January 1, 1970 (Vol. , No. )

Nicholas Miliaras, Ph.D. ATCC

Oncologists and basic research scientists may finally have found some common ground in the cell culture dish.

When President Richard Nixon signed into law the National Cancer Act of 1971, declaring the “War on Cancer,” he began what is now a 40-plus year-long effort to eliminate cancer as a major cause of death. At the time, curing cancer probably seemed a realistic goal for a nation that had just put a man on the moon.

Much progress has been made since then in controlling some of the lifestyle and environmental causes of cancer and advances in medical imaging allow for earlier detection of breast and prostate tumors. Thanks to increases in funding for basic cancer research, we also know more about the molecular biology of the cell now than ever before. Despite these advances, cancer mortality has not decreased significantly in the past few decades. In fact, cancer is soon predicted to overtake cardiovascular disease as the number one killer in developed countries.1 So how can we find a path to victory? It may be closer than we think.

Perhaps the greatest challenge to developing a highly effective anticancer drug is that the mechanisms underlying the development of tumors are different for each type of cancer. Chemotherapeutic drugs such as Paclitaxel (Taxol) function nonspecifically by disrupting cell division. Therefore, while these drugs are highly effective at stopping active cell division in tumor cells and inducing cell death, they also target healthy cells, which results in many of the undesirable side effects of chemotherapy. More importantly, anticancer drugs are only partially effective at preventing tumor growth and do not treat all cancer types. When most of these drugs were developed, they were tested for cytotoxicity on a few cancer cell lines prior to tests in animal models and clinical trials. They often do help extend the lives of patients during treatment, but the cancer often returns.

The major reason why chemotherapy isn’t more effective is that each patient is genetically distinct; not everyone will metabolize a given drug the same way. Also, the cancers themselves have different genetics. The Human Genome Sequencing Project was completed in 2003. Since then, next-generation DNA sequencing technologies have been developed that allow multiple genomes to be sequenced in parallel, so it is now possible to identify and catalog mutations that occur in different cancer types.2

Despite this increasing body of knowledge, the exact process by which a healthy cell surrounded by normal tissue becomes cancerous remains largely unknown. However, an extensive review of published research from different areas of cancer cell biology reveals that there are six new capabilities or “hallmarks” that normal cells acquire when they become cancerous.3 These include: continued signaling for cell growth and division, failure to respond to suppressors of cell division, a diminished capacity to undergo programmed cell death, the ability to continue dividing indefinitely (replicative immortality), the ability to form new blood vessels (angiogenesis), and the ability to invade other tissues and form new tumors (metastasis).3 Genomic instability, which is both a cause and a consequence of a cell becoming cancerous, facilitates the cell’s ability of acquiring these hallmarks.

The cancer genome sequencing projects have identified mutations occurring primarily in genes that control cell growth and division. Many of these mutations occur in genes that link signaling from extracellular factors to cell growth, such as the EGF receptor, components of the MAP Kinase pathway, and p53, which is a critical link between genomic damage and cell death; p53 mutations occur in all cancers.

Researchers may now combine this wealth of genetic information for sequenced cancer cell line genomes with large-scale testing against a battery of anticancer drugs to determine which drug will work best to kill cancer cells based on the mutational and gene expression profile of individual cell lines.

An example of this approach is the Cancer Cell Line Encyclopedia, a project at the Broad Institute.4 In this study, Barretina and colleagues profile mutations and gene expression for 479 cell lines representing 36 tumor types and tested the response of these cell lines to 24 anticancer compounds. This group find a correlation between gain of function mutations in the MAP Kinase pathway component BRAF and the NRAS gene and sensitivity to the MEK inhibitor drug PD-0325901. They also observe that high expression of insulin-like growth factor (IGF) in multiple myeloma cell lines correlates with sensitivity to the IGF1 receptor inhibitor AEW541. In Ewing’s sarcoma cell lines, increased expression of the DNA topoisomerase I gene SLFN11 correlates with sensitivity to topoisomerase inhibitors such as topotecan.4

A second example of this approach is a similar study by Garnett and colleagues that screens 639 human cell lines representing a broad range of cancers for 64 common mutated cancer genes, as well as changes in the expression of 14,500 genes.5 They analyze the cytotoxic response of these cell lines to 130 anticancer compounds, including existing drugs and drugs in development. In all cancer cell lines, this group finds that loss of function mutations in p53 results in resistance to nutlin, an inhibitor of a negative regulator of p53. They also observe that loss of function mutations in the retinoblastoma protein (RB1), which inhibits cell cycle progression in healthy cells, results in resistance to PD-0332991 and that a chromosomal translocation common to Ewing’s sarcoma cell lines correlates with sensitivity to poly (ADP) ribose polymerase (PARP) inhibitors.5

The War on Cancer is now in its fifth decade and while many battles have been won, the major decisive victory that will turn the tide and make cancer a manageable, if not curable, disease still awaits us. For years, oncologists have tested experimental drugs on cancer patients without much knowledge of how the drugs work, while basic research scientists have dissected the biochemical mechanisms of how cancer cells grow and divide. These two groups have different intellectual frameworks, cultures, and agendas, so working towards a common goal has been difficult.

They may finally have found some common ground in the cell culture dish. High-throughput DNA sequencing has revolutionized genetic medicine and it is now possible to use this technology to find the most effective drug for a specific type of cancer by testing a large collection of cell lines. This approach will become more accessible and affordable, so it will soon be possible to determine the best treatment for individual patients based on their genetic profile and that of the cancer being treated and cancer mortality should decline significantly as a result. Although it has taken over forty years to reach this point, it may well have been worth the wait.

Nicholas Miliaras, Ph.D.

Nicholas Miliaras, Ph.D., is a cell biology specialist at ATCC.

1 Kolata, Gina (April 24, 2009). “As Other Death Rates Fall, Cancer’s Scarcely Moves”. The New York Times. http://www.nytimes.com/2009/04/24/health/research/24cancerside.html.
2 The Sanger Institute: Catalogue of Somatic Mutations in Cancer (COSMIC): http://www.sanger.ac.uk/genetics/CGP/cosmic/
3 Hanahan, D and Weinberg, R.A. (2011). Hallmarks of Cancer: The Next Generation. Cell 144, 646-674. PubMed: 10647931
4 Barretina, J, et al. (2012) The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607
5 Garnett, M.J., et al. (2012) Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570-575

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