Image Credit: © Radomir Jovanovic – stock.adobe.com
In recent years, antibody-drug conjugates (ADCs) have dominated the oncology space, capturing attention and investment as powerful, targeted cancer therapies. While ADCs represent an important advancement, the field of DNA damage response (DDR) has quietly fallen into the background despite its transformative potential to address complex cancer pathways and complement other therapeutic approaches.
The initial wave of DDR inhibitors offered critical insights, teaching scientists how to target DNA repair mechanisms and uncovering the underlying biology that drives these responses. DDR is a mechanism that has evolved to prevent the inheritance of DNA damage in daughter cells, helping to maintain tissue homeostasis and allowing cells to function normally.
In cancer, cells have developed enhanced mechanisms to repair damaged DNA, enabling them to survive therapeutic approaches and thrive in the context of high genomic instability that drives tumor growth. Because cancer cells rely on these pathways to survive, targeting DDR pathways can lead to an accumulation of DNA damage in these cells, ultimately triggering cell death.
Today, with more sophisticated tools and a deeper understanding of DDR biology, we’re better equipped to design next-generation DDR inhibitors that are more precise, durable, and effective by pinpointing the oncogenic drivers that create DDR dependencies (synthetic lethality). We don’t simply need to reprioritize DDR; we need to recognize it as a long-term strategy to develop an arsenal of therapies that can profoundly impact patient outcomes.
Reflecting on the first wave of DDR research
The first wave of DDR research, especially with early PARP inhibitors, opened a new door to treating cancer by blocking cancer cells’ ability to repair their DNA. This initial phase demonstrated that targeting DNA repair could be powerful, particularly in cancers with specific genetic weaknesses.
It also revealed some challenges, such as drug resistance over time and adverse effects (AEs) that made treatment difficult for some patients. In this context, the concept of synthetic lethality and DDR dependency, through the identification of BRCA and HRD biomarkers, was first clinically demonstrated and established as an important component for successful DDR development.
These experiences have been invaluable, teaching us what works, what doesn’t, and how to improve. Now, we’re better prepared to create the next generation of DDR inhibitors that are more refined and adaptable to benefit even more patients and types of cancer and to better identify the patients who will respond to such treatments.
Advances in DDR inhibitor development
With rapid advancements in medical technology, patients now have more choices in cancer treatment, including a range of targeted drugs and immunotherapies. Our increased understanding of the mechanisms by which our drugs work, combined with deeper tumor characterization through novel technologies, offers researchers the opportunity to develop more selective treatments.
These innovations help ensure that DDR inhibitors hit their targets more efficiently, which means they can work better while causing fewer AEs. Through these techniques, and by using the insights learned from the first wave of DDR, researchers and drug developers can help create more effective and tolerable treatments for patients.
In addition, using multi-faceted approaches is creating new possibilities for DDR therapies. By targeting the several pathways involved in DNA damage response, researchers can develop combination therapies that address resistance and improve treatment effectiveness.
This would help treat a wider range of cancers and tailor therapies to fit individual patients’ needs. As the industry gains more insights into how cancer works, these strategies will be crucial for making DDR inhibitors more successful and ultimately improving patient outcomes.
Expanding the scope of DDR
As we enter an era of improved understanding of DNA repair mechanisms and the biological nuances of various tumors, we are in a prime position to develop more targeted therapies that can effectively address different cancer types. Earlier treatments mainly targeted the protein PARP, but the key is to look beyond just one or two specific pathways.
By expanding the range of targets for DDR inhibitors, researchers could further boost the standard of care drug efficacy against the patients’ select cancer type. Research is now leading us to look at other important proteins, such as ATM, ATR, or WEE1, some of the main gatekeepers of DDR, where each of these targets have distinct indications and molecularly defined populations in which they are effective. The broader scope here thus means treatment can be effectively tailored to tackle the weaknesses of different cancer cells, making them more effective overall.
Recent advances in the spotlight, such as ADCs and radioligand therapies (RLTs), still rely on the traditional approach of inducing DNA damage through chemotherapy or radiotherapy—only now delivered in a more tumor-specific way. This highlights the continued relevance of targeting DDR, both in today’s landscape, in which chemotherapy and radiotherapy are the standard of care, and in the future as ADCs and RLTs become more prevalent.
The mechanisms of efficacy and resistance remain consistent, which means the approaches to overcoming them also stay relevant. In fact, this selective delivery broadens DDR’s therapeutic potential, as tolerability—a frequent limiting factor when combining DDR with chemotherapy or radiotherapy—could improve with the safer, more targeted delivery through ADCs and RLTs, potentially opening the therapeutic window for effective DDR combinations.
Furthermore, with the increasing utility and exponential growth of AI approaches in life sciences, we now have new opportunities for biomarker discovery by interrogating large data sets in ways that were previously impossible. Utilizing these technologies for improved biomarker identification and subsequent patient stratification allows further optimization of the approaches we can take in DDR development.
We’ve already begun witnessing significant advancements in targeted DDR inhibitors for cancer therapy, marking a shift toward more precise and personalized treatment options that address the unique challenges of various tumors. As we continue to explore these new targets and improve drug delivery systems, we can anticipate seeing therapies that not only enhance treatment efficacy but also reduce AEs for patients.
To sustain momentum in this area of research and development, we must prioritize investments in DDR inhibitors and foster collaboration among scientists, clinicians, and industry leaders, ensuring that these promising therapies reach those who need them most. In doing so, we take significant steps toward transforming cancer care and enhancing the quality of life for patients around the world.
Luke Piggott, Principal Scientist at Debiopharm
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- Source: https://www.appliedclinicaltrialsonline.com/view/reprioritizing-dna-damage-response-leveraging-lessons-learned-develop-next-generation-inhibitors