An article published this year in Science Magazine titled "Combining Targeted Drugs to Stop Resistant Tumors" outlines the current battle being waged by drug companies and oncologists to come up with "Targeted Chemotherapies" to inhibit pathways associated with specific types of cancer or specific mutated proteins. Conventional chemotherapy normally targets quickly proliferating cells throughout the body. While this is a somewhat effective strategy, it creates side effects which render the therapy almost as debilitating as the disease. Targeted chemotherapies are designed to affect aspects of a tumor's molecular machinery which are crucial to its survival. For example, a recently developed drug called Tarceva acts to inhibit EGFR (Epidermal Growth Factor Receptor) by associating with the ATP binding site on EGFR tyrosine kinases in patients suffering from non-small cell lung cancers. While this approach has seen moderate levels of success, cancer has proven to be a more resilient target than initially anticipated.
According to the article, about 10% of patients treated with Tarceva see dramatic reduction in tumor size. However, the average patient saw the return of their cancer within a year, despite initial success of the drug. This phenomenon of initial success followed by development of resistant tumors is not isolated to Tarceva. In fact, Most targeted therapies for cancer experience a large proportion of patients who develop resistances. The article outlines several recently developed therapies which, despite preliminary success, have been thwarted by cancer's ability to adapt.
In the case of Tarceva, it has been discovered that tumors have multiple ways of escaping the drug. In about 50% of all patients treated with Tarceva, a specific new mutation of EGFR (T790M) arose which was insensitive to the drug's inhibition. Alternatively, some tumors have been found to overexpress a different receptor (MET) to replace EGFR altogether. Tumor adaptations such as these present major problems to treatment and drug development.
As a way to resolve this issue, the article presents the idea of cocktail drugs designed to not only inhibit the tumor's initially defective pathway, but also any known pathways of escape. For instance, Researchers are now working on a cocktail drug incorporating the EGFR inhibitor in Tarceva as well as an additional MET inhibitor. Combining therapies is not a new concept, but by using a cocktail of targeted drugs and preemptively blocking the common methods of evasion employed by tumor cells, researchers hope to find a way to induce consistent cancer remission over a span of many years.
The question that then comes to mind is: If tumors are able to evade the first, and even second generation of targeted therapies with apparent ease, what's to stop them from continuing to develop new escape routes, and increasingly "clever" ways to circumvent an inhibited pathway? Are there other factors that will be present to stimulate tumor growth even after all targeted options have been exhausted? It is as if Cancer is a metaphorical "hole" or series of holes in proper cellular function. Through targeted chemotherapies, we are essentially just "plugging the holes" until a time when doctors run out of "plugs" for a patient's cancer, and the cancer wins.
Companies are rushing to develop a myriad of targeted therapies, many of which are destined to be part of a cocktail drug. Although targeted chemotherapies show more promise than any other previous method, they are likely just another step in the right direction. The scientific community should keep in mind that while targeted chemotherapies such as Gleevac and Tarceva are the ones with the most immediate pay-off both financially for them, and in terms of treatment, it is other lines of research which will likely lead to the overall solution. For instance, the field of immunotherapy could potentially allow the body to fight off cancer by activating tumor antagonizing functions of the immune system. But this is getting a little ahead of ourselves. Technology must advance, and fields such as cancer immunotherapy and adaptive therapy must receive more exposure and funding, but in the meantime, targeted chemotherapy will have to suffice to effectively "plug the holes".
