Are we funding the right cancer research?

Since President Richard Nixon declared a 'War on Cancer' with the signing of the National Cancer Act of 1971, the US has spent more than $100 billion on cancer research. While there have been some recent hopeful statistics about improvements in cancer mortality rates in the US and in Europe, the results have not been dramatic. In the same period that saw heart disease death rates drop by a third, cancer death rates have stayed relatively the same since 1950, proving just how challenging it is to fight a disease that boils down to the body itself running a muck.

Many hope that advances in genetics -- actually identifying and treating the specific gene mutations in each person’s cancer on an individual basis -- will bring us closer to personalized therapies and be the cancer treatment breakthrough the world has been waiting for. But, recent research from Cancer Research UK shows that genetic cancer treatment may be much more complex than previously thought. These researchers conducted the first ever genome-wide analysis of genetic variation between different regions of the same tumor, using kidney cancer samples. Their analysis found that the majority of genetic faults, about two-thirds of them, were not shared with other biopsies from the same tumor, meaning that every individual tumor can have multiple genetic mutations that would each need to be treated. The researchers point out that they were able to trace the origins of particular subtypes of cancer cells back to earlier mutations by analyzing the location of shared mutations. With this information, they were able to create a diagram of how the mutations evolved and may be able to identify targets for treatment. But, the bottom line is that most genetic cancer treatments will be complicated and expensive.

As Dr. Dan Longo wrote in an editorial accompanying this study in the New England Journal of Medicine, some had envisioned a future in which a cancer patient would be given state of the art genetic treatment after just one tumor biopsy. But, as this research points out, “a serious flaw in the imagined future of oncology is its underestimation of tumor heterogeneity -- not just heterogeneity between tumors, which is a central feature of the new image of personalized medicine, but heterogeneity within an individual tumor.”

This may all sound like a lot of cancer doom and gloom. But, even though it sounds like a setback, every increase in our understanding of cancer, even if it means that the road will not be as easy, is a step forward. And, while genetic treatment research continues, other tacks to treat cancer are coming to the fore. One of the most intriguing is proteomics -- the study of the body’s proteins. While changes to gene expression are the part lists that lead cells to become cancerous, proteins are the actual building materials used to build a cancerous cell. They are what really makes cancer happen in the body. By understanding what precisely is going on at the protein level, we can understand how cancer actually functions.

Two key players in this expanding research area are Daniel Hillis and David Agus, the principal investigators of the University of Southern California Physical Sciences-Oncology Center. While they are unlikely collaborators -- Agus is a MD who has spent a career combating cancer, while Hillis comes from a computer engineering background and has worked on projects as varied as founding the technological consulting company Applied Minds, serving as the head of Research and Development of Walt Disney Imagineering, and building a clock built for the super-long haul -- Agus and Hillis are now aiming to change the face of cancer diagnosis and treatment. 

As he discussed in a TED talk in 2010, Agus, along with other researchers, realized many years ago that being able to see what was happening at the protein level is crucial to treating cancer. But, at the time, reading individual proteins was a long and complicated process, where one mistake meant that the entire process needed to be started over. Because of this arduous process, protein analysis was not available to individual cancer patients. But, then Agus heard about Hillis, and his company Applied Minds, and thought they might be able to help. After a few failed attempts (Hillis admits that he only called Agus back after the famed venture capitalist John Doerr, entrepreneur and investor Bill Berkman and Al Gore all told him to call), Agus and Hillis finally met, and they both admit it changed their careers.

Together, they set to work developing an automated process to index proteins. In support of their work, they received a $16 million grant from the National Cancer Institute in 2009 to fund the opening of their current center at USC. They also founded a private company to offer proteomic assays and approaches to cancer treatment. In February, the company, Applied Proteomics, Inc. (API), announced $22.5 million in funding and named a new CEO.

Agus, Hillis and their team were successful in developing a system to identify proteins in a drop of blood. As Hillis wrote via email, “API now has the capability to accurately measure tens of thousands of protein markers in samples of blood and cerebral spinal fluid,” an invaluable tool in “developing more accurate and less invasive diagnostics for systemic diseases like cancer.” (For a stunning explanation of their technique, check out Hillis’ TED talk.) Now, they are working on developing a complete model of cancer in mice. As Hillis explains, “We are using all the tools in the book -- genetics, expression analysis, proteomics, microscopy, imaging -- to study the development of a particular kind of cancer in a particular line of mice. The idea is to build a predictive computational model of how this particular cancer develops at the level of the cell, the tumor and the entire organism. Surprisingly, this has not been done before. We hope the model will be accurate enough to predict exactly how the mouse will respond to different treatments. Of course, this is hard, and we may not succeed. If it works on these mice, it may someday work on humans.”

Another company working on the proteomic approach to cancer management is the UK-based Proteome Sciences. Along with products used in drug development and other diseases, the company has a portfolio of patented biomarkers around which they are building cancer-related products, as their COO Ian Pike shared. One of their first products, which they are developing with researchers at the Buck Institute in Novato, Calif., and the Moffitt Cancer Center in Tampa, Fla., will be a test to determine how responsive a breast tumor will be to anti-estrogen therapy. The company is also working on methods to detect cancer autoantibodies, which are produced by the body in response proteins created by tumors. Measuring these autoantibodies may prove to be a valuable early marker for cancer. Proteome Sciences has licensed their intellectual property related to this technology to Oncimmune, a company specializing in cancer detection, for the development of lung cancer testing, with tests for other cancers in the works.

As Pike said in an email, “At the end of the day, essentially all disease processes are caused by protein activity and understanding how protein function is regulated is critical to making the most informative diagnosis and treatment selection.” Most cancer is due to post-translational modifications to cellular signalling pathways that are not coded by the genome. Because of this, proteomics “will be a major future component of cancer diagnosis and management.” To further explore cellular signaling, Proteome Sciences is developing the SysQuant™ profiling service, which provides a system-wide analysis of phosphorylation in cancer signalling pathways by quantifying the levels of phosphorylation at several thousand different sites on over 1,000 proteins involved in cell signalling. The system has shown promise in testing with tumor cell lines and samples, and the company is hopeful that it will one day be useful in specifically tracking how cancer responds to certain treatments. 

Applied Proteomics and Proteome Sciences are just two examples of research on alternative methods of understanding cancer. Another example of this movement is the National Cancer Institute’s Physical Sciences in Oncology initiative. This program, which was started several years ago and also provides funding to the USC Center helmed by Agus and Hillis, is the first to reach out to experts in the physical sciences -- physicists, mathematicians, chemists and engineers -- to seek new approaches to fight cancer. At 12 centers across the US, researchers are tackling never before-focused on questions about cancer, from the evolution of the disease to the possibility of creating mathematical models of cancer.

In the wake of so much money spent with little progress and many other pressing disorders requiring attention, some are calling for a smaller percentage of the National Institutes of Health budget to be spent on cancer research. But a crucial element of this funding debate is that not all cancer research is created equal. While traditional therapies may not be reaping the desired results and personalized genetic medicine is very expensive, new, cross-disciplinary approaches to fighting cancer may be only the economical way forward.

 

 

Check out David Agus talking about proteomics in this TED talk: