p53: Toward Drugging What Hasn’t Been Drugged… Yet

Advances in the understanding of human genetics in relation to cancer have led to promising discoveries—numerous targeted therapeutics that treat and, one day, may even be able to prevent and/or cure certain forms of malignancies by modulating a patient’s genes. And no gene plays a more integral role in regulating cancer than p53, the body’s natural first line of defense in blocking tumor formation and metastasis, hence its “Guardian” namesake (see “Awakening Guardian Angels” or “Awakening the ‘Guardian of the Genome”).

To prevent cells, which undergo various forms of stress over their lifetime (e.g., due to radiation, oxidation, carcinogens) from dividing uncontrollably (the hallmark of cancer), p53 activates proteins that arrest cell division and repair damaged DNA. In instances where the harm is extensive, and even irreparable, p53 can trigger apoptosis, or a process by which the body automatically destroys aberrant cells.

The problem emerges when p53, as a potent tumor-suppressor, begins to improperly function either due to inactivation or, more commonly, mutation, essentially giving cancer cells the green light to become viable and eventually turn malignant, spreading to other parts of the body. In fact, genomic sequencing shows that cancer mutations can be found in nearly everyone, with over half of all human malignancies (see human cancers by organ site, pdf) based on p53 mutations, again, thus compromising the body’s ability to fend off cancer.

Unfortunately, getting p53-activating drugs out-of-the-lab and to-the-bedside has been challenging due to the complexity of the p53 pathway and toxicities associated with gene-based therapeutic strategies. Despite its discovery in 1979 (e.g., see The Rise of p53p53—30 Years OnThe TP53 Gene Network in a Post-Genome Era)—selected by Science magazine as “Molecule of the Year” in 1993, making the cover of Newsweek in 1997—no p53 drug, so far, has been approved by the FDA. Many researchers thus refer to targeting p53, one of the Big Three "tough nuts to crack" (RAS and MYC the other two; see Sanofi's partnership with Warp Drive Bio), as an example of trying to drug “the undruggable.”

Dr. Jay Bradner, a former Dana-Farber scientist and current President of the Novartis Institutes for BioMedical Research, feels this expression does not, however, capture the spirit of research: “The field has created a mystique around certain targets, regarding these challenges as insurmountable, but this is contrary to what the public trusts us to do. What the phrase means is ‘we haven’t drugged it yet.’”

In a series of follow-up posts, we’ll describe how Innovation is making progress toward positioning Kevetrin, the company's novel oncology compound, toward becoming possibly the first p53-modulating, orally-delivered drug approved for treatment in cancer patients.

Source: http://p53.free.fr/p53_info/p53_cancer.html