Exploring New Molecular Targets for Anti-cancer Therapy
Amil Shah , Clinical Professor, Department of Medicine, University of British Columbia
Amil Shah is Clinical Professor of Medicine at the University of British Columbia. His practice focusses on gastrointestinal and lung cancers. Among his administrative/academic roles, he chaired the Gastrointestinal Tumour Group at BC Cancer, and served as Associate Dean of the Vancouver-Fraser Medical Program at UBC. His research interest is the molecular pathogenesis of cancer.
The importance of regulatory non-coding RNAs
Abstract
Despite the rational design of targeted anti-cancer therapy to act on specific cellular proteins, its overall efficacy for many common cancer types falls short of expectation. The increasing evidence for the crucial role of regulatory non-coding RNAs in tumorigenesis puts them in the crosshairs for new drug development.
1. What is targeted anti-cancer therapy?
Targeted anti-cancer therapy broadly refers to the use of drugs that interfere with specific molecules (molecular targets) required for tumour growth. It differs from traditional cytotoxic chemotherapy, which exploits small differences in the metabolic pathways of normal and cancer cells, to preferentially destroy the malignant ones. The basis of targeted therapy lies in the observation that cancer is caused by mutations in special genes, called oncogenes and tumour suppressor genes, which regulate processes involved in cancer development: cell proliferation, cell death, growth factor signalling and immune function. Different compounds have been developed to reverse the effects of these mutations, many of which are now in clinical use. They largely comprise small molecule tyrosine kinase inhibitors and monoclonal antibodies, which inhibit signal transduction pathways. Many protein enzymes, called kinases, are dysregulated in cancer due to activation by gain-of-function mutation, gene amplification and chromosomal rearrangement, and are, therefore, good candidates for targeted therapy. A second class of targeted therapy is monoclonal antibodies, of which there are three categories: (i) those binding to extra-cellular ligands, like vascular endothelial growth factor (VEGF); (ii) those directed to cell membrane receptors, like human epidermal receptor 2 (HER2); and (iii) those directed to membrane-bound proteins, like CD20 on the surface of B-lymphocytes. More recently, immune checkpoint inhibitors, which directly or indirectly activate host anti-tumour immunity, have been developed; these include antibodies against programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
2. How successful is targeted therapy?
Targeted therapy is particularly effective for some uncommon cancers, such as the tyrosine kinase inhibitors of the bcr-abl 1 fusion protein in chronic myelogenous leukemia, or the mutated kit receptor tyrosine kinase in gastrointestinal stromal tumours. Similarly, monoclonal antibodies, like rituximab and obinutuzumab, either alone or in combination with chemotherapy, are efficacious for chronic lymphocytic leukemia by targeting CD20. Overall, however, despite its rational design, the effectiveness of targeted therapy for the common epithelial cancers, such as those of the breast, lung, colorectum and prostate, is modest and progress continues to be incremental. Further, its optimal use with chemotherapy and other treatment modalities, like surgery and radiation, remains under study. More than 30 years have passed since the introduction of targeted therapy in the clinic, and despite over 500 drugs being approved, curing most common human cancers remains a formidable challenge, especially if they are surgically unresectable.
3. What are the drawbacks of targeted anti-cancer therapy?
A major obstacle to the success of targeted therapy is the emergence of drug resistance with subsequent cancer relapse. Moreover, it was anticipated that by blocking specific mutant proteins, targeted therapy would cause less harm than chemotherapy or radiation therapy. Unfortunately, the toxicity of targeted therapy is not inconsequential due to unexpected cross-reactivity with normal cells. Common side effects from targeted therapy include skin rash, fever, fatigue, joint ache, headache, dry or itchy eye with or without blurred vision, nausea, diarrhoea, constipation, bruising, bleeding, and high blood pressure. Less commonly, some targeted therapy can cause heart failure, hypothyroidism, increase in liver enzymes, or a reduction in white blood cells with consequent risk of infection. It may also cause lung inflammation (pneumonitis).
4. Why has targeted anti-cancer therapy fallen short of expectations?
Targeted anti-cancer drugs are designed to act on specific proteins in the highly interconnected pathways associated with the cell cycle. This strategy may, however, be too narrow to achieve durable control of malignant cells insofar as it does not take into account some fundamental molecular events responsible for the initiation and progression of cancer. In this regard, the role of the genomic regulatory network is paramount, and tumorigenesis is increasingly being linked to its disruption. Therefore, in developing novel drugs, it is important to consider the mechanisms underlying the malignant state. Several lines of evidence now suggest that various key cellular processes, including cell proliferation and differentiation, are orchestrated by a rich network of regulatory non-coding RNAs (ncRNAs), from the onset of embryogenesis through adulthood.
5. What is the significance of the regulatory ncRNA network?
As cells become more complex over evolutionary time, the amount of genetic information, particularly regulatory information, increases exponentially. New regulators are needed for new genes, and some of these new regulators also require regulation to ensure that their activity is harmoniously integrated into the existing circuitries of the cell. The protein-based systems of prokaryotes have a limited capacity to develop regulatory connections and they quickly become saturated. On the other hand, ncRNA systems can efficiently scale up the number of regulatory connections required for the fully integrated network in higher eukaryotes. In metazoans, large segments of the genome are transcribed into ncRNAs with diverse cellular functions; these include regulatory signals, molecular decoys, scaffolds for protein-protein interactions, and guides to targets in the genome. In humans, although about 75% of the genome is transcribed into RNA, only about 2% is actually translated into proteins (coding RNA) whilst the majority is non-coding. These discoveries support the notion that ncRNAs are the architects of increasing complexity in multi-cellular organisms.
6. What is the nexus between multi-cellular complexity and tumorigenesis?
An essential biological requirement in multi-cellular organisms is cell differentiation, through which the different cell types are generated from the same genome. Each cell type is defined by its distinct gene-expression profile. This arises from the dynamic interactions among its genes, each of which influences the activity of others. The unique property of self-organization in a dynamic system enables the spontaneous formation of novel patterns from the interactions of its components. The system eventually settles down into a state of equilibrium that constitutes a cell type. The critical, stable outcomes towards which a dynamic system evolves over time are referred to as “attractor states”.
A logical extension of the concept of a cell as an attractor state is that a cancer cell also represents a specific attractor state. It exists in the genomic space of all possible configurations that a dynamic system can be found in at any given time. The cancer attractor state is not usually expressed, but mutations can alter the contours of the genomic landscape and enable state transitions, allowing cells to veer from regular differentiation pathways and enter unused attractor states. Among these, are gene-expression programs that encode the cancer phenotype.
Regulatory ncRNAs collectively determine which gene regulates which genes, and under what conditions. Therefore, they represent a separate, higher-order regulatory network that governs mutually interacting genes. There is growing evidence that disruption of the ncRNA network underpins tumorigenesis.
7. How does this viewpoint of tumorigenesis differ from the somatic mutation theory?
The prevailing somatic mutation theory of cancer asserts that the step-wise accumulation of about four or five mutations in oncogenes and tumour suppressor genes over time is sufficient to drive a normal cell to transform into a malignant one. This contrasts with the viewpoint that a cancer arises from a functional error in the cell development process. Stated another way, modifications of the ncRNA regulatory network cause a developmental miscue that triggers tumorigenesis. Regulatory ncRNAs operate in a nuanced manner to reset the cell’s epigenetic program. Each component of the ncRNA circuitry individually exerts a small effect. For example, individual single nucleotide variants (SNVs) or single nucleotide polymorphisms (SNPs) associated with disease, including cancer, appear to have little effect on their own, but collectively they have the potential to disrupt key cellular functions. In addition to SNVs/SNPs, there is the almost universal occurrence of widespread mutational events due to kataegis, chromothripsis and chromoplexy in cancer, all of which affect ncRNA transcripts. Consequently, multiple ncRNA alterations are present in cancer, and these have important implications for therapy.
8. What are the implications of dysregulation of the ncRNA network for new anti-cancer drug development?
The traditional approach of searching for new therapeutic compounds follows a “lock-and-key” model: a drug target (a mutation) is like a lock and the right drug (a protein designed to bind to the mutation, thereby stopping its activity) is the key. However, advances in genomics and systems biology are reshaping our understanding of cancer pathogenesis, and incorporating this knowledge into the drug development process seems prudent. In response to the urgent need for innovative solutions, targeting aberrant ncRNAs could guide anti-cancer drug development. Since different cancers have different patterns of ncRNA expressions, which are specific for each cancer type, ncRNAs are valid therapeutic targets. A variety of nucleic acid-based therapeutics are at hand, including RNA molecules, such as antisense oligonucleotides, small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), anti-miRNAs, miRNA mimics, miRNA sponges, and therapeutic circRNAs. These can directly target any ncRNA of interest through complementary base-pairing to modulate its expression and function. This mode of action is a salient consideration, since, in contrast to protein-based targeted therapy, nucleic acid-based therapeutics act at the genetic level.
9. What are the challenges of nucleic acid-based therapeutics for cancer?
At a practical level, delivering nucleic acid-based therapeutics to the correct site can be difficult, especially in certain organs like the brain. Rapid advances are being made in delivery platforms, and several drugs are now in clinical trials for cancer. It is also important to be clear-eyed that each new nucleic acid-based drug brings with it unknown side effects, such as cellular off-target effects, systemic mis-targeting or immune activation. A high degree of vigilance regarding patient safety is, therefore, required as these drugs are introduced into the clinical setting.
Another concern is the far-reaching influence of the ncRNA regulatory network within the cell. The patterns of the multi-level network connectivity are still not completely elucidated, and, in all likelihood, they determine not only the network’s output, but its vulnerability to perturbations. In other words, a minor modulation by a therapeutic agent could have unintended downstream consequences. The analytical power of bioinformatics should decipher the dynamic links and balances among the ncRNA species to allow reliable predictions of the network’s behaviour. This is important, since multiple elements in the network are likely disrupted during tumorigenesis, and, therefore, the simultaneous targeting of several different ncRNAs might be required to contain errant signalling. This would be critical consideration in selecting treatment on an individual basis.
In conclusion, ncRNAs determine the cell’s epigenetic blueprint, and they play crucial roles in health and disease. While nucleic acid-based therapeutics directed at regulatory ncRNAs are a novel class of drugs for cancer, there are challenges. Progress in this area will require large-scale genome studies and high quality experimental functional validation. If successful, it would represent a triumph of precision-drug development.
Abbreviations
siRNA: small interfering RNA
shRNA: short hairpin RNA
miRNA: microRNA
circRNA: circular RNA
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