Why DNA Damage Response deserves renewed focus in cancer therapy

In the rapidly evolving field of oncology, timing is everything. With the swift pace of scientific discoveries and a continuously deepening understanding of cancer biology, the oncology landscape is on the cusp of significant transformation. The convergence of advanced research tools, a growing understanding of tumour biology, and urgent unmet patient needs makes this the perfect moment to reignite focus on DNA Damage Response in cancer therapy. While recent innovations like antibody-drug conjugates (ADCs) and radioligand therapies (RLTs) have captured widespread attention, the critical role of DDR pathways in combatting resistance and improving outcomes remains underappreciated. This oversight represents a missed opportunity to leverage one of the most potent mechanisms for targeting cancer’s Achilles’ heel.

A strategic pivot back to DDR

The need to refocus on DDR extends beyond science – it is driven by an urgent necessity in patient care. Cancer therapies are evolving rapidly alongside advances in tumour profiling and precision medicine, yet tumour resistance remains a formidable challenge, preventing the success of many existing treatments. DDR pathways offer a unique avenue to exploit cancer’s reliance on DNA repair mechanisms, strategically overcoming resistance and driving treatment innovation. By targeting specific vulnerabilities in cancer cells, DDR therapies can complement other modalities, including ADCs, to improve overall treatment effectiveness, long-term survival and patient outcomes.

The initial wave of DDR therapies, particularly Poly(ADP-ribose) polymerase inhibitors (PARPi), demonstrated the concept of synthetic lethality in cancer treatment over a decade ago. However, focusing solely on PARP limits the full potential of DDR. New targets such as ATR, WEE1 and MYT1 are emerging as critical players in the DDR landscape, offering avenues to address diverse cancer types – including ovarian, breast and prostate cancers – while also tackling resistance mechanisms. By broadening the scope of DDR research,

scientists can develop therapies tailored to specific molecular signatures, ultimately expanding the reach and impact of this approach. Prioritising DDR innovation is not just an opportunity but a necessity to stay ahead of tumour adaptation and resistance, ensuring more effective and lasting solutions for patients.

Why now? the perfect intersection of science & technology

Several factors have aligned to make this an ideal moment to refocus on DDR. Breakthroughs in genomic profiling and molecular biology have deepened our understanding of DDR pathways, revealing new opportunities for therapeutic intervention. Advancements in drug delivery systems, such as antibodies or peptides carrying DNA damaging agents, are significantly expanding the therapeutic window for DDR inhibitors. These innovations enhance the precision and tolerability of treatments, enabling DDR therapies to seamlessly integrate into multimodal regimens that target both primary tumours and metastatic disease.

Simultaneously, artificial intelligence (AI) and machine learning (ML) are transforming DDR research by dissecting the complex interplay between DNA repair and cancer progression with unprecedented precision, allowing for streamlined identification of novel biomarkers and optimised patient stratification. These technologies empower researchers to predict which patients are most likely to benefit from DDR-based therapies, advancing the era of personalised cancer treatment. Furthermore, high-throughput screening technologies and more translationally relevant preclinical models are accelerating the development of next-generation DDR inhibitors, reducing both the time and cost of bringing these therapies to clinical use. Together, these advancements are paving the way for therapies that address tumour-specific vulnerabilities while minimising collateral damage to healthy tissues, creating a robust foundation for the resurgence of DDR-based approaches in oncology.

The power of combination therapies

Combination therapies represent one of the most promising frontiers for DDR-based approaches. DDR inhibitors can amplify the effectiveness of established treatments, such as chemotherapy and radiotherapy, by heightening tumour susceptibility. Additionally, they can enhance the efficacy of targeted therapies, such as ADCs, by intensifying DNA damage selectively in cancer cells. Exploring these combinations may provide new avenues for overcoming resistance and improving treatment precision.

These synergies not only bolster therapeutic impact but also have the potential to deliver more durable and wide-ranging benefits across various cancer types. Resistance remains a persistent challenge in oncology, yet DDR research offers unique solutions to this issue. Tumours frequently adapt to evade initial therapies, but DDR  inhibitors can intervene by disabling the repair pathways that facilitate such evolution. By simultaneously targeting multiple DDR mechanisms or integrating DDR inhibitors into multimodal treatment strategies, researchers are paving the way for overcoming resistance and improving long-term patient outcomes.

The path forwards

As oncology continues to advance, the renewed focus on DDR represents a critical opportunity to address some of the most pressing challenges in cancer care. By prioritising investment in DDR research and fostering collaboration across disciplines, the scientific community can unlock the full potential of this approach. This will result in therapies that not only improve survival rates but also enhance the quality of life for patients worldwide.

Now is the time to act. By leveraging the unique advantages of DDR pathways and integrating them into the broader oncology landscape, we can transform the standard of care and usher in a new era of precision cancer therapy.

Meet Luke Piggott

Luke Piggott is Principal Scientist at Debiopharm, where he plays a key role in driving clinical and scientific research progress. With extensive experience in developing novel therapeutics, spanning discovery to clinical trials, he oversees  both preclinical and clinical pharmacology of assets from Phase I to III. With a profound understanding of clinical research procedures (ICH GCP), Luke excels in interpersonal communication, fostering relationships and collaborations with key opinion leaders (KOLs). His expertise is focused on oncology, particularly in the preclinical and clinical development of innovative therapeutics from concept to late-stage clinical trials.