Yogen Saunthararajah, MD
Co-Leader, Developmental Therapeutics Program
Cleveland Clinic Cancer Institute
Case Comprehensive Cancer Center
Today, only three types of nonresectable adult cancers are routinely cured: some types of lymphoma and myeloid leukemia, and testicular cancer (Figure)
. This overall picture has not changed substantially in the past 20 years, an indication of the extraordinarily high failure rate of drug development in oncology. The costs of this failure rate shifts to patients and their families, contributing to the financial complications of a cancer diagnosis.
One of the central reasons that curing cancer has been so problematic is the dysfunction of TP53
, the single most common genetic alteration in cancer. At the Cleveland Clinic, we have been studying ways to overcome the problem of aberrant TP53
activity safely and effectively in several hard-to-treat solid tumors, including through the development of a promising experimental new drug.
Through this research focus, we can answer some of the most basic questions in cancer: Why can we cure some cancers but not others? Why are treatments so arduous? Why does oncology drug development have a 95% failure rate?
These are related questions, with related answers. Most importantly, the conceptual leap needed to render these questions obsolete is laid out clearly before us—for all the scientific complexity appended to cancer, its essence is simple: cells that grow and divide and do not stop.
For cells to grow and divide is completely normal; this defines life. But, abnormal (cancer) is when such growth and division does not cease. Why do the billions of healthy cells dividing in our body cease and desist? The main, natural reason is that the dividing cells arrive at their intended lineage-differentiation fate. Another reason it ceases is that an emergency brake—apoptosis—activates when damage or stress of some sort is sensed, requiring a delay for repair or orderly self destruction.
Figure. Global Cancer Incidence and Mortality Rates
World Health Organization. Global cancer incidence and mortality rates/100,000. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr. Published December 12, 2013. Accessed Octover 12, 2015.
Cancers, to be cancers, must avoid these natural brakes... but, how? Apoptosis is a complex cellular program executed by the master transcription factor p53. Cancer cells, which by their very nature are damaged and/or stressed, frequently physically remove or inactivate the gene for p53 (TP53
Radiation and the vast majority of current cancer drugs have the intent of inducing apoptosis (cytotoxicity). This is hard to do if p53 is missing.
Meanwhile, normal dividing cells with intact p53 readily undergo apoptosis in response to our severe stressful treatments. In fact, the absence of p53-system alterations distinguishes the disseminated cancers we routinely cure from the ones we do not. Thus, it is a fundamental therapeutic deficiency that we have hundreds of drugs that intend apoptosis, but no drugs that broadly intend differentiation. Why? It is relatively easy to develop treatments that stress or poison cells and turn on the emergency brake in the test tube; this concept for treating cancer was established decades before we knew about p53.
Moreover, at that time we did not understand the complex mechanisms of cell differentiation, and how cancers avoided this routine mode of cell cycle exit.