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You’re a Mean One, Mister p53

December 16, 2021

Perspectives (and Other “Wonderful, Awful Ideas” for Defeating a Molecular Villain) From the ASH Presidential Symposium

Natasha Szuber, MSc, MD

Dr. Natasha Szuber (@NatashaSzuber) is a hematologist-oncologist at Maisonneuve-Rosemont Hospital, University of Montreal in Quebec, Canada, specializing in myeloid disorders, particularly myeloproliferative neoplasms, and has further interests in clonal hematopoiesis and iron metabolism. She received her MSc at McGill University in Montreal, her MD at University of Montreal, and did her Advanced Hematology Myeloid Fellowship at Mayo Clinic in Rochester, Minnesota. Dr. Szuber remarked that she was “born, raised, and currently still residing in Montreal…It's a beautiful, vibrant city if you can look past the orange construction cones and innumerable potholes!” 

While Dr. Szuber is “relatively new” to the ASH family, she is looking forward to collaborating further in coming years and was just selected to participate in the ASH Clinical Research Training Institute this year. Fun fact: Dr. Szuber enjoyed a “past life as an aspiring rock n' roll star, recorded three albums, and toured with my band across Canada before finally surrendering to the call to med school.” 

As sure as archetypes of good and evil have pervaded virtually every classic storybook in history, make no mistake that the p53 mutation has achieved cult status, in hematologic speak, as an undeniable, first-class villain. Be it in the mold of Darth Vader, Voldemort, or in keeping with the holiday season, the Grinch… any way you look at it, the p53 anomaly is the harbinger of bad news. And yet in its native state, the TP53 gene located on the short arm of chromosome 17 wields the power of tumor suppression, encoding a transcription factor that responds to cellular stresses by regulating cell cycle arrest, apoptosis, senescence, and DNA repair mechanisms, essentially safeguarding our DNA from cellular miscreants. It is these protective mechanisms that have earned TP53 the appellation “guardian of the genome,” justifying the expected biological devastation observed when this vanguard goes rogue. In fact, TP53 is the most frequently mutated gene in human malignancies, not a record most members of the gene world would be particularly proud to hold. From a hematologic standpoint, p53 mutations are present in up to 20 percent of patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) and confer exceedingly poor prognosis. Moreover, harboring the p53 mutation predicts resistance to standard-of-care therapies, including allogeneic hematopoietic stem cell transplant, the only potential cure. So how do we as a hematology community tackle this molecular villain? Thus far, we’ve approached it as any aspiring hero would, relying on quintessential skills and good-guy dictums: know your enemy, know your environment, do your research, and stay focused. Also, it doesn’t hurt to have some powerful armor and gadgets. That’s right, it’s time to pull out our jingtinglers, our floofloovers, and our great big electro whocarnio flooks! After all, we are going after a mutation that’s as cuddly as a cactus… 

This year’s Presidential Symposium chaired by ASH President Dr. Martin Tallman aptly entitled “Dawn of a New Era – Targeting p53 Mutant Hematologic Malignancies,” took place on Tuesday; it was set to succeed, and succeeded it did… The fundamental themes as Dr. Tallman explained included, “the biology of p53, drug development in an effort to restore normal p53 function, and active agents targeting p53 in both acute and chronic hematologic malignancies (HMs).” When asked how p53 was selected as the topic for the Symposium, he affirmed, “P53 appears to be part of a universal pathway which can be perturbed to influence tumor cell resistance and potentially restore sensitivity to targeted agents.” He added, “The identification of effective agents targeting a universal pathway may prove to be a major therapeutic advance.” The nearly 300 hits returned by the search for “TP53” from among this year’s abstracts are also, decidedly, a testament to its ever-mounting relevance. Dr. Tallman was joined by a valiant team of experts who covered the wide range of p53’s molecular kingdom (we’re talking well beyond Mount Crumpit, here). Dr. Carol Prives reviewed normal and aberrant structure and function, as well as some historical perspectives. She led with what she deemed were the “big questions,” including: “What are the most important targets and pathways for tumor growth and metastasis? Are all p53 mutants created equal? Do different hotspot alleles have different unique functions and impact? Can we really connect our experimental work to what goes on in cancer patients?” She answered these and more, and I urge you to go back to her presentation as you binge-watch your missed ASH content, as it represented, at least for me, a veritable masterclass in p53 biology. 

Dr. Guillermina Lozano next presented mechanisms contributing to cancer cell addiction to mutant p53 and introduced therapeutic prospects. Dr. Lozano detailed some state-of-the-art techniques generated in her laboratory at the MD Anderson Cancer Center in order to study p53 mutations, including elegant mouse models, CRISPR-based systems enabling mutant p53 to be turned on and off, and single-cell sequencing capturing those early responses following mutant p53 deletion. The latter ultimately led to identification of the ROS pathway and ferroptosis networks as principal mechanisms involved in tumor cell death (I believe we all shared a real sense of denouement to the story here … undaunted scientists: 1, grinchy mutation: nil). She further applied these models to rationalize therapeutic opportunities, including MDM2 inhibitors and agents converting mutant p53 to wild-type p53. 

Finally, Dr. Matthew Davids focused more specifically on current therapeutic strategies to target p53-mutated HMs. He first outlined the primary challenge saying, “TP53-mutated HMs represent a major unmet need, as they are rarely sensitive to the conventional cytotoxic chemotherapies that can cure other non-TP53–mutated HMs.” He also put this into a global perspective, acknowledging that TP53 mutant cancer would be responsible for the deaths of more than 500 million people alive today, in the absence of new therapeutic advances. Dr. Davids then discussed five cardinal therapeutic strategies, which include “disease control, targeting downstream of p53, combination approaches, immune-based therapies, and restoring wildtype p53 function.” Among the take-home points were the tenets that “there is no one-size-fits-all approach, and different HMs may require different approaches.” Dr. Davids cited an example, “In chronic lymphocytic leukemia, single-agent venetoclax can be durably effective, whereas in AML it is not, and combination approaches are needed.” A particularly attractive approach to explore prospectively, he imparted, would be “combinations of novel compounds that can restore wildtype p53 function with agents that directly target the pathophysiology of a particular HM.” He also offered future directions, listing exploitation of synthetic lethality, noncoding RNAs, and nanomedicine-based therapies as promising candidates. Dr. Davids concluded by highlighting two key points: the first being that “the recent progress therapeutically has been fueled by the elegant advances in our understanding of the basic science of p53 biology discussed in detail by the other speakers in the session,” and the second, that “although therapy for p53-mutant HM has improved recently, much work is still to be done, as outcomes are far from optimal.” 

Overall, the atmosphere of the session was cautiously optimistic. Dr. Prives invited us to join in the legion of crusader-scientists in taking down this alphanumeric bad guy: “Hopefully I’ve inspired you to consider thinking about this [p53] in terms of your own research.” It was also somewhat refreshing to capture how, even though we know a lot about p53 (see multiple presenters quoted as disappointedly uttering “I don’t have time to show you all this”), we still have so many questions. So while we’re not quite ready to stand hand-in-hand singing “Fahoo fores, dahoo dores,” we are beginning to get the sense that p53 is (nearly) in our grasp, and that, so long as we continue to puzzle and puzzle (till our puzzlers are sore), we might just vanquish this genetic scoundrel. Just as the Grinch is, in part, a story about the indomitable power of optimism, we look forward to someday putting this villain, the abysmally contemptible p53, to rest. The epitaph, would read, and I quote: “… Stink, stank, stunk"! – THE END – 

Dr. Szuber indicated no relevant conflicts of interest. 

 

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