TP53: The Elephant in the Precision Oncology Room

Yogen Saunthararajah, MD

Professor, Medicine

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.

Targeting “Off” Enzymes

The good news is that now we understand how cancer cells avoid everyday differentiation-mediated cell cycle exits: cancer “stem” cells are actually committed progenitors, expressing supra-physiologic levels of master transcription factors of lineage-differentiation, most likely because this is needed for high-grade activation and stabilization of MYC, the ancient master transcription factor coordinator of cell growth and division.To avoid terminal differentiation despite lineage-commitment, cancers genetically inactivate genes for selected coactivators or “On” enzymes (eg, SMARCA4, PBRM1, KMT2A), resulting in aberrant epigenetic repression instead of the activation of hundreds of late-differentiation and proliferation-terminating genes. This epigenetic repression is mediated by the unbalanced action of corepressors or “Off”’ enzymes.

Pharmacologic inhibition of these “Off” enzymes (eg, DNMT1) rebalances toward residual “On” enzymes and restores the intended lineage-differentiation fate of cancer cells, terminating cell growth and division physiologically, without need for p53, and without killing any normal cells. Inhibition of “Off” enzymes triggers differentiation-mediated cell cycle exits across the cancer histological and genetic spectrum, indicating the general nature of this cancer strategy, just as p53-system attenuation is cancer histology agnostic as a stratagem to avoid apoptosis. Crucially, this science is translatable in the near-term (only lack of funding stands in the way!), since enzymes such as DNMT1 can, in principle, be drugged by the generic agents decitabine and 5-azacytidine. Decitabine and 5-azacytidine, however, have terrible pharmacology, with trivial penetration into solid tissues and very brief plasma half-lives. Also, these drugs have not been explicitly applied in a way to avoid apoptosis (to avoid toxicity) and maximize DNMT1-depletion (to increase p53-independent cell cycle exits of cancer cells). Cleveland Clinic is developing a pharmacologically rational, orally bioavailable version of decitabine (oral THU-decitabine) with a multihour half-life and pan-tissue distribution, that does penetrate solid tissues. This agent has completed phase I clinical trials, which proved the pharmacologic premise, and we hope to begin clinical trials in refractory/ relapsed metastatic pancreatic and lung cancers before the end of the year.

At this time, there is only one cancer, a rare type of acute myeloid leukemia called acute promyelocytic leukemia, that is routinely treated with differentiation- intending treatment. In fact, switching from apoptosis to differentiation as the method of treatment converted this leukemia from the worst to the best in terms of overall survival.

Scientifically, there is no reason this route to durable, nontoxic cancer control should be restricted to only this rare form of leukemia.