2009: 

Pharmacogenetics and pharmacogenomics of anticancer agents

R. Stephanie Huang, PhD and Mark J. Ratain, MD; Section of Hematology and Oncology, Department of Medicine, Cancer Research Center, University of Chicago, Chicago, IL

Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made in the field of pharmacogenetics and pharmacogenomics using a five-stage architecture, which includes 1) determining the role of genetics in drug response; 2) screening and identifying genetic markers; 3) validating genetic markers; 4) clinical utility assessment; and 5) pharmacoeconomic impact. Examples are provided to illustrate the identification, validation, utility, and challenges of these pharmacogenetic and pharmacogenomic markers, with the focus on the current application of this knowledge in cancer therapy. With the advance of technology, it becomes feasible to evaluate the human genome in a relatively inexpensive and efficient manner; however, extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside. CA Cancer J Clin 2009;59:42–55. http://intl-caonline.amcancersoc.org/cgi/content/abstract/59/1/42

Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

Janaiah Kota et al., Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies. Cell, 137(6), 1005-1017, 12 June 2009 http://www.cell.com/retrieve/pii/S0092867409004462

 Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction 

 Ji Luo, Nicole L. Solimini and Stephen J. Elledge. Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA. Abstract: Cancer is a complex collection of distinct genetic diseases united by common hallmarks. Here, we expand upon the classic hallmarks to include the stress phenotypes of tumorigenesis. We describe a conceptual framework of how oncogene and non-oncogene addictions contribute to these hallmarks and how they can be exploited through stress sensitization and stress overload to selectively kill cancer cells. In particular, we present evidence for a large class of non-oncogenes that are essential for cancer cell survival and present attractive drug targets. Finally, we discuss the path ahead to therapeutic discovery and provide theoretical considerations for combining orthogonal cancer therapies. Cell. 36(5), 6 March 2009, Pages 823-837 http://www.cell.com/

Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

Elizabeth A. Richey, E. Alison Lyons, Jonathan R. Nebeker, Veena Shankaran et al Northwestern University Feinberg School of Medicine, 303 E Chicago Ave, Olson Pavilion Ste 8250, Chicago, IL 60611. Conclusion. AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs. Journal of Clinical Oncology, Vol 27, No 26 (September 10), 2009: pp. 4398-4405 http://jco.ascopubs.org/cgi/content/abstract/27/26/4398

Controlling the cost of innovative cancer therapeutics

Nafees N. Malik. Abstract: The cost of monoclonal antibody therapies for cancer is soaring out of control. Healthcare payers and patients are increasingly struggling to meet the high costs, which can be up to US$100,000 a year. A number of methods have been proposed to control these costs—government price controls on cancer drugs, biosimilars and novel drug pricing strategies. This article discusses what the impact of these strategies would be in terms of their ability to reduce costs and their effect on innovative cancer drug discovery. Nature Reviews Clinical Oncology 6, 550-552 (September 2009), http://www.nature.com/nrclinonc/journal/v6/n9/abs/nrclinonc.2009.113.html

2008: 

Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index 

Jagath R Junutula, Helga Raab, Suzanna Clark et al. Genentech Inc., DNA Way, South San Francisco, California 94080, USA. Abstract: Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display–based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity. Nature Biotechnology 26, 925 - 932 (2008) http://www.nature.com/nbt/journal/v26/n8/abs/nbt.1480.html

Systematic Survey of Therapeutic Trials for Metastatic Colorectal Cancer: Room for Improvement in the Critical Pathway

Scott Kopetz, Michael Overman, David Z. Chang, Katrina Y. Glover, Imad Shureiqi, Robert A. Wolff, James L. Abbruzzese, Cathy Eng. From the Departments of Gastrointestinal Medical Oncology and Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Abstract: Conclusion Current clinical trials for metastatic colorectal cancer are deficient in the investigation of agents directed at a novel therapeutic target, overuse phase II studies of FDA-approved agents, and fail to incorporate enrichment trial designs as encouraged by the FDA initiative. Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2000-2005.  http://www.jcojournal.org/cgi/content/abstract/26/12/2000

Nanoparticle therapeutics: an emerging treatment modality for cancer

Davis, Mark E. and Chen, Zhou (Georgia) and Shin, Dong M. Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA. Abstract: Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, we highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer. Nature Reviews Drug Discovery, (2008), 7 (9). pp. 771-782. http://www.ncbi.nlm.nih.gov/pubmed/18758474

For the last 30 years, the International Agency for Research on Cancer has prepared estimates of the global cancer burden. Beginning in 1975 with broad estimates of numbers of new cases for 12 common types of cancer in different areas of the world. Overall, there were 10.9 million new cases, 6.7 million deaths, and 24.6 million persons alive with cancer (within three years of diagnosis). The most commonly diagnosed cancers are lung (1.35 million), breast (1.15 million), and colorectal (1 million); the most common causes of cancer death are lung cancer (1.18 million deaths), stomach cancer (700,000 deaths), and liver cancer (598,000 deaths). The most prevalent cancer in the world is breast cancer (4.4 million survivors up to 5 years following diagnosis).

FIGURE 1. Estimated Numbers of New Cancer Cases (Incidence) and Deaths (Mortality) in 2002. Data shown in thousands for developing and developed countries by cancer site and sex.

(Figure 1 adapted from Parkin et al., CA Cancer J Clin 2005; 55:74-108  http://caonline.amcancersoc.org/cgi/content/abstract/55/2/74)

FIGURE 2. Incidence, Mortality, and Prevalence by Location.

(Figure 2 adapted from Parkin et al., CA Cancer J Clin 2005; 55:74-108  http://caonline.amcancersoc.org/cgi/content/abstract/55/2/74)

FIGURE 3 Ten Leading Cancer Types for Estimated New Cancer Cases and Deaths, by Sex, United States, 2009

(Figure 3 adapted from Jemal et al., CA Cancer J Clin 2009; 59:225-249. http://caonline.amcancersoc.org/cgi/content/abstract/59/4/225?etoc)

Figure 3 indicates the most common cancers expected to occur in men and women in 2009. Among men, cancers of the prostate, lung and bronchus, and colon and rectum account for about 50% of all newly diagnosed cancers. Prostate cancer alone accounts for 25% (192,280) of incident cases in men. On the basis of cases diagnosed between 1996 and 2004, an estimated 91% of these new cases of prostate cancer are expected to be diagnosed at local or regional stages, for which 5-year relative survival approaches 100%.

This year alone, nearly 8 million people will die of cancer worldwide. Sixty percent of all cancer is preventable. One-third can be cured if detected early and treated adequately. By 2030, there could be 27 million incident cases of cancer, 17 million cancer deaths annually and 75 million persons alive with cancer within five years of diagnosis. Cancer is projected to become the leading cause of death worldwide in the year 2010. The burden of cancer doubled globally between 1975 to 2000. It is estimated that it will double again by 2020 and nearly triple by 2030 (source: http://livestrongblog.org/).