Recent Patents on Anti-Cancer Drug Discovery - Volume 4, Issue 3, 2009

The first lines of defense in the human innate immune system are membrane receptors called Toll-like receptors (TLRs). This family of receptors functions as primary sensors to recognize microbial pathogens. Subsequent binding of ligands to TLRs lend to the activation of cellular signaling pathways that regulate expression of genes related to inflammation and immunity. The discovery and supporting evidence of functional and structural diversity suggests TLRs are key participants in cellular immunity and are important to various medical conditions including the tumor microenvironment. TLR heterogeneity emphasizes the role of these receptors and suggests a new opportunity to develop therapies targeting specific or multiple TLRs that may contribute to the treatment of a myriad of diseases including various cancers. In this article, we intend to focus on a number of recently issued patents related to TLRs and to propose the relevance of these patents to novel treatments for cancers.

Cervical cancer is the second most frequent malignancy affecting women worldwide. The highest incidences occur in the developing world, where, in most countries, cervical cancer is the leading cause of cancer mortality in women. Although surgery and chemoradiotherapy can cure 80-95% of women with early stage cancer and 60% of locoregionally advanced cancer, the recurrent and metastatic disease remains a major cause of cancer death. The current cytotoxic treatment options for advanced and metastatic cancer demonstrate modest results, with response rates of maximum 30% and overall survival of less than 10 months. Given this limited degree of success with conventional therapies, interest has increased in other therapeutic alternatives. In this way, targeted agents are emerging as potential candidates for improving survival in cervical cancer patients. In this review we highlight the main current therapeutic strategies for cervical cancer and summarize the most relevant patents from the latest five years. Special attention was given to patents with potential applications in the clinical practice.

Non-invasive in vivo imaging offers great potential to facilitate translational drug development research at the animal testing phase. The emerging luminescent nanoparticles or quantum dots provide a new type of biological agents that can improve these applications. The advantages of luminescent nanoparticles for biological applications include their high quantum yield, color availability, good photo-stability, large surface-to-volume ratio, surface functionality, and small size. These properties could improve the sensitivity of biological detection and imaging by at least 10- to 100-fold and make them an exceptional tool for live-cell imaging. In this review patents on applications of semiconductor quantum dots for in vivo imaging are discussed.

Human epidermal growth factor receptor (HER) signaling is frequently associated with the development and progression of several types of cancers. Both the MAPK and the PI3K/Akt pathways have been implicated as effectors of HER signaling by promoting anti-apoptotic and pro-proliferative effects in cancer cells. As a result, many anti-HER drugs have been developed and patented for use in cancer therapy. One such drug that was recently approved for clinical trials is lapatinib (Tykerb, GW572016). Lapatinib is a small molecule inhibitor that is active at the ATP binding site of the tyrosine kinase involved in HER signaling. Importantly, this drug has dual specificity acting at the ATP binding sites of both HER-2 and HER-1 (EGFR). This review therefore summarizes the current knowledge based on pre-clinical and clinical evidence of the therapeutic effects of lapatinib against cancer and the promising strategy of combination therapy with the possibility of circumventing the problems of drug resistance commonly faced by chemotherapeutic drugs.

Eradication of cancer cells is imperative for a successful treatment of tumours. In addition to the existent chemotherapy or radiation therapy, other novel immunotherapeutic strategies to fight tumours are currently under investigation. One of these is cancer vaccination, an approach aimed at inducing effective immune responses in the host against defined tumour antigens. Among several classes of cancer vaccines, the subunit vaccines based on the single and multi epitope-approach are worthy of note as they offer an exquisite specificity in targeting only tumour cells. In this review we will focus on the significant advances made in the development and use of epitope-based cancer vaccines, reporting a selection of important and recent patents on tumour antigen discovery and epitope design for immunotherapy of cancer.

Amrubicin is a synthetic anthracyclin analogue that has significant activity in Japanese patients with extensive stage small cell lung cancer (ES-SCLC). There has not been significant advances made in the treatment of this disease in last several years and new therapies are desperately needed to change the natural history of this disease. Preliminary data has shown that amrubicin possesses anti-tumor activity in patients with extensive stage small cell lung cancer in the western population. Clinical trials are on going to evaluate this agent further in Europe and US. If effective, it may be an invaluable addition into the current armamentarium to treat this deadly disease. The review includes patent coverage on the treatment of small cell lung cancer.

Aldo-keto reductase 1 member B1 (AKR1B1) is pathogenically involved in diabetic complications by driving glucose flux through polyol pathway; a variety of AKR1B1 inhibitors has been developed for the treatment of diabetic complications and a body of invaluable preclinical and clinical data have been collected through decades' efforts. Recent studies have shown that some AKR1B1 inhibitors demonstrate strong inhibitory activity to aldo-keto reductase family 1 member B10 (AKR1B10), a protein identical to AKR1B1, in vitro and in cancer cells. AKR1B1 and AKR1B10 are overexpressed in human tumors, such as liver, breast, and lung cancer, and may play a critical role in the development and progression of cancer through carbonyl detoxification, retinoic acid homeostatic regulation, and lipid metabolic control, as well as the activation of tobacco smoke carcinogens. Therefore, AKR1B1 inhibitors may represent a novel class of antitumor agents; and the clinical data assembled in diabetic clinics would greatly assist the transition of these inhibitors to cancer clinics. This article summaries the current understanding of the expression and function of AKR1B1 and AKR1B10 in human cancers and reviews the patents and papers of AKR1B1 inhibitors. Authors' opinions concerning the current and future development of AKR1B1 and/or AKR1B10-specific inhibitors are discussed.

DNA topoisomerase is one of drug targets in cancer therapy. Camptothecin is a plant alkaloid derived from the Chinese tree Camptotheca acuminate. It has been demonstrated that the plant alkaloid camptothecin (CPT) caused DNA damage by specifically targeting DNA topoisomerase, effectively devastating a broad spectrum of tumors. Although the anti-tumoral activity of CPT has been intensively studies for nearly fifty years, recent advances in drug delivery systems of CPT have considerably improved this drug's efficiency. In this review, we will summarize the current status of CPTderived anti-cancer drugs in literatures and patents and highlight their clinical application.

Albumin is a versatile drug carrier in anti-cancer drug delivery system and it also has an actively targeting capacity to tumors. Recently, nanoparticle albumin-bound (nab™) paclitaxel (nab-paclitaxel; Abraxane®) has been approved in 2006 for use in patients with metastatic breast cancer who have failed in the combination chemotherapy, and so the nab-technology has attracted much interest in the anti-cancer drug delivery system. The details about the preparation, characterization and evaluation of nab-paclitaxel (ABI-007) are discussed. The pharmacokinetics, pharmacodynamics and the clinical trials of ABI-007 are also reviewed. Furthermore, the recent applications of nabtechnology in the anti-cancer drug delivery systems are summarized by virtue of the patents pertaining to nab-technology. To sum up, nab-technology has a great potential of being applied extensively in the field of anti-cancer agents delivery in the future in order to acquire the good safety and better therapeutical effect.

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