On the Horizons
Cancer Progress Report 2013: Contents
In this section you will learn:
Combinations of molecularly targeted therapies based on cancer biology are likely to become part of the standard of cancer treatment in the near future.
Small, synthetic noncoding nucleotides (DNA or RNA) are being actively investigated for their potential to precisely eliminate the effects of disease-causing genetic mutations.
Cancer research has taught us that the collection of diseases we call cancer is complex at every level and that it is adaptive, continually developing ways to evade even our most precise treatments. It is clear, however, that the more we understand about the ways in which cancer arises and adapts, the better we are at treating it. For example, we previously thought that the only unique characteristic of cancer cells were their ability to rapidly divide. As such, we treated cancer patients with drugs that target all dividing cells, even normal ones. Now, we can identify specific genetic alterations within cancer cells that can fuel their division, and develop drugs that precisely target the molecular abnormalities that arise as a result of these modifications.
As we continue to pursue a comprehensive understanding of the biology of cancer at all stages — the root causes of its initiation, growth, and metastasis — and at all scales, from genes, to molecules, to cells, to humans, novel strategies for making further strides in the prevention, detection, diagnosis, and treatment of cancer will appear on the horizon. Regardless of what these next breakthroughs against cancer are, they will surely come from a convergence of scientific disciplines, a diversity of scientific and health care practitioners, as well as a variety of approaches. A problem as complex as cancer will undoubtedly require a multifaceted solution.
The Near Horizon
As discussed throughout this report, cancer cells are rife with genetic alterations that give them a competitive growth advantage when compared to noncancerous cells. Cancer research has provided us with the ability to identify these alterations and to develop novel and effective medicines that target cancer cells with some of them. Due in large part to the presence of many different alterations within a patient’s cancer, however, cancers can adapt and fuel their growth through an alteration other than the one blocked by a given medicine. This leads to continued or worsened disease.
Near-term breakthroughs against cancer are likely to come from simultaneously blocking the alterations that drive the primary and adaptive growth advantages, forcing the cancer to stop growing and ultimately die. This approach has been successfully used for decades using combinations of a variety of cytotoxic, or nontargeted, chemotherapies, but these have lacked the precision of our current medicines and often are highly toxic. Within a few years we are likely to see many more clinical trials evaluating molecularly targeted therapies in rational combinations determined by our enhanced understanding of cancer biology. In fact, some early trials testing rational combinations of molecularly targeted therapies are underway. For example, the combination of dabrafenib and trametinib, which block different components of the same cancer-driving signaling network, is already showing promise as a treatment for some patients with metastatic melanoma (150) (see
Two Drugs: One Cancer-driving Pathway). Likewise, a combination of two immunotherapies that target different immune checkpoint proteins, ipilimumab and nivolumab, are showing early benefit for patients with advanced melanoma (115) (see
Releasing the Brakes on the Immune System).
This approach, however, requires that we understand enough about the underlying biology of cancer to be able to accurately predict the alternative growth advantages most likely to be used by the cancer. The knowledge required to do so will come from a variety of sources including whole-genome sequencing, patient-derived xenograft testing (see sidebar on
Patient-derived Xenografts), and predictive mathematic modeling of cancer behavior using systems biology and evolutionary theory.
Even armed with this deeper understanding of cancer biology, much work needs to be done to determine the order, duration, and dosing of the combination of anticancer agents being used. Here again, mathematical modeling and systems biology approaches will be critical to narrowing the nearly infinite permutations into a manageable subset that can be tested in clinical trials. Perhaps one of the most intriguing areas of combination therapy will be adding the new immunotherapies to radiotherapies, chemotherapies, and molecularly targeted therapies to enhance clearing of the tumor by the immune system (see
Special Feature on Immunotherapy).
We are just beginning to mine our cache of existing tools and drugs to develop rational combinations that are likely to provide better and more durable cancer responses than any of the agents alone. Continued research will speed these breakthroughs within the next few years.
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The Distant Horizon
Of the nearly 3 billion bases in the human genome, only about 1.5 percent code for the various proteins a cell uses to function. Just more than a decade ago, researchers made the important discovery that some of the remainder of the genome codes for molecules called noncoding RNAs, which naturally regulate gene usage and therefore the production of proteins.
Since that discovery, small, synthetic noncoding RNAs and DNAs have become vital tools in research laboratories worldwide. Researchers are also exploring the possibility that their ability to dampen gene usage and protein production can be exploited for patient benefit. Unfortunately, the use of synthetic noncoding nucleotides (DNA or RNA) in this way has been hampered by our inability to effectively deliver them to a patient’s cancer.
When combined with whole-genome sequencing, the clinical use of small, synthetic noncoding nucleotides could potentially revolutionize cancer treatment. Here, the identification of the exact mutations fueling an individual’s cancer would be identified through whole-genome sequencing. An anticancer therapeutic composed of small, synthetic noncoding nucleotides would then be prepared to potentially eliminate the abnormal protein(s) produced by these mutations, negating the competitive growth advantage of the cancer cells.
Because of the potential power of small, synthetic noncoding nucleotides, this is, and has been, a very active area of research. The infrastructure and technology to produce such therapeutics are already in place, and in some cases in early clinical testing. Given our rapid pace of discovery across all scientific sectors, it is likely that anticancer therapies based on small, synthetic noncoding nucleotides will one day benefit patients. Continued progress is incumbent upon continued research and investment in this area.
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Progress Report 2013 Contents