The practical challenge associated with implementing a complementary “broad-spectrum” approach to prophylaxis and therapy is bridging the gap between what the disease biology suggests we need and the restrictions that are inherent to the current system of cancer research and care.
Oncologists currently rely heavily on a small number of (older/legacy) cytotoxic therapies and a large number of newer targeted therapies1 to treat most cancer types. These drugs have all earned individual approval following several stages of successful clinical trials in which the individual drugs are tested to the brink of toxicity (for maximum dosage and effect) and to show efficacy against a particular cancer type. Once adopted, genomic and proteomic laboratory data (from individual patient’s tumor specimens) may then be used to identify therapeutic targets of relevance for the administration of these FDA-approved agents (or targeted agents undergoing approved clinical trials) which serve as the basis of the most commonly employed standard of care.
Although this approach is very rigorous, it has resulted in an inherent weakness that results in a capability gap in the clinic. When intratumoral heterogeneity is high and multiple molecular targets are relevant, there are practical limits to the number of targets that can be pursued (due to the toxicity of these drug combinations). Additionally, there are restrictions on clinical utilization of FDA-approved cancer drugs since these therapies can only be used for FDA-approved indications. This means the patient’s tumor must not only demonstrate the relevant molecular target(s), it must also be the specific cancer cell type designated in the FDA-approved indication. So there are instances where relevant molecular targets are identified but FDA-approved combinations are not clinically available possible that will reach a broad enough range of the known targets; and/or the therapies that are available are not approved for that cancer cell type (i.e., making such indications ineligible for payment by the payors). In these cases, clinicians must default to the limited targeted therapies available combined with older cytotoxic therapies, even though well-recognized disease relapse2 (caused by adaptive resistance), serious side effects, and even treatment-related mortality3 can result. In some instances, this criteria can be bypassed if a physician wants to use a targeted agent (off-label) for another cancer type, but for funding reasons this is not common practice and occurs only 30 percent of the time4.
The Halifax Project taskforce that focused on this issue started with a thorough review and examination of the disease biology and decided that the heterogeneity found in many cancers needed a better solution. The idea they articulated is powerful in that it builds on what we have learned from combination chemotherapy, which has shown us that mechanistic synergies are helpful. So focusing on a broad-spectrum of targets (especially in cancers that consist of many varied subpopulations of immortalized cells) is a rational clinical methodology for therapeutic implementation.
Image adapted from The Hallmarks Cancer: The Next Generation, 2011
However, it does not necessarily follow that every therapeutic molecule with potential to reach a particular target must first be able to show clinical efficacy when tested on its own against a particular cancer type (which is currently the format for clinical trials of cancer drugs). Indeed, the actions of these chemicals on certain targets (tested on their own) may never be powerful enough to meet the standards that we have established for approving individual cancer therapies. It is true that an isolated action of a chemical on certain targets in some cancers may be adequate to slow or stop cancer (this is the basis of modern targeted therapy). However, an isolated action on other targets of relevance may still be important if our goal is to act on many different subpopulations of cells in many different ways. There are many overlapping pathways and networks of signaling in cancerous cells so some targets may simply not be adequate on their own to have a meaningful therapeutic impact against that cancer. The point of focusing on a broad-spectrum of targets is to address this issue, so when the actions of many chemicals aimed at many targets are combined, we should anticipate an impact that is greater than that which would be produced by any single chemical acting on any single target, site, or mechanism.
In other words, when we create a prioritized list of rational molecular targets for a given cancer, not all targets will be equally important, and acting on one of them alone may never produce the kinds of results we need. But if we combine two or more chemicals that are aimed at two or more rational targets in a given cancer, and we rely on dose-levels that are non-toxic, we may exert significant anti-cancer effects. The accumulation of mechanistic actions by those chemicals may still produce important anti-cancer outcomes that are greater than combined actions on any single target (due to synergistic effects).
This approach makes perfect sense as an engineered solution (i.e., given what we now know about the disease biology), but the idea of using chemicals and biological targets that have not been individually proven in clinical trials for a specific cancer type, is not the manner in which individual chemicals are currently approved for use as cancer therapies.
- Palumbo MO, Kavan P, Miller WH, Jr., et al. Systemic cancer therapy: achievements and challenges that lie ahead. Frontiers in pharmacology. 2013;4:57.
- Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Jr., Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546-1558.
- Niraula S, Seruga B, Ocana A, et al. The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs. J Clin Oncol. 2012;30(24):3012-3019.
- Conti RM, Bernstein AC, Villaflor VM, Schilsky RL, Rosenthal MB, Bach PB. Prevalence of off-label use and spending in 2010 among patent-protected chemotherapies in a population-based cohort of medical oncologists. J Clin Oncol. 2013;31(9):1134-1139.