Recent Patents on Anti-Cancer Drug Discovery - Volume 4, Issue 2, 2009

β-Glucans are cell wall constituents of many plants and microorganisms. However, β-glucans are not expressed on mammalian cells and are recognized as pathogen-associated molecular patterns by pattern recognition receptors. β- Glucans have been used to treat cancer and infectious disease for many years as biological response modifiers with varying and unpredictable efficacy. Recent studies have demonstrated the mechanism of action of yeast-derived β-glucan in combination with anti-tumor monoclonal antibodies in cancer therapy. in vitro and in vivo Data indicate that successful combination therapy requires complement activation and iC3b deposition on tumors and complement receptor 3 (CR3) expression on granulocytes. The defined effector cells are CR3+ neutrophils. This review provides a brief overview of this combination therapy in cancer and describes in detail the β-glucan composition and receptors, mechanism of action, and preclinical studies in human carcinoma xenograft models. Current and future developments are also discussed to provide our own point of view on this combination therapy in potential clinical investigations. Relevant patents are discussed.

Elevated RhoA/Rho kinase and p21-activated kinase signaling have been shown to promote cancer development and metastasis and have drawn much attention as potential targets of anti-cancer therapy. Elevated RhoA and Rho kinase activity promote cancer cell invasion and eventually lead to metastasis by disrupting E-cadherin-mediated adherens junctions and degradation of the extracellular matrix. Elevated p21-activated kinase activity promotes invasion by stimulating cell motility but also promotes cancer cell survival and growth. In this review we describe normal functions of RhoA/Rho kinase and p21-activated kinase signaling, mechanisms that lead to constitutive activation of RhoA/Rho kinase and p21-activated kinase pathways, and processes by which constitutive RhoA/Rho kinase and p21-activated kinase activity promote cancer development and progression to more aggressive and metastatic phenotypes. In addition, we summarize relevant patents on RhoA/Rho kinase and p21-activated kinase as targets of anti-cancer therapy and discuss the clinical potential of different approaches to modulate RhoA/Rho kinase and p21-activated kinase signaling.

The Ras-MAPK pathway is important to orchestrating a cell's response to external and internal stimuli. This pathway is commonly dysregulated in cancer, including bladder cancer. Multiple components of this complex pathway have been identified as potential targets for drug development. After initial preclinical studies many drugs targeting the Ras-MAPK pathway are being studied in phase II clinical trials for advanced bladder cancer either alone or in combination with other chemotherapeutic agents. Drugs presently in clinical trials inhibit the tyrosine kinases, including FGFR, EGFR, ERBB2, and PDGF, either through small molecule tyrosine kinase, dual kinase or farnesyltransferase inhibitors. Recent drug patents targeting the Ras-MAPK pathway in cancer are becoming more selective with the potential for improved therapeutic response and better toxicity as compared to the more universal MAPK pathway inhibitors. In the present review we summarize the importance of the Ras-MAPK pathway in cancer with a focus on bladder cancer and discuss current drugs and recent patents (2004-2008) that target this important pathway in bladder cancer.

Low productivity and the escalating costs of drug development have been well documented over the past years. A fraction of new pre-clinical compounds successfully pass experimental test batteries, and less than 10% of these compounds that enter clinical trials ultimately make it to the market. These challenges in the “critical path” of drug development will be discussed for drugs in the field of oncology, regarding the i) the impact of FDA and EMEA guidelines, and ii) microdosing studies/phase 0 trials before a drug enters phase I to III, to inform drug development, compressing drug development timelines and decision-making for continuation into clinical trials. Moreover, this review should embark on i) how to find new key molecules involved in life-and-death decision of a cell, how ii) old drugs will have a revival for new indications, because of novel information for their mode of action, and iii) how the revolutionary advances - high-throughput technologies, gene therapy and the deciphering of the human genome - do have their potential to develop personalized therapy. Therapy has progressed from an age of administering herbal remedies and organ extracts to an era of meticulously planned drug discovery, when pharmaceutical industry was born in a Western understanding. The relevant patents are discussed.

Renal cell carcinoma (RCC) represents five percent of adult epithelial cancers and clear cell RCC is the most frequent histological subtype. Improved understanding of the molecular pathways implicated in the pathogenesis of RCC has led to the development of specific targeted therapies to treat the disease. Five new medications have been shown to increase progression-free survival (PFS) in patients with metastatic clear cell RCC: bevacizumab, sorafenib, sunitinib, everolimus, and temsirolimus. Bevacizumab (+ interferon-alpha), sunitinib, and temsirolimus (in poor-risk groups) have proven to be effective as first-line palliative treatments. Sorafenib has demonstrated benefits in patients that have failed prior therapy, as has everolimus after failure of sorafenib and/or sunitinib. This paper provides a comprehensive review of the new targeted therapies currently available in clinical practice to treat patients with metastatic unresectable renal cell carcinoma. The relevant patents are discussed.

The current use of antineoplastic drugs in human therapy causes a substancial number of toxic or side effects which consequently lead to a reduction of the amount of drug to be administered, and in some cases to discontinuation of the therapy. A reduction of the amount of drug to be administered or discontinuation of the therapy causes an increase in primary tumour growth and/or the occurrence of tumour metastases. For this reason, the development of new anti-cancer drugs with lower side effects is necessary. This review gives a general idea about the origins of cancer and the importance of cyclooxygenase-2 (COX-2) in oncogenesis. Evidence from clinical and preclinical studies indicates that COX-2-derived prostaglandins participate in carcinogenesis, inflammation, immune response suppression, apoptosis inhibition, angiogenesis, and tumour cell invasion and metastasis. The recent anti-tumour drugs are based on tests of known selective COX-2 inhibitors and on the drawing and synthesis of new potent derivatives. Maybe, this can be the way to obtain new anti-tumour drugs with very low collateral effects. Selective COX-2 inhibitors are being mixtured with new anti-cancer drugs in order to obtain better results in the regression of cancers. Some natural products are selective COX-2 inhibitors and have anti-inflammatory and anti-cancer properties. The relevant patents are discussed.

Large-scale (∼36,000 atoms) long-time (30 ns each) molecular dynamics (MD) simulations on the complex of imatinib and 16 common mutants of the ABL tyrosine kinase domain have been performed to study the imatinib resistance mechanisms at the atomic level. MD simulations show that long time computational simulations could offer insight information that static models, simple homology modeling methods, or short-time simulations cannot provide for the BCR-ABL imatinib resistance problem. Three possible types of mutational effects from those mutants are found: the direct effect on the contact interaction with imatinib (e.g. some P-loop mutations), the effect on the conformation of a remote region contacting with imatinib (e.g. T315I), and the effect on interaction between two regions within the BCR-ABL domain (e.g. H396P). Insights of possible imatinib resistance mechanisms, not consistent with current consensus, are revealed from various analyses and our findings suggest that drugs with different binding modes may be necessary to overcome the drug resistance due to T315I and other mutations. The relevant patents are discussed.

Currently, the surgical management of pancreas cancer is recognized around the world as inadequate. Longterm survival is rare even though there is a potentially curative R0 resection. There is a strong rationale for the use of chemotherapy in the operating room to reduce local-regional and hepatic sites of recurrent/progressive disease. Gemcitabine monotherapy administered by an intraperitoneal route in the operating room with hyperthermia and then for long-term treatment postoperatively has a strong pharmacologic basis. The exposure of peritoneal surfaces to intraperitoneal gemcitabine is approximately 500 times the exposure that occurs within the plasma. By analogy to another lethal disease, ovarian cancer, intraperitoneal gemcitabine chemotherapy used following potentially curative resection is supported. Data that shows a superiority of multiagent chemotherapy to gemcitabine monotherapy has not been reported. A standardized treatment with intraoperative chemotherapy monitoring of gemcitabine would greatly facilitate further improvements in pancreas cancer treatment and lead the way to an evolution of more successful treatment strategies of this dread disease. The aim of this review is to present the recent available medical information and patents applicable to patients with resected pancreatic cancer.

For sustained growth, tumors are dependent upon neovascularization to feed their massive demand for nutrients and oxygen. Cancer cells produce growth factors and activators that stimulate vessels in the surrounding tissue to form a new circulatory network around the tumor. Therapies aimed at reducing the blood flow to the cancer cells can slow down tumor growth and reduce metastasis. This review describes novel anti-angiogenic agents, including antibodies directed against vascular growth factors and angiotensin II, pharmaceutical compounds and natural metabolites derived from plants and microorganisms. The relevant patents are discussed. These agents may become valuable anti-cancer therapeutics in the future, as a supplement to chemo- and radiation-therapy.

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