Source: American Society of Clinical Oncology

Key Points:

• The p53 gene is mutated or deleted in approximately half of all cancers, and the p53 signaling pathway is disrupted in the remaining half.
• Although research focused on designing effective therapies that target the p53 pathway has proven challenging, the different strategies of targeting p53 have shown varying efficacy in clinical trials to date.
• Future studies in this area will likely focus on a combination of therapeutic approaches that incorporate p53 targeting with immunotherapy or other agents.

Introduction to p53’s Role in Cancer

The TP53 gene, commonly known as p53, stands as the most frequently mutated gene across all cancers, with mutations or deletions identified in approximately half of cases. While research has explored targeting p53 for therapeutic intervention, the complexity of p53’s role in the cell—spanning DNA repair, apoptosis, and cellular metabolism—makes it a challenging target. Despite this, new therapies are emerging, with promising strategies incorporating p53 modulation combined with immunotherapy or other agents as Key Players.

The p53 protein acts as a crucial tumor suppressor, initiating processes like cell cycle arrest, apoptosis, and DNA repair in response to cellular stress. The gene’s role in high-grade cancers such as ovarian and triple-negative breast cancers underlines its importance. Dr. Michael J. Duffy from University College Dublin highlights, “p53 is particularly mutated in some of the most aggressive cancers we currently have”. Despite the general role, finding drugs that target the altered p53 protein has proven complex.

Targeting p53: Clinical Trials and Challenges

Efforts to restore wild-type p53 function or inhibit its interaction with regulators like MDM2 have yielded some success in clinical trials. For instance, the agent idasanutlin, an MDM2 antagonist, has reached phase 3 trials in acute myeloid leukemia. Additionally, small moleunds, COTI-2 and APR-246, have shown preclinical efficacy, specifically in cancers with mutant p53. However, binding sites on mutant ug targeting are rare, and the vast diversity of p53 mutations means a single treatment is unlikely to cover all cases.

Recent Breakthroughs: The PYNNACLE trial investigated PC14586, a novel drug designed to selectively bind and restore the function of the Y220C mutation—a mutation present in various solid tumors. Dr. Duffy remarked, “This compound binds to a specific mutation in mutant p53…creating a pocket where inhibitors can bind”. Preliminary results indicate a promising single agent with low toxicity, with researchers planning a phase 2 trial to further test its efficacy.

Exploring Statins as Potential p53 Modulators

Beyond s, the search for p53-targeting therapies has led researchers to explore statins, widely known for cholesterol management. Research suggests that statins might destabilize mutant p53, possibly due to their impact on metabolites essential for the stability of heat shock proteins. Clinical trials are underway to determine if statins might be repurposed for p53-mutated cancers.

Looking Ahead: Combination Therapies Hold Promise

Experts anticipate that strategies will likely combine p53-targeting therapies with immunotherapies or other agents. Dr. Joaquina C. Baranda, leading a study at The University of Kansas, said, “One approach is combining therapies that directly inhibit mutant p53 with agents targeting the downstream pathway”. This combined approach could provide a durable response in p53-mutant cancers.

The quest to target p53 remains an ambitious goal in oncology, with ongoing clinical trials hinting at potential breakthroughs. By combining novel p53-targeting agents with immunotherapy and established drugs like statins, researchers hope to overcome the challenges of targeting the most frequently mutated gene in cancer.

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References

1. Duffy MJ, Synnott NC, O’Grady S, Crown J. Targeting p53 for the treatment. Semin Cancer Biol. 2022;79:58-67.
2. Huang J. Current developments of targeting the p53 signaling pathway for cancer treatment. Pharmacol Ther. 2021;220:107720.
3. Dr. Michael J. Duffy, University College Dublin.
4. Konopleva MY, Röllig C, Cavenagh J, et al. Indasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial. Blood Adv. 2022;6(14):4147-4156.
5. Synnott NC, O’Connell D, Crown J, Duffy MJ. COTI-2 reactivates mutant p53 and inhibits growth of triple-negative breast cancer cells. Breast Cancer Res Treat. 2020;179(1):47-56.
6. ASCO Annual Meeting, PYNNACLE Trial Results.
7. PC14586 trial results. ASCO Annual Meeting, 2022.
8. O’Grady S, Crown J, Duffy MJ. Statins inhibit proliferation and induce apoptosis in triple-negative breast cancer cells. Med Oncol. 2022;39(10):142.
9. Parrales A, Ranjan A, Iyer SV, et al. DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway. Nat Cell Biol. 2016;18(11):1233-1243.
10. Dr. Joaquina C. Baranda, University of Kansas.
11. Telfah M, Iwakuma T, Bur A, et al. A window of opportunity trial of atorvastatin in p53-mutant and p53 wild type malignancies. J Clin Oncol. 2019;37(suppl 15)