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Drug Targets for Breast Cancer
Informa Healthcare, Jan 2006, Pages: 170
Breast cancer is a complex heterogeneous disease characterized by uncontrolled growth and spread of abnormal cells. It is also very prevalent, with reports from the World Health Organization estimating that more than 1.2 million people will be diagnosed with breast cancer in 2005, worldwide. In the United States, breast cancer is the second most common cancer in women (following skin cancer) with 212,930 new cases estimated for 2004 and an associated 40,840 deaths. In Europe, approximately 200,000 women are diagnosed with breast cancer each year (41,000 in the UK). Consequently, breast cancer is a high-priority research area and is recognized as one of the most aggressively pursued diseases in the history of medicine.
Breast Cancer Therapeutics
Encouragingly, cancer drug therapy is in a time of major transition. This time has been described by the pharmaceutical company, Bristol Myers Squibb (New York, NY), as a “golden era,” where decades of cancer research are now being translated into development of next generation therapeutics. Current pharmaceutical pipelines are testimony to the intensity of breast cancer drug development with at least 50 investigational drugs/drug combinations in clinical development.
Breast cancer treatment generally comprises of combinations that include surgery, radiotherapy, hormonal therapy, and chemotherapy. Clinical pipelines now reflect the emergence of two additional new therapy classes, namely, “innovative therapy” and “immunotherapy.” Presently, treatment is somewhat dominated by hormone or endocrine therapy as approximately 70% of breast cancers are hormone-responsive. In particular, and since the mid-1970s, the antihormonal drug, tamoxifen (Nolvadex®; AstraZeneca plc, London, UK), has become established as a “gold standard” of treatment for hormone-responsive breast cancers. More recently, new and improved hormonal therapies have emerged and are expected to ultimately replace tamoxifen.
These primarily include the aromatase inhibitors and to a lesser extent, “pure estrogens.” Three key approved aromatase inhibitors are Arimidex® (anastrazole, AstraZeneca plc, London, UK), Femara® (letrozole, Novartis AG, Basel, Switzerland), and Aromasin® (exemestane, Pfizer Inc, New York, NY). Faslodex® (fulvestrant; AstraZeneca plc London UK) is an approved “pure estrogen.” Current pipeline developments include new aromatase inhibitors and additional indications for approved therapies. Additionally, three endocrine therapies (known as SERMs) are in development. These therapies have estrogen-blocking activity against breast and endometrium tissue while maintaining estrogen protective activity against the bone and heart, for example. With an increasing range of endocrine therapies comes an increasing range of options for the physician and patient.
In addition to hormonal/endocrine therapy, the three other classes of drug therapies relevant to breast cancer are “innovative therapy,” “immunotherapy,” and chemotherapy. Innovative and immunotherapy represent a new approach in cancer treatment known as targeted therapies. These “new generation” therapies are built on a foundation of at least two decades of breast cancer research—and development of a major knowledge base on the molecular etiology of breast cancer. The output of these studies is the identification of new drug targets, which has accelerated drug development. Drugs associated with innovative therapies generally target key
signaling molecules/pathways associated with cancer development. These include drugs that target growth factor receptors (e.g. the EGF or IGF receptor), angiogenesis, farnesylation, the MEK pathway, the mTOR pathway, apoptosis, DNA synthesis and repair, and the proteasome. Some small molecules in development target more than one pathway such as lapatinib (GlaxoSmithKline plc, Brentford, Middlesex, UK), a dual tyrosine kinase inhibitor that targets EGFR and HER2. This capacity considerably expands the therapeutic potential of this drug with potential for overcoming drug resistance that may develop against one pathway.
The “immunotherapy” class comprises largely of therapeutic vaccines and monoclonal antibodies. Immunotherapy acts to harness the potential of patients own immune system (or boost its potential) to fight cancer. No therapeutic vaccines have yet been approved for breast cancer but several are in advanced development. PANVAC™-VF (and docetaxel) is in Phase II of development at Therion Biologics (Cambridge, MA). This vaccine is based on the principle of educating the immune system to recognize cancer-specific antigens and cause an immune response. At Dendreon Corp. (Seattle, WA), a breast cancer vaccine is in Phase I of development that targets HER2 positive cancers. In parallel to vaccine development is adjuvant development. With propensity to enhance the immune response, relevant adjuvants are in development at Galencia Pharmaceuticals (Birmingham, AL) and Corixa Corp. (Seattle, WA). Another major component of immunotherapy is monoclonal antibody development. The first approved monoclonal antibody for breast cancer is Herceptin® (trastuzumab; Genentech, Inc, South San Francisco, CA). This has been a major success and is used to treat patients with HER2/neu positive phenotypes. Herceptin®, FDA approved in 1998 is now under investigation as a treatment for early-stage HER2-positive cancer. HER2 diagnostic testing has been a significant parallel development to Herceptin® approval and has paved the way for tailoring of therapies to a specific patient, indicative of a new trend towards personalized medicine or pharmacogenomics.
Chemotherapy, which generally interferes with the process of cell division of cancer cells, is a treatment approach utilized over many decades. Although efficacious, new generation therapies hold promise for much reduced side effects. New technologies such as liposomal packaging allow more drug to be delivered more efficiently to the target site. One example of this is Doxil® (doxirubicin; J&J Pharmaceutical R&D (Raritan, NJ). Another approach is reducing the usage of solvents (and some of the associated side effects) used with chemotherapy drugs. Abraxane™
(Abraxis Oncology, CA), is a new mode of chemotherapy where drugs are packaged via binding to albumin. This solvent-free combination reduces problems such as hypersensitivity and allows more optimal dosing. Another advance among chemotherapy agents is the increase in combinations therapies; a factor that expands their therapeutic potential. In support of the trend towards less harsh chemotherapy, AstraZeneca has recently doubled its R&D capabilities in the pursuit of kinder, gentler, more effective cancer medicines.
Breast Cancer Technologies
Underlying development of breast cancer therapeutics is a diverse array of enabling technologies. These include technologies associated with gene cloning and characterization, gene expression profiling, proteomics, RNAi, bioinformatics, population genetics, and biomarkers. Central to many of these technologies is their ability to probe the molecular basis of disease. One output of the study of the molecular basis of breast cancer is the identification of new biomarkers.
These can provide “early warnings” of cancer from simple serum tests, as available from Tripath Imaging, Inc (Burlington, NC), for example. At Veridex LLC (Warren, NJ), circulating tumor cells are a focus for metastasis detection and prognostic information. Molecular markers or biomarkers also provide a basis for diagnostic tests, which allows for more accurate prognosis. The FDA approved two diagnostic tests for HER2 testing as a prelude to Herceptin® therapy. These are the Ventana Inform test (Ventana Medical Systems) and the Pathyvision test (Abbott-Vysis partnership). Prediction of cancer metastasis is an area of investigation through gene expression profiling of breast cancer samples. This facilitates identification of “gene signatures” relating to breast cancer and is an approach utilized at Agendia BV (Amsterdam, The Netherlands) and Ipsogen (Marseille, France). Clinically relevant insights of breast cancer gene expression are also emerging by application of proteomics to bio-fluids and biopsy specimens. Integrating the knowledge banks accumulating in breast cancer is taking place through the emerging science of bioinformatics. IT-based infrastructure is being utilized in initiatives such as the National Cancer Institute’s Bioinformatics Grid, a platform for data sharing at a national level.
Breast Cancer Markets
Oncology is recognized as the third largest segment of the world’s pharmaceutical markets. The oncology market has estimated global sales of $40 billion, with growth projected at 10%. Of this segment, the market associated with breast cancer therapeutics is approximately $6.2 billion, the largest market in oncology. In the breast cancer market, clinical pipelines exhibit a wide range of new generation “innovative” and “immunotherapy” drug candidates. Consequently, transformation of the oncology marketplace is predicted over the next decade. Growth in the market is expected to be driven by the ageing population and increases in the incidence of breast cancer. Sales revenues of endocrine therapies in 2004 for breast cancer are just under $2.0 billion. Revenues have been increased significantly by the approval and uptake of aromatase inhibitors. This increase counterbalances a drop in revenue from drugs such as Nolvadex®, which have come off patent recently. In looking ahead, GlaxoSmithKline’s lapatinib (an innovative therapy) is forecast to achieve blockbuster sales in 2012 and is a frontrunner of the innovative class. In chemotherapy, Abraxane (Abraxis Oncology, CA) is set to become a key cytotoxic.
The Future and Breast Cancer
Breast cancer treatment is set to change significantly. More targeted therapies with reduced adverse effects are likely to soon dominate the market place. Therapeutics relating to the innovative therapies and immunotherapies are likely to be the most novel. The sector eagerly awaits progress with therapeutic vaccines in development, in particular. Realization of the therapeutic potential of these therapies is likely to make a large impact as concepts such as “immune surveillance” for micro-metastasis are tested. Approval of combination therapies is likely to expand therapeutic and market potential of existing therapies. Similarly, single agents that target multiple pathways are also likely have increased therapeutic and market potential. Gentler, more technologically advanced chemotherapy treatments are emerging. Given these developments, the challenge now is to intensify research so that the intricacies of molecular signaling pathways might be further elucidated and more drug targets identified. These new approaches to cancer treatment, along with healthy clinical pipelines provide hope for halting breast cancer progression, amelioration of symptoms, and improvement in a patient’s quality of life.
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