New Approaches for Cancer Therapies: Targeting the DNA Damage Response

The DNA damage response (DDR) is a mechanism within our cells that detects damaged DNA and supports its repair. Mutations in genes involved in this pathway are frequently found in cancers, which cause DNA to become increasingly unstable and promote tumor growth and development. As a result, targeting the DDR has become a promising prospect for the development of new cancer therapies.

Technology Networks spoke with Dr. Niall Martin, CEO of Artios Pharma, to find out more about the advances in this field, the challenges of developing DDR-targeting drugs and how these can be incorporated into cancer therapies.

Sarah Whelan (SW): What is the DDR pathway, and how does it work?

Niall Martin (NM): The human body employs a highly sophisticated and coordinated cellular network focused on preserving DNA integrity during states of cell replication or damage, known as the DDR. The process involves a highly regulated cascade of protein signaling pathways and is designed to prevent the replication of cells with faulty DNA by either repairing the damage or triggering cell death.

SW: How is DDR affected in cancer?

NM: Cancers often develop or become more aggressive due to genomic instability that arises from mutations or aberrations in DNA that contribute to uncontrolled growth, proliferation and metastatic spread of tumorigenic cells. One of the hallmarks of cancer cells is the downregulation or loss of certain DDR pathways, leading to the upregulation of compensatory DNA repair pathways to help maintain tumor cell viability. Cancer cells can become highly dependent on these compensatory pathways for survival, making them an effective and highly selective DDR cancer target.

In 2005, two back-to-back Nature publications, one of which was co-authored by myself and Artios’ CSO, Graeme Smith, demonstrated cancer-specific cell death in BRCA-mutated cancers via inhibitors of a DDR enzyme called poly (ADP-ribose) polymerase, or PARP. PARP inhibitors were shown to selectively kill cancer cells by targeting a PARP-mediated DDR backup mechanism on which cancer cells become dependent when normal BRCA1 and BRCA2 homologous recombination repair (HRR) mechanisms become deficient. These papers demonstrated a new concept in cancer therapeutics known as “synthetic lethality”, which occurs when cell death is triggered by the loss of two key factors – such as DDR activity from both the PARP and BRCA1/2 processes – but not by the loss of either factor alone.

Since then, mechanistic understanding of DDR biology has advanced, leading to a wave of companies exploring therapeutic opportunities targeting new aspects of the DDR through synthetic lethality or beyond into other areas of DDR biology. Druggable opportunities under investigation focus on alternative DDR pathways upregulated under certain conditions that create therapeutic openings to exploit a tumor-selective target and ultimately drive tumor-specific death across diverse cancers.

Polymerase theta (Pol-theta) is an example of a new emerging DDR target being pioneered by [the DDR company] Artios. Resistance to first-generation PARP inhibitors is now well recognized in the clinical setting and has underscored the need for new DDR targets to overcome both de novo and acquired resistance to PARP inhibitors. Pol-theta is a DNA repair enzyme involved in an alternative DNA double-strand break repair process that PARP-resistant cells can become dependent on, supporting the potential to prevent or address PARP resistance in different tumor types. Interest in Pol-theta also stems from its minimal or non-expression in normal cells and its observed upregulation in numerous cancers. This selective expression pattern suggests that Pol-theta inhibitors may have a favorable therapeutic index because of a more focused impact on tumor cells.

SW: Why has it previously proved difficult to target the DDR pathway therapeutically?

NM: There are two main challenges in targeting the DDR pathway therapeutically. The first is the multitude of enzymes that are important in the DDR. These have substantially different mechanisms of action to kinases, which have been the primary focus of most druggable targets in cancer cell biology. DDR targets include nucleases, helicases and polymerases, which contain structural elements that are less characterized and accessible to drugging and therefore require novel mechanistic classes of drugs.

The second challenge stems from initial concerns surrounding blocking the mechanisms that repair DNA damage in cells. These may inadvertently induce toxicity in normal cells, which raises the possibility of whether DNA repair systems that emerge selectively or are upregulated in cancer cells can be targeted to avoid impact on normal cells.

SW: Are there DDR-targeting drugs in development or approved for clinical use? How successful and effective have these been in trials?

There are currently four PARP inhibitors on the market: olaparib, niraparib, rucaparib and talazoparib. Analysis of over 10 years of extensive clinical data has proven that this therapeutic approach is highly effective as a monotherapy and has the potential to synergize with several chemotherapies and other agents, including immune checkpoint inhibitors. The desire to combine PARP and other DDR inhibitors with conventional chemotherapy is driving the search for highly selective next-generation DDR targets with the potential for lower cytotoxicity and improved combination approaches.

The next wave of therapeutic opportunities looking to target DDR includes inhibitors targeting Pol-theta and the DNA repair protein ataxia telangiectasia and Rad3-related protein kinase (ATR), which are being explored by Artios, AstraZeneca, Repare and Merck KGaA. Potential opportunities for both Pol-theta and ATR include monotherapy, PARP inhibitor combinations and immune checkpoint inhibitor combinations. Artios, as well as having the ATR inhibitor ART0380, has also begun clinical studies on two Pol-theta inhibitors – ART4215 and ART6043 – which we believe are the first specific, rationally designed Pol-theta inhibitors in clinical development. Other companies, including Ideaya and Repare, are also pursuing Pol-theta inhibitor programs, which are in preclinical development and have yet to enter clinical trials.

SW: How do you think successful DDR-targeting therapies could impact cancer treatment? How would they be used clinically?

NM: The research and drug development environment surrounding DDR has greatly matured over the last 20 years, enabling more sophisticated identification of new targets. DDR proteins and pathway relationships are better depicted and annotated and can be interrogated in more advanced ways, including through artificial intelligence, high-content biological screening, gene editing technologies and more physiologically relevant cancer models such as genetically engineered mouse models and patient-derived xenografts. There have also been improvements in medicinal chemistry approaches to structurally target challenging proteins across the DDR pathway and better ways to evaluate their clinical potential using more refined preclinical models.

Cancer is a very tough and adaptive disease that will continue to fight back against many of the treatments developed against it. We believe combination therapies are going to be important in this regard and, within this, inhibitors of the DDR will have a major role to play in combining and working with other types of therapies. The hope is to give the oncologist of the near future a tool kit of different options to use in the fight against cancer. A large proportion of developing cancer cells use the DDR to become aggressive or to become resistant to current treatments, which means there will always be a need for different types of drugs to kill those cancer types that affect the DDR processes.

As the DDR treatment landscape continues to unfold, it is becoming increasingly clear that there are large untapped therapeutic opportunities through synthetic lethality and other DDR modalities. As scientists, we are dedicated to exploring novel approaches that target the totality of DDR to help address resistance, durability and other unmet needs for difficult-to-treat cancers. As initial pioneers in targeting DDR with drugs, we are excited to help further evolve the field by applying the expertise and learnings we have acquired over the past two decades.

Dr. Niall Martin was speaking to Sarah Whelan, Science Writer at Technology Networks.