Glioblastoma, the most common and aggressive type of brain cancer claimed the life of Sen. Edward Kennedy and 17,000 others every year. Conventional treatments have never offered much help to patients with brain cancer.

We need alternative treatments, using the immune systems. Just like the vaccines we give for measles, mumps and the flu, the idea is to prevent cancer from coming back. Dr. Andrew Parsa, a University of California at San Fransisco (UCSF) neurological surgeon who is leading the study of the vaccine, called Oncophage, with $150,000 in funding from the National Brain Tumor Society and other patient groups and another $150,000 from the federal government. Dr. Parsa is testing that theory with a ground-breaking clinical trial at UCSF Medical Center. Working with a biotech company, his team used a piece of Wheatley's tumor, to create a vaccine engineered to target specific cancer. A woman Joyce Wheatley became the first in the country to try a new vaccine to stop a brain tumor from reoccurring. The idea is to combine the tumor vaccine early, while the cancer is being weakened by chemotherapy and radiation. The hope is patients will then be able to manage the disease using their own immune system.

Traditional chemotherapeutic drugs don't work well in combating this type of cancer. Part of the problem is the body's blood-brain barrier, which is designed to shield the organ from chemicals - but also blocks lifesaving therapies from reaching it. Tumor cells also become quickly resistant to medicines. Vaccines, also called immunotherapies, take a different approach. Using a multistep approach, they are created from a patient's own tumor. The vaccine actually provokes a tumor-specific immune response that is patient specific. T-cells, the killer compound of the immune system, track down the cancer and try to kill it.

The approach seems counterintuitive - if the body's natural immune response could combat the cancer, the tumor should have perished and never needed treatment. A more vigorous defense is needed. If it works, it will reinvigorate a strategy for treating cancer that has long held conceptual promise but has proved difficult to deliver.

Many experimental vaccines have stumbled in clinical trials and none is yet approved in the United States. One of the greatest disappointments was in 2005, when final testing of the anti-melanoma vaccine Canvaxin showed that people getting the drug did not live longer than those getting the placebo. This year, a drug named Provenge, an immunotherapy for prostate cancer, has been shown to lengthen life for four months but has not yet earned approval by the U.S. Federal Drug Administration.

Scientists say that one challenge is that most drugs in development are first evaluated in patients with fairly advanced cancer - but many of these patients are so sick that they're immune-suppressed. Cancer vaccines may work better when the tumor is smaller. Scientists also say that ‘one should have to have the right type of vaccine, the right type of cancer, the right type of patient and the right type of environment to cure’.

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

AADAUTECH 

The Cancer Drug Discovery & Therapeutics Blog was started in January 2009. It updates therapeutic targets and drug discovery in the area of cancer. Most of what you read here are updates of recent and new research in cancer therapeutics. Got a cancer news story you think belongs here? Lets discuss. So if you have an interest in cancer and cancer related discovery, please register and join others like you in an ongoing, vibrant dialog.