Empowering Lung Cancer Care: RNA Therapeutics Expand Treatment Frontiers
Challenges in Lung Cancer Treatment
Lung cancer stands as the leading cause of cancer-related deaths, both in Ireland and worldwide, making it a prominent contributor to the global burden of cancer mortality. Particularly, factors such as tobacco usage, exposures to substances like asbestos and radon, are among the key risk factors in the development of lung cancer. While therapy resistance remains a primary concern, conventional approaches such as surgical procedures, radiotherapy, and chemotherapy can result in notable success for select patients. However, a frequent outcome is the emergence of severe side effects, which can significantly diminish the quality of life for many individuals. Additionally, the effectiveness of these treatment methods remains limited, particularly for those with advanced-stage lung cancer, leading to reduced survival rates.
The primary challenges in treating lung cancer revolve around therapy resistance, the potential for toxic side effects, and the lack of available targeted therapies (Figure 1). In this context, the need to find more effective solutions against the challenges of lung cancer treatment has become inevitable. The limitations in treatment options, especially for advancedstage lung cancer patients, have necessitated the development of novel and effective approaches. This article will discuss a promising new type of therapy targeting a fundamental yet often overlooked molecule – RNA- and its potential to overcome these challenges in lung cancer treatment.
RNA Therapeutics: A Promising Frontier in Lung Cancer Treatment
In recent years, an exciting new therapeutic modality has emerged in the form of ‘RNA therapeutics’ (RNATX). RNA, typically associated with messenger RNA (mRNA), are often thought to be transient molecules derived from proteincoding genes which are translated into proteins in our cells. However, another class of RNA molecules called long noncoding RNA (lncRNA) which do not encode for proteins and far outnumber such protein-coding genes, exist and function as mature RNA molecules throughout our cells. RNA therapeutics is based upon a core feature of nucleic acids – sequence complementarity, allowing for precise targeting of gene targets. RNATX encompasses strategies to target cellular nucleic acids using, for example, antisense oligonucleotides (ASOs), which are artificially created therapeutic RNA molecules, introduced into cells to specifically target cancer-associated RNA, including both mRNA (protein-coding) and lncRNA (non-protein-coding). The general goal of RNATX is either to deplete cancer-promoting genes, or provide tumor-suppressing RNA molecules for therapy. In all cases, artificially created therapeutic RNA are delivered to the patient through a variety of means such as systemic delivery as required for lung cancer.
RNATX induces and orchestrates a variety of cellular responses. These responses range from guiding protein synthesis and disrupting conventional protein production to serving as targeted agents, all contingent upon the specific RNA sequence utilized. The spotlight on RNATX has intensified, particularly due to its remarkable success in swiftly generating COVID-19 vaccines. However, it’s worth noting that the potential of RNATX extends far beyond vaccines. For instance, in the realm of cancer treatment, RNATX presents a remarkable case as seen through the application of ASOs in targeting the well-explored oncogenic JAK-STAT pathway. Researchers undertook this approach in the context of patients diagnosed with diffuse large B-cell lymphoma, resulting in impressive efficacy and safety outcomes.
RNATX presents a host of advantages over conventional treatments, including cost-effectiveness, minimal side effects, and the precision targeting of tumor cells. This, in turn, carries the potential to usher in a paradigm shift in lung cancer treatment, which urgently requires novel therapeutic approaches.
The allure of RNATX in lung cancer treatment lies in its potential to surmount drug resistance and unintended off-target interactions, both key issues in lung cancer treatment. In contrast to traditional chemotherapy or radiation which often influences both healthy and cancerous cells, RNATX, can be engineered to zero in on highly expressed lncRNA genes, primarily found in cancer cells. LncRNA genes although vast in number (over 50,000) still remain poorly understood. They are positioned as ideal targets for RNATX as they exhibit higher levels of cell and cancer specificity, compared to mRNA or protein-coding genes. Both the level of gene targeting precision and tumor-specificity holds the promise of minimizing collateral damage to healthy tissues, thus elevating the overall quality of life for patients.
Moreover, the adaptable nature of RNATX provides a versatile platform, capable of being tailored to various types of lung cancer, accommodating even specific genetic mutations within tumors. This adaptability is especially pivotal in tackling the heterogeneous nature of lung cancer, where tumors exhibit diverse genetic profiles and distinct responses to treatments. Hence, RNATX may be fashioned into a truly ‘personalized’ therapy for every individual tumor.
Nevertheless, every type of therapy depends on identifying targets, or vulnerabilities in the diseased cell. Despite the significant promise held by RNATX, identifying optimal molecular targets for these therapies remains a challenge due to our incomplete knowledge of the disease. The selection of appropriate target genes or proteins is pivotal to ensure treatment effectiveness while mitigating the risk of undesired outcomes.
To navigate these challenges, selecting optimal ASO therapy targets demands critical criteria. These targets should play vital roles in lung cancer tumorigenesis, remain exclusive to cancer cells, be susceptible to ASO intervention, and boast robust validation through extensive studies. Furthermore, these targets should exhibit minimal toxicity and demonstrate the potential to synergize effectively with other treatment modalities. This process necessitates comprehensive research to unravel the molecular pathways driving lung cancer progression, identifying critical genes contributing to tumor growth, metastasis, and treatment resistance.
This is where the application of advanced technologies such as high-throughput sequencing, bioinformatics, and computational modeling comes into play. By identifying genes frequently mutated in a significant portion of lung cancer patients, such as EGFR, ALK, KRAS, and PD-L1, or pathways unique to lung cancer cells, scientists can meticulously devise RNA-based interventions that disrupt these processes with precision. This could potentially trigger tumor regression or even eradication.
In summary, RNATX offer a targeted and adaptable approach that holds immense promise for revolutionizing lung cancer treatment by minimizing side effects and optimizing patient outcomes. Yet, unlocking this potential hinges on a profound understanding of lung cancer biology and the meticulous identification of optimal therapeutic targets through cutting-edge technological methods. This could mark the dawning of a transformative era in effective and personalized lung cancer treatments.
In the unfolding narrative, long non-coding RNAs (lncRNAs) emerge as promising RNATX targets, representing a vast class of RNA molecules that primarily do not encode proteins. This challenges the conventional notion that RNAs predominantly act as intermediaries for protein synthesis, as stipulated by the central dogma. Unlike the role of messenger RNA (mRNA) in relaying genetic instructions from DNA to proteins, lncRNAs instead exist as functional, mature RNA molecules. LncRNAs bring to light the intricacies and diversity inherent in the genetic landscape. Despite their limited or absent protein-coding capacity, lncRNAs wield a multifaceted influence across various cellular processes. Through modulation of gene expression, interaction with other RNA molecules, and orchestration of intricate regulatory networks, lncRNAs unveil a comprehensive layer of genetic control extends beyond than that of protein-coding genes.
LncRNAs have been shown to possess a wide spectrum of regulatory functions, from chromosome dosage compensation to modulation of chromatin states, cell differentiation, and basic cellular functions (Figure 2). However, the specific functions and mechanisms of many of these lncRNAs remain unclear. At this juncture, further research is needed to better comprehend the role of lncRNAs in cancer.
In the realm of cancer biology, the allure of lncRNAs lies not only in their potential to expand our understanding of basic disease processes, but also in their potential as ground-breaking therapeutic targets. Herein lies the question of paramount importance: why are lncRNAs more attractive therapeutic prospects than widely-studied proteins? The answer lies in their unique attributes. Generally, lncRNAs are more cell-type and cancer-specific than protein genes. They also outnumber protein genes over 2.5 times and have more specific downstream genetic regulatory networks. These attributes place lncRNAs as ideal candidates for precision RNATX due to the intrinsic specificity of both their expression and function, as compared to proteins. The ability to orchestrate multiple processes simultaneously grants them an unprecedented level of influence over cellular behavior. Moreover, lncRNAs can serve as central regulators, modulating entire cascades of gene expression, thereby holding the power to delicately balance aberrant cellular states – a feat that proteins alone often do not to accomplish.
LncRNAs play a key role in finely modulating gene expression, determining the phenotype of cancer cells, and influencing regulation of cellular processes. Aberrant lncRNA expression in cancer cells has been shown to impact fundamental cancer mechanisms such as cellular proliferation, apoptosis, invasion, and metastasis. Furthermore, lncRNAs can intricately regulate signaling pathways and precisely cell cycle regulation, thereby influencing the tumor microenvironment. These critical findings underscore the potential of lncRNA differential expression in cancer as viable therapeutic targets.
The development of lncRNAbased therapeutics holds a crucial role in lung cancer treatment. These approaches offer a tailored strategy that aims to disrupt cancer cell functions, halt growth and spread, while also targeting treatment-resistant cells. The specific high expression of oncogenic lncRNAs in cancer cells indicates their potential use as therapeutic targets, with the potential to minimize side effects by sparing non-tumor cells.
While previous studies have identified a range of differentially expressed lncRNAs in lung cancer, our knowledge of their specific functions in lung cancer remains limited and requires further investigation.
Targeting lncRNAs with ASOs
Traditionally, targeting RNA molecules with small molecule inhibitors has been challenging due to a limited understanding of the dynamic tertiary structures of RNA molecules. However, ASOs offer a promising avenue for lncRNA targeting. ASOs are synthetic RNA molecules designed solely based on sequence information, capable of specifically acting on genes or transcripts using principles of sequence complementarity.
Mechanisms of ASOs
ASOs can modulate target RNA levels through various mechanisms. Some mechanisms involve directing the activity of RNase H for RNA degradation of the target genes, while others inhibit translation (with mRNA) or biogenesis of the target RNA. Additionally, ASOs can impact RNA splicing, polyadenylation, and cellular localization (Figure 2). The specific mechanism depends on ASO design and therapeutic objectives.
In conclusion, utilizing ASOs to target lncRNAs presents a promising strategy in cancer treatment. The distinct attributes of lncRNAs and the flexibility of ASOs position them as compelling candidates for therapeutic interventions. Preclinical and clinical investigations provide evidence of the potential of lncRNA-targeted therapies. Ongoing research holds the potential to develop effective treatments for cancer and other diseases, harnessing the capabilities of lncRNAs and ASOs.
ASO-Based Approaches and Their Clinical Implications
Despite the formidable challenges encountered in developing lncRNA-based therapies, our research underscores substantial advancements in this field. Leveraging ASOs and CRISPR-based methods, we harness targeted precision to modulate lncRNA expression, potentially mitigating side effects. Nonetheless, it’s imperative to acknowledge inherent obstacles, encompassing effective ASO delivery to target tissues, the risk of unintended interactions leading to off-target effects, and the potential for immune responses following therapy. Concurrently, the evolution of nano-particle-based delivery systems and other innovative technologies holds promise in surmounting these challenges, thereby amplifying the efficacy, specificity, and overall safety of lncRNA-based therapeutics. Navigating these intricacies demands a fusion of cutting-edge science and unwavering dedication, propelling transformative strides in patient care and treatment paradigms.
ASO therapy extends its potential across a spectrum unmet medical needs. Notably, it shows promise in tackling neurodegenerative disorders like spinal muscular atrophy and ALS, genetic anomalies such as Duchenne muscular dystrophy and cystic fibrosis, and even cancer, where ASOs could perturb tumor growth by precisely targeting oncogenes. In the realm of cancer, numerous lncRNAs have surfaced as viable therapeutic targets across diverse cancer types, with encouraging preclinical findings. For instance, MALAT1 and HOTAIR, implicated in lung and breast cancer progression respectively, exemplify potential targets for tailored treatment approaches. Clinical trials validating the reliability and effectiveness of lncRNA-based interventions are imperative to substantiate their worth in cancer therapy.
ASOs, as versatile therapeutic tools, can be administered through various routes based on the target tissue. Intravenous (IV) injection is a common method for achieving systemic delivery, reaching multiple organs and tissues, including the lung. Additionally, subcutaneous injection offers a means for localized effects or the precise targeting of specific tissues. This multifaceted administration approach aligns ASO therapies with the diverse requirements of patients and diseases, enhancing their clinical applicability.
In summation, the promise of ASO therapy in addressing an array of maladies via pinpointed genetic and molecular modulation is undeniable. While challenges persist, ongoing research and clinical endeavors propel the field forward, highlighting the potential for ASOs to emerge as invaluable instruments within the medical armamentarium.
Conclusion
As the GOLD Lab team, our transition from the University of Bern to University College Dublin (UCD) has ushered in a new era of exploration, one focused on the untapped potential of lncRNAs as therapeutic targets in cancer, with focus on lung cancer. Through a blend of computational approaches and hands-on experimentation, our goal has been to not only innovate within lncRNA therapeutics but also empower fellow researchers with our insights.
Our journey exploring the genomic dark matter of cancer, particularly non-small cell lung cancer (NSCLC) and KRAS-mutant NSCLC, has been marked by synergy between bioinformatics expertise and cutting-edge CRISPR screens. Our screens encapsulate crucial cancer hallmarks, offering a novel perspective for understanding the complexities of lung cancer. Our unique pipeline, designed from the ground up, identified 80 oncogenic lncRNAs that emerged as overexpressed specifically in NSCLC.
This select group of lncRNAs has not remained a mere discovery but has become the bedrock of our mission—a mission driven by the pursuit of understanding. As we delve into their functional roles, we’re unraveling the intricate choreography that these lncRNAs perform within the complex pathways of tumorigenesis and cancer progression. And as we look toward translation to the clinic, combining cutting-edge technologies with the application of ASOs, we envision breakthroughs in developing targeted therapies at the frontier of RNATX. Our journey, while ambitious, has not been without its challenges. Through the crucible of in vivo and in vitro experiments employing high-precision ASOs, we’ve validated our curated list of target lncRNAs we had identified. The fusion of data-driven discovery and clinical significance underscores the importance of our research not just as a theoretical exercise, but as a stepping stone toward efficient cancer treatment. We believe in the transformative power of our work, requiring validation through rigorous experimentation, to unlock promising therapeutic avenues in the fight against lung cancer. Our group aims to provide promising ASOs to progress onto clinical trials and further investigations, bridging the gap between our discoveries and tangible patient outcomes. With every confirmed hypothesis and validated ASOs, our efforts progress towards therapies which we hope leads to extended lives, improved quality of life, and elevated survival rates for lung cancer patients.
Written by Zekiye Altan1, Dylan Harvey1, Rory Johnson1,2,*
1School of Biology and Environmental Science, University College Dublin, Dublin D04 V1W8, Ireland
2Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin D04 V1W8, Ireland *Correspondence to: rory.johnson@ucd.ie
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