Despite remarkable successes in the clinic, the development of targeted anticancer therapies remains challenging with disappointingly high failure rates. This can, at least in part, be attributed to the misapplication of targeted therapy directed against pan-essential genes, whereby efficacy is attenuated by dose-limiting toxicity. Recognising the challenges and opportunities associated with these drugs is of utmost importance for the next generation of cancer therapeutics.
“Identifying specific targetable characteristics in biology has always been a major challenge in cancer research. Thirty years ago I published an article in Virchow Archiv B cell pathology as part of my PhD thesis (with support of Judah Folkman) entitled “Desmin-positive stellate cells associated with angiogenesis in a tumour and non-tumour system”.3 In this research, we observed a striking similar vascular reaction in the two systems. Here also the search of specific patterns of tumoral vessels have faced similarities with the normal angiogenic reaction. Specific therapeutic targeting of tumoral endothelial cells suffers resistance. In this light, Vincent Geldhof defended his PhD thesis on the 6th May 2021 with the title: “Simply the b(r)east- endothelial cell heterogeneity in health and disease.” All systemic anti-cancer treatments faced the problem to find the optimal therapeutic index with optimal therapeutic advantage and limited toxicity to normal cells. The understanding of the involvement of pan-essential genes and how to cope with them in different cancer types can lead to major advances in cancer treatment.”
A key component of successful drug development is the assessment of the therapeutic index (TI), the ratio of the dose or exposure of a drug required to elicit the desired therapeutic effect compared with the dose or exposure at which toxicity becomes limiting. While cytotoxic chemotherapies generally have a low TI, the development of targeted drugs provided an alternative route to achieve high TIs. However, therapeutics targeting pan-essential genes will often have low TIs in the same range as what is seen with chemotherapy.1 Therefore, it is important to understand the key features of successful chemotherapy and targeted therapy agents and outline recurrent challenges to drug development efforts targeting pan-essential genes. Consideration for the specific challenges associated with targeting pan-essential genes will likely contribute to the improvement of the high clinical failure rates we are facing today in the field of oncology.
To date, only 5.1% of all oncology drugs that enter phase I clinical trials progress to Food and Drug Administration (FDA) approval.2 One potential explanation for this high failure rate in oncology lies in the misapplication of the targeted therapy paradigm to the drugging of pan-essential genes. In general, a gene can be referred to as pan-essential if losing that gene leads to loss of fitness or cell death in multiple normal tissues or cell lineages in humans. Pan-essential genes include regulators of the cell cycle (PLK1,CDK1, CDK7, CDK9, AURKA, AURKB, CDK4/6), epigenetic regulators (DNMT1, BRD4, HDAC3), protein homeostasis regulators (NEDD8, 20S proteasome subunits), and DNA-damage response modulators (ATR, WEE1, CHK1).1 Examples of inhibitors targeting pan-essential genes in cancer include histone deacetylase (HDAC) inhibitors, aurora kinase inhibitors, polo-like kinases and CDC7 inhibitors. Of these, only the HDAC inhibitors vorinostat, belinostat, romidepsin and panobinostat have been granted FDA approval. However, their efficacy is modest and the overall clinical benefit is marginal due to the severity of associated adverse events. Therefore, lessons learned from previous targeting of pan-essential genes should be taken into account to benefit the discovery of next generation cancer therapeutics.1
Common pitfalls when targeting pan-essential genes include the misidentification of pan-essential genes as selective-essential targets based on limited preclinical modelling or the inability to stratify and enrich the clinical trial population. Furthermore, also inadequate attention to therapeutic pharmacology and the lack of a therapeutic window due to on-target toxicity or inhibitor polypharmacology might play an important role. In addition, therapeutic failure often occurs late in drug development, rather than during therapeutic optimisation. As such, several strategies to improve the development of ‘next-generation’ pan-essential target inhibitors should be considered. First of all, developing therapeutics that target pan-essential genes requires careful target prioritisation and validation in multi-omic and functional datasets. In addition, biomarkers that enable patient stratification should be identified through expanded preclinical models. Furthermore, different dosing strategies based on pharmacokinetics, pharmacodynamics and toxicology should be explored in order to optimise the dosing, schedule and drug formulation. Combination strategies with highly selective therapeutics might significantly improve the TI of therapeutics targeting pan-essential genes. On a final note, also future basic science efforts to thoroughly understand the fundamental biology of pan-essential genes, and their specific involvements in different cancer types, will benefit the discovery of the next generation of cancer therapeutics.1