable” targets, focused either at the pathway enzymes or at the plasma-membrane-bound metabolite transporters. Outlined in this review are pre-clinical studies that have led to the discovery of promising drug candidates to target tumor-metabolic flux, and ensuing patents, with descriptions of the biochemical rationale for the combinatorial strategy of a particular metabolic pathway-drug candidate pair.

Recent results obtained from research on the intermediary metabolism of tumor cells have uncovered the biochemical reprogramming that takes place upon malignant transformation. Many features have been highlighted that are currently being exploited for specific chemotherapy. Many more will become available shortly as a consequence of the recognition of potentially useful targets for treatment. General interest in this area can be gauged by the number of recent patents that have been deposited, or are in the process of application. Because the metabolic subversion that is a hallmark of cancer cells involves a disruption of its homeostasis, the regulatory pathways dealt with in this review were broadly divided into those that encompass the main stages of the cell cycle and its various regulatory mechanisms and those that involve the aerobic glycolysis typical of cancer cells. It becomes apparent that both, the cell cycle and the intermediary metabolism are interconnected and rely on reactions many of which are dependent on kinases and phosphatases. Kinases and phosphatases are responsive to cellular redox signaling and may have a key role in determining whether cells progress towards malignant transformation as a result of continuous oxidative stress. The results discussed here underline aspects of the signaling pathways that lend themselves to specific inhibition by natural and synthetic compounds. The mitochondria and its role in programmed cell death are briefly commented, but special emphasis is placed on biochemical regulation at the level of chromatin structure, particularly the reactions that involve acetylation and deacetylation of histones. Within this context, inhibitors that act on histone deacetylases are discussed as promising alternatives to available treatments.

Cancer is a multi-factorial disease resulting in uncontrolled division of body cells, with difficult and complex suppression. The main treatment strategy for this disease depends on killing of tumor cells that usually exist in the proximity of normal body cells. During the course of treatment, the healthy cells should not be affected by the toxic doses of the drug. Therefore, it seems that combination drug therapy is a suitable solution to address the mentioned concern. Indeed the use of multiple drugs with different actions and/or targets, in order to overcome the tumor cells, can lead to decreased drug effective dose and increased protection of normal cells against antitumor drugs. This review is focused on informatics applications in cancer combination drug therapy. At first, a brief description of recent findings on biology of resistance to cytotoxic agents is covered. Then, combinational drug therapy in cancer treatment, cheminformatics applications of synergistic compounds in cancer therapy, strategies used to overcome MDR (Multi Drug Resistance) and combinational drug therapy in cancer treatment have been discussed in the continuation. Natural compounds synergistic with anticancer agents have been reviewed in the following topics and lastly, the recent patents in the related area of combinational therapy are briefed.

Despite recent advances in treatment of head and neck cancer, survival has not improved as expected. Bcl-2 family proteins play important role in regulating apoptosis. Recently, newer molecules have been developed for inhibition of Bcl-2 related proteins. We, herein aim to discuss the importance of Bcl-2 family proteins to the development of head and neck cancer and how the targeted-therapy for inhibition of Bcl-2 and related proteins, based on new drugs and recent patents, could improve the efficacy of the systemic therapy.

Primary malignant central nervous system (CNS) tumors only represent about 2% of all cancers. However, they are very often associated with high morbidity and mortality. Despite current standard-of-care therapy, such as surgery, irradiation, and chemotherapy, neither cure nor any toxic therapy against malignant CNS tumors has been developed so far. Nanotechnology may alter this situation. It offers a new promise for cancer diagnosis and treatment. This emerging technology, by developing and manufacturing materials using atomic and molecular elements, can provide a platform for the combination of diagnostics, therapeutics and delivery to the tumor, with subsequent monitoring of the response. This review focuses on recent developments in cancer nanotechnology with particular attention to nanoparticle systems, important tools for the improvement of drug delivery in brain tumor. The latest advances in both the research sector and in recent patents for cancer imaging and therapy are discussed.

For the last few years new therapeutic options for primary cutaneous T-cell lymphoma (CTCL) have been recently introduced into clinical trials, particularly for patients with advanced stage and refractory disease. Systemic treatment uses biological response modifiers, such as fusion molecules, rexinoids, interferons as well as monoclonal antiobodies, and new antiproliferative drugs, such as histone deacetylase inhibitors, proteasome inhibitors or forodesine. This review focuses on recent advances in the development of systemic agents for CTCL including both novel patented compounds and novel therapeutic protocol of intervention.

MicroRNAs (miRNAs) are a new class of negative regulators that repress gene expression by pairing with their target messenger RNAs (mRNAs). There are hundreds of miRNAs coded in the human genome and thousands of target mRNAs participating in a wide variety of physiological processes such as development and cell identity. It is therefore not surprising that several recent reports involved deregulated miRNAs in the complex mechanism of human carcinogenesis, and proposed them as new key regulators to correct the unbalanced expression of oncogenes and tumour suppressor genes exhibited in cancer cells. This review summarises most of the recent patents related to the use of miRNA signatures in cancer diagnosis and prognosis, the detection and profiling of miRNAs from tumour samples and the identification of oncogenes and tumour suppressor genes targeted by miRNAs, as well as new cancer therapies based on miRNA modulators.

Hepatocellular carcinoma (HCC), a major form of primary liver cancer, is one of the leading causes of cancer related deaths worldwide. Hepatitis B and C infections are major risk factors for the development of HCC. Currently, the treatment options are rather limited, and the prognosis for this malignancy is poor for most of these patients. RNA interference has emerged as an innovative technology for gene silencing and as a potential therapeutic for various diseases, including cancer. HCC has been widely chosen as a model system for the development of RNAi therapy due to the convenience and availability of effective delivery of RNA molecules into liver tissues. Targets for HCC treatment include HBV and HCV viruses, oncogenes, as well as cellular genes mediating angiogenesis, tumor growth and metastasis. Here, we summarized the progress of RNAi therapeutics in HCC treatment, relevant patents, potential challenges and prospects in the future.

Epigenetic modulators play significant roles in carcinogenesis. DNA methylation and histone modifications are the two major epigenetic modifications involved in transcriptional regulation. Many histone modification enzymes and DNMTs are up-regulated in cancer cells, and contribute to malignant transformation. The majority of the current “new generation” of anticancer drugs target abnormally overexpressed oncogenic proteins such as kinases or receptors which mediate oncogenic signal transmission. Overexpression or accumulation of these oncoproteins in cancer is caused directly or indirectly by genetic or epigenetic abnormalities in tumor-associated genes. Among these changes, epigenetic changes in DNA and histones can be caused by aberrant expression of epigenetic modulator proteins in cells. Recently, it has been revealed that UHRF1, which is up-regulated in various cancers, links DNA methylation and histone modifications through binding to hemi-methylated DNA, and also to trimethylated histone H3K9. The UHRF1 complex includes HDAC1, Tip60, G9a, and maintenance and de novo DNMTs. Many of these are reported to be involved in carcinogenesis. Several anticancer drugs targeting epigenetic-machinery such as HDAC inhibitors, and DNMT inhibitors have been developed. Even though these drugs showed some effect on several types of cancer, mild to severe adverse reactions have been observed. In this article, the relevant patents on the strategies to develop safer anticancer drugs targeting epigenetic modulators, focusing on members and modifiers of the UHRF1 complex, are discussed.

Epigenetic modifications have been causally linked to cancer development and progression, and are potentially reversible by drug treatments. The N-terminal tails of histones contain amino acid residues modifiable by posttranslational modifications such as acetylation. Given that HDAC inhibitors induce cancer cell differentiation and death, an increasing number of these compounds has been synthesized in the last ten years. Many HDAC inhibitors are in clinical trials for the treatment of cancer. Two of them, the hydroxamic acid (SAHA) and Romidepsin (FK 228), are approved in the second line treatment of refractory, persistent or relapsed Cutaneous T Cell Lymphoma (CTCL). The growing evidence of the potential benefits of an anti-cancer treatment based on the use of HDAC inhibitors have led to a large number of patent applications all over the world. The aim of this review is to give an overview of the basic current knowledge and molecular mechanisms of HDAC inhibitors and their clinical trials as well as to focus on the recent patent applications existing in the field of HDAC inhibitors and cancer treatment between 2008 and 2010 in USA.

The serine/threonine kinase Akt has proven to be a significant signaling target, involved in various biological functions. Because of its cardinal role in numerous cellular responses, Akt has been implicated in many human diseases, particularly cancer. It has been established that Akt is a viable and feasible target for anticancer therapeutics. Analysis of all Akt kinases reveals conserved homology for an N-terminal regulatory domain, which contains a pleckstrin-homology (PH) domain for cellular translocation, a kinase domain with serine/threonine specificity, and a C-terminal extension domain. These well defined regions have been targeted, and various approaches, including in silico methods, have been implemented to develop Akt inhibitors. In spite of unique techniques and a prolific body of knowledge surrounding Akt, no targeted Akt therapeutics have reached the market yet. Here we will highlight successes and challenges to date on the development of anticancer agents modulating the Akt pathway in recent patents as well as discuss the methods employed for this task. Special attention will be given to patents with focus on those discoveries using computer-aided drug design approaches.

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.