Lethal Weapon

Cancer often develops or becomes aggressive because of genomic instability that arises from mutations or aberrations in DNA. These lead to uncontrolled growth, proliferation, and metastatic spread of tumorigenic cells. The body employs a highly sophisticated and coordinated cellular network focused on preserving DNA integrity during states of cell replication or damage, known as the DNA damage response (DDR), designed to prevent the replication of cells with faulty DNA by either repairing the damage or triggering cell death.

Exploiting this inherent genomic protection is a therapeutic area that presents a challenging target for two main reasons. First, the multitude of enzymes important in the DDR 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. A second challenge stems from initial concerns surrounding the blocking mechanisms that repair DNA damage in cells. These may inadvertently induce toxicity in normal cells, which raises the question of whether DNA repair systems that emerge selectively or are upregulated in cancer cells can be targeted to avoid impact on normal cells while specifically affecting cancer cells.

Killing cancer
 

In 2005, we were authors on one of two back-to-back papers in Nature demonstrating cancer-specific cell death in BRCA-mutated cancers via inhibitors of a DDR enzyme called PARP – poly (ADP-ribose) polymerase (1, 2). 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.

Following the Nature publications, Cambridge-based biotech firm KuDOS dosed the first patient with its new oral PARP inhibitor, KU-59436. In 2014, this product was approved and marketed as LYNPARZA (olaparib) by AstraZeneca for patients with advanced forms of hereditary BRCA-mutated ovarian cancer (3) and later for BRCA-mutated breast cancer (4). In 2019, olaparib was approved as a first-line maintenance treatment for germline BRCA-mutated metastatic pancreatic ductal adenocarcinoma.

PARP inhibitors’ ability to selectively induce synthetic lethality in cancer cells now extends beyond mutations in BRCA1 and BRCA2 to include other homologous recombination repair deficiencies (HRDs). This led to the approval of olaparib in 2020 beyond BRCA mutations and into germline and somatic HRR gene mutations in metastatic castration-resistant prostate cancer. Olaparib is now approved in first-line maintenance of BRCA-mutated advanced ovarian cancer; HRD-positive advanced ovarian cancer in combination with bevacizumab; maintenance for recurrent ovarian cancer; adjuvant treatment of germline BRCA-mutated (gBRCAm), HER2-negative, high-risk early breast cancer; first-line maintenance of gBRCAm metastatic pancreatic cancer; and HRR gene-mutated metastatic castration-resistant prostate cancer (5).

Praise for PARP
 

Olaparib not only became the first approved PARP inhibitor, but also represented the first approved drug targeting the DDR. There are now four PARP inhibitors on the market: olaparib, niraparib, rucaparib, and talazoparib. Over 10 years of extensive clinical data have proven that this therapeutic approach is highly effective as a monotherapy and has the potential to synergize with several chemotherapies (chemopotentiation) and other agents, including checkpoint inhibitors. These combination approaches are designed to address PARP-mediated DDR mechanisms that become activated to enable tumor resistance to DNA-damaging treatments such as radiation and chemotherapy. The desire to combine PARP inhibitors with conventional chemotherapy has driven the search for highly selective next-generation PARP inhibitors with the potential for lower cytotoxicity and improved combination approaches.

Since olaparib gained market approval, mechanistic understanding in DDR biology has advanced, leading to a wave of companies exploring therapeutic opportunities that target new aspects of the DDR beyond synthetic lethality. 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. This next wave includes inhibitors targeting ataxia telangiectasia and Rad3-related protein kinase (ATR), which are being explored by AstraZeneca (6), Artios (7), Repare (8), and Merck KGaA (9).  Potential opportunities include monotherapy, PARP inhibitor combinations, and immune checkpoint inhibitor combinations.

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 not only better depicted and annotated, but can be interrogated in more advanced ways, including through artificial intelligence, high-content biological screening, gene editing technologies, and more physiologically relevant cancer models that include 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, as well as better ways to evaluate their clinical potential using more refined preclinical models.

An unfolding treatment landscape
 

A decade and a half later, the commercial picture surrounding the DDR has changed significantly. Our focus at Artios is to develop drugs that target pathways across the totality of the opportunities the DDR offers, with DNA polymerase-theta (Pol-theta) emerging as a novel target of particular interest. 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. 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 patient types. Interest in Pol-theta also stems from its minimal or no expression in normal cells and its observed upregulation in numerous cancers (associated with poor prognosis). This selective expression pattern suggests that Pol-theta inhibitors may have a favorable therapeutic index because of a more focused impact on tumor cells.

Clinical studies on Pol-theta inhibitors have recently begun, with Artios’ ART4215 and ART6043 compounds – which we believe are the first specific, rationally designed Pol-theta polymerase inhibitor in clinical development. ART6043 is entering a first-in-human phase I clinical trial in patients with advanced or metastatic solid tumours (10). One part of the clinical trial development of these novel inhibitors is to test whether they can overcome PARP-inhibitor resistance as a single agent in particular patient types, and also in new studies for combination with PARP inhibitors such as AstraZeneca’s Lynparza and Pfizer’s TALZENNA. Other Pol-theta inhibitors in preclinical development have yet to enter clinical trials. Ideaya has a Pol-theta program targeting the helicase function, which is part of a strategic partnership with GSK signed in 2020 (11). Repare Therapeutics also has a Pol-theta program in partnership with ONO Pharmaceuticals (12).

As the DDR treatment landscape continues to unfold, it is becoming increasingly clear that there are large untapped therapeutic opportunities beyond synthetic lethality. 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.