p53 in the Clinics
December 19, 2012
Initially ignored by many researchers as an outsider molecule of minor importance in carcinogenesis, p53 took over 10 years to rise to the status of “guardian of the genome (1992)” and “molecule of the year” (1993). Yet, despite all the hype of the 1990s, the path from molecular discoveries to clinical application has been frustratingly long and winding for p53. It is only in recent years that breakthroughs have started to accumulate, opening doors to applications of the huge amount of knowledge accumulated on p53 into clinical practice. If p53 is not yet part of the everyday cancer management, with the rapid diversification of translational research on p53 detection and treatment, the road towards major clinical applications is now rapidly clearing up.
Discovered in 1979, the p53 protein has now reached the full maturity age of 33—which does not necessarily mean that it is ready to deliver healing miracles in public health care. In 2005, the first p53 book entitled “25 Years of p53 Research” highlighted the development of the p53 field and its profound impact on concepts in cancer research. The book emphasized the role of p53 as a regulator of cell cycle checkpoints and cell death in response to multiple cellular stresses. It also reviewed experimental models for studying p53, as well as knowledge on the prognostic and predictive value of tumor-associated p53 mutations and emerging therapeutic strategies for restoring p53 function in tumors. Since the publication of the first p53 book, the p53 field has developed at an ever-increasing pace and p53 researchers have uncovered novel and entirely unexpected functions and aspects of p53. There has been substantial progress on the significance of the genetic diversity of p53 and on mutations as biomarkers in molecular pathology. Research on p53-based therapy has intensified dramatically with the development of several drugs that target the p53 pathway. Thus, there have been considerable advances on the potential applications of p53 in the clinic.
The goal of this new p53 book is to capture these developments as the field moves into a next phase with strong emphasis on translational research. The present book covers the most striking advances in p53 research and clinical applications that emerged over the last few years. These advances include:
1. Establishing a role for p53 in biological processes such as energy metabolism and fertility: Although p53 was previously thought to act mainly as a cellular trigger for cell cycle arrest or cell death, accumulating evidence has shown that p53 also regulates cell oxidative metabolism and the cellular response to nutrient deprivation. In addition, p53 has a role in fertility. These and other findings have led to the notion that p53’s main task is to ensure the fidelity of a wide range of biological and physiological processes.
2. Uncovering the fundamental role of p53 in stem cell biology and in generation of induced pluripotent stem cells (iPS): Stem cells and regenerative medicine is a dynamic research area with great promises for clinical application. Studies have demonstrated that p53 controls the division and renewal of stem cells and that p53 in fl uences the efficiency of induction of pluripotent stem cells from differentiated somatic cells. Therefore, p53 is a key protein to be considered in new strategies for implementing stem cell-based therapy in the clinic.
3. Understanding the interconnections between p53 family members, p63 and p73, and particularly their roles in cancer: Although not frequently mutated in cancer, both p63 and p73 are involved in cancer development through altered regulation and expression of isoforms that lack the N-terminal transactivation domain. Novel insights into p63 and p73 may lead to improved diagnosis and better prediction of prognosis and therapy response in cancer.
4. Pioneering translational research on the impact of p53 status on prognosis and clinical outcome in human cancer: It is now well established that p53 mutation is associated with poor prognosis in most cancers, particularly in breast cancer. Current challenges are (1) to better assess the function of p53 in tumors through new powerful techniques such as genome-wide analysis of the p53 pathway; (2) to determine in which context p53 status is clinically predictive of response to therapy and disease outcome; and (3) to develop diagnostic tests adapted to routine clinical practice.
5. Identifying germline TP53 mutations not just as the basis of a rare form of familial cancer, but as one of the main forms of inherited predisposition to cancer: Germline TP53 mutations are more common than previously considered (occurring in about 1 to 2,500 to 5,000 births) and are also extremely diverse in their impact on cancer risk. Furthermore, the discovery of a common founder mutation predisposing to cancer in Brazil provides a paradigm for searching for other population clusters in which germline TP53 mutations might occur at a high frequency.
6. Developing p53-based methods for cancer therapy and bringing them to clinical trials: These approaches include long-awaited developments in gene therapy using viral vectors and their evaluation into several clinical contexts. Moreover, p53 researchers have identified small molecules that either activate wild-type p53 in wild-type p53-carrying tumors or restore wild-type function to mutant p53 in mutant p53-carrying tumors. In most cases these molecules are still at a preclinical stage. However, at least two compounds, one that targets the p53-Mdm2 complex and induces wild-type p53 expression, and one that targets mutant p53 and restores its conformation and pro-apoptotic activity, have recently been tested in phase I clinical trials. Further studies should clarify whether these molecules have potent anticancer efficacy in larger cohorts of patients. Also, a number of novel molecules that reactivate wild-type or mutant p53 are under way.
This short survey makes it clear that p53 is ripe for clinical application. In fact, p53 is already in the clinic, although not yet included in routine analysis and still far from being used for targeted therapy. Exactly how could p53 be exploited for improved cancer diagnosis and treatment in oncology clinics around the world? This book shall address this and its related questions and hopefully provide information that will be useful and inspiring to both basic cancer researchers and clinicians. We strongly believe that the coming 10 years will be the decade of “p53 in the clinic,” with major benefits for early detection, prognosis, allocation of personalized treatments, and, ultimately, cancer patient survival.
Pierre Hainaut, Magali Olivier, Klas G. Wiman