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The 2024 Plenary Program banner event of the American Association of Cancer Research (AACR) has shed new light on the sophisticated mechanics of cancer biology, specifically the role of genome instability in cancer genesis and progression. A showcase of fundamental research taking center stage provided fertile grounds for potential therapeutic strategies.
At the University of California, San Diego School of Medicine, Professor Don Cleveland’s research points to a novel mechanism through which cancer develops. Known as chromothripsis, it refers to the shattering of chromosomes that leads to the accumulation of abnormal pieces in micronuclei (cell structures). The action of the N4BP2 nuclease facilitates this process, with the DNA repair protein TOPBP1 playing a complex role by facilitating the incorrect reassembly of these shattered pieces. These faulty DNAs amplify certain oncogenes, thus promoting cancer and enabling drug resistance. Cleveland’s studies also hint at a role for the Epstein-Barr virus (EBV) in promoting cancer. This is achieved when viral protein EBNA1 tethers to an EBV-like DNA sequence which instigates MLL-containing chromothripsis, ultimately leading to cancer formation.
In another notable research endeavor, Dr. Michael Kastan from Duke University has recognized potential therapeutic effects of inhibiting DNA repair proteins such as ATM and DNA-PK. This could potentially aid in sensitizing cells to radiation. An innovative chemical inhibitor dubbed XRD-0394 is currently in phase I clinical trial for safety and pharmacokinetics evaluation. Preliminary results are promising, with no dose-limiting toxicities reported and indications of successful ATM inhibition in patient tumor samples.
The dichotomy between the roles of ATM and DNA-PK was elucidated. Whereas both proteins play vital roles in DNA repair and are signal transducers in response to DNA damage, their activity isn’t essential to cell survival. Perhaps most striking is that cells lacking either protein are still sensitive to radiation. Understanding this delicate interplay could pave the way for more effective treatments that tactfully strike a balance between minimizing damage to healthy cells and optimizing cancer cell eradication.
– Genome instability refers to the shattering of chromosomes, contributing to cancer development.
– Micronuclei are structures where the shattered chromosomes accumulate.
– Chromothriptic cells amplify gene expression and drive drug resistance.
– DNA repair proteins ATM and DNA-PK can be targeted for sensitizing cells to radiation.
– An investigational inhibitor XRD-0394 is under phase I clinical trial for targeted inhibition of ATM in patients.
References:
Reference 1: AACR 2024 Plenary Program Kicks Off With New Insights Into Early Cancer Biology
Reference 2: Don Cleveland’s research at the UC San Diego School of Medicine
Reference 3: Dr. Michael Kastan’s research at Duke University