Why RNAi-Based Oncology Must Move Beyond Single-Target Thinking

A conversation with Robert Schickel, Ph.D., CEO and cofounder, NUAgo Therapeutics

As solid tumors continue to outmaneuver highly selective therapies, RNAi therapeutics are opening the door to broader systems-level approaches to cancer treatment. In this Q&A with Advancing RNA and Life Science Connect Acquisition Editor Michael Soloway, Robert Schickel, Ph.D., CEO and cofounder of NUAgo Therapeutics, discusses adaptive tumor biology, network-based targeting, RNAi delivery challenges, and the future of computationally driven oncology strategies.

Advancing RNA: Why is the “one gene, one drug” framework increasingly insufficient in solid tumors?

RS: Cancer progression in solid tumors is rarely maintained by a single mutation or pathway in isolation. While tumors may contain dominant oncogenic drivers, long-term survival and therapeutic resistance are sustained through adaptive survival networks that evolve under therapeutic pressure. Solid tumors are adaptive biological systems composed of interconnected signaling networks that evolve through clonal evolution and therapeutic pressure. While highly selective therapies have transformed treatment for certain patient populations, solid tumors frequently evade these interventions through compensatory pathway activation and rewiring survival networks.

The “one gene, one drug” model assumes tumors behave in a linear fashion. In reality, tumor biology is dynamic, adaptive, and nonlinear. We believe oncology needs to move toward approaches capable of disrupting broader cancer survival programs rather than selectively inhibiting individual pathways or molecular drivers in isolation to generate more durable responses.

Advancing RNA: Why are solid tumors so adept at adapting around selective therapies?

RS: Solid tumors are biologically heterogeneous systems composed of diverse subclonal populations with distinct genetic, metabolic, and survival states. Selective therapies are designed to target specific components or pathways that drive tumor progression while leaving cancer survival networks intact, allowing therapy-resistant subclonal populations to persist and grow. The tumor microenvironment further amplifies resistance through immune interactions, inflammatory signaling, hypoxia, vascular constraints, and metabolic stress. Tumors are continuously evolving ecosystems capable of adapting around narrowly selective interventions.

Advancing RNA: How has our understanding of tumor survival evolved, and what does that mean for RNAi therapeutics?

RS: Cancer biology has increasingly shifted from viewing tumors primarily as discrete genetic alterations toward understanding them as dynamic adaptive survival systems. Tumor persistence and resistance emerge from coordinated interactions across signaling pathways, transcriptional programs, metabolic states, stress responses, and the microenvironment.

This is important for RNAi therapeutics because endogenous RNA interference and microRNA-mediated regulation naturally operate through coordinated post-transcriptional control of interconnected gene networks rather than isolated targets alone.

As oncology continues to recognize the limitations of narrowly selective intervention strategies in heterogeneous solid tumors, RNAi therapeutics provide an opportunity to move beyond single-target inhibition toward coordinated disruption of adaptive survival programs at the systems level.

Advancing RNA: What are the greatest limitations in current RNAi oncology strategies?

RS: Many RNAi oncology strategies still apply traditional target-centric drug development frameworks to a new modality. In most cases, RNAi therapeutics are designed to selectively inhibit individual genes or pathways, which may not fully address the adaptive biology of aggressive solid tumors.

While RNAi therapeutics provide powerful tools for modulating gene expression, the biological challenge in solid tumors is often not simply whether a target can be inhibited, but whether suppressing a single target meaningfully disrupts the broader survival architecture sustaining tumor persistence and adaptation.

Another major limitation remains delivery, particularly outside the liver, where achieving efficient intracellular uptake, durability, and safety continues to be difficult. More broadly, the field is still evolving toward a systems-level understanding of tumor survival dependencies.

Advancing RNA: What does a systems-level RNAi approach look like in practice?

RS: A systems-level approach begins with recognizing that cancer cells depend on coordinated survival architecture rather than isolated molecular events. The question is no longer simply how to inhibit a single pathway but how to disrupt the interconnected biological programs that sustain tumor survival, adaptation, immune evasion, and resistance.

RNAi therapeutics are important in this context because endogenous RNA interference naturally regulates interconnected gene networks through coordinated post-transcriptional control.

The goal is not indiscriminate targeting. The goal is to identify and disrupt core survival architecture that tumors depend upon to persist, adapt, and evolve under therapeutic pressure.

Advancing RNA: How can small RNAs disrupt multiple survival pathways simultaneously?

RS: Small RNAs function through endogenous RNA interference mechanisms that modulate gene expression at the post-transcriptional level. Unlike therapies designed to inhibit single proteins or receptors, small RNAs simultaneously target multiple interconnected genes involved in tumor survival, adaptation, stress responses, and resistance. This reduces the tumor’s ability to compensate through pathway substitution or adaptive rewiring. The goal is coordinated disruption of survival architecture rather than single-target inhibition.

Advancing RNA: What advantages do RNAi therapeutics offer compared with small molecules or antibodies?

RS: Traditional small molecules and antibodies generally interact with a limited number of proteins or extracellular pathways. RNAi therapeutics operate at the level of gene regulation, creating the potential, if properly designed, to influence broader adaptive survival programs. RNAi may also expand access to intracellular or historically difficult to drug targets. We view RNAi therapeutics as complementary modalities that may broaden the range of therapeutically addressable disease mechanisms in oncology rather than replace existing therapeutic approaches.

Advancing RNA: What are the biggest translational challenges associated with network-based targeting?

RS: One major challenge is balancing sufficient disruption of tumor survival architecture with preservation of normal tissue function because interconnected biological networks regulate both malignant and normal cellular processes in highly context-dependent ways.

This complexity makes biomarker development more difficult. Network-based therapies may require integrated biomarker strategies capable of capturing adaptive tumor states, pathway interactions, and dynamic biological responses over time rather than relying exclusively on static genomic markers.

Translational modeling also remains challenging because human solid tumors are highly heterogeneous and continuously evolve under selective pressure from both therapy and the microenvironment. Predicting how coordinated network modulation will behave clinically across diverse tumor states remains an active area of translational research.

Advancing RNA: How should efficacy and biomarker strategies evolve?

RS: As therapies increasingly move beyond single-target inhibition, biomarker strategies will need to evolve beyond binary mutation-based frameworks. Biological state, adaptive responses, immune context, and pathway interactions may become increasingly important indicators of therapeutic effect and tumor response.

Similarly, durable disease control, suppression of adaptive resistance, and sustained alteration of tumor evolutionary behavior may ultimately become as important as short-term radiographic response.

Advancing RNA: Where might next-generation RNAi approaches have the greatest impact?

RS: Systems level RNAi approaches may be particularly important in aggressive solid tumors characterized by extensive heterogeneity, adaptive resistance, and distributed survival signaling. These settings often produce only transient responses to highly selective therapies because tumors adapt through compensatory signaling and clonal evolution. Such approaches may be most valuable where tumor survival depends on coordinated adaptive survival programs rather than single dominant molecular dependencies.

Advancing RNA: How important are computational biology and AI-driven modeling?

RS: Computational biology is becoming increasingly important because tumor survival emerges from highly interconnected biological systems that are difficult to fully understand through linear analytical approaches alone. AI-driven modeling may help identify adaptive survival dependencies, coordinated vulnerabilities, and emergent resistance patterns that are difficult to detect through traditional target-centric frameworks. These approaches may also improve our ability to model tumor evolution dynamically rather than relying exclusively on static molecular snapshots.

Advancing RNA: What role does the tumor microenvironment play in resistance?

RS: The tumor microenvironment plays a central role in therapeutic resistance because tumors exist within highly interactive ecosystems composed of immune, stromal, inflammatory, vascular, and metabolic components that continuously shape tumor behavior and therapeutic response. Resistance often emerges not only from tumor intrinsic changes but from dynamic interactions between tumor cells and the surrounding microenvironment under selective pressure. RNAi approaches may provide opportunities to influence both tumor-intrinsic biology and broader microenvironmental interactions simultaneously.

Advancing RNA: What misconceptions still exist around RNAi therapeutics in oncology?

RS: One misconception is that RNAi therapeutics are simply another form of conventional targeted therapy. In reality, endogenous RNA interference naturally regulates adaptive gene regulatory networks rather than isolated proteins alone.

Another common misconception is that RNAi therapeutics are limited to narrow applications. While delivery and translational challenges remain, the biological potential of RNAi is considerably broader than many early assumptions suggested.

At the same time, expectations should remain grounded in rigorous biology and clinical translation. RNAi therapeutics are powerful regulatory tools, but their success will ultimately depend on identifying meaningful biological vulnerabilities and translating those findings safely and reproducibly in patients.

Advancing RNA: How could RNAi oncology evolve beyond today’s precision medicine framework?

RS: Precision medicine represented an important advance, but much of oncology still defines precision as matching individual mutations to highly selective therapies. Over time, oncology needs to evolve toward systems focused on understanding how adaptive survival programs and tumor microenvironment interactions collectively sustain cancer persistence and resistance.

RNAi therapeutics will help move the field beyond isolated pathway inhibition toward coordinated modulation of adaptive tumor biology and survival architecture.

Advancing RNA: What excites you most about the future of systems-level RNAi therapeutics?

RS: Most exciting is the possibility of fundamentally changing how oncology approaches complex adaptive diseases such as solid tumors. Systems-level RNAi therapeutics will help shift oncology from sequential inhibition of individual pathways toward coordinated disruption of adaptive survival architecture. Key milestones will include advances in delivery, stronger translational validation, improved computational modeling, and durable clinical activity in difficult to treat solid tumors where highly selective therapies have historically produced only transient responses.

About The Expert:

Robert Schickel, Ph.D., is the CEO and cofounder of NUAgo Therapeutics, a biotechnology company focused on developing small RNA-based therapies targeting critical survival gene networks in cancer. With more than 15 years of experience across biotechnology and pharmaceuticals, he has led strategy, business development, and scientific innovation to advance novel therapeutics for unmet medical needs.

Schickel brings deep expertise in portfolio strategy, M&A diligence, and asset valuation, having led over 100 assessments across disease areas and market opportunities. He has developed global corporate and commercial strategies for life sciences companies and is widely published in peer-reviewed journals, reflecting his strong foundation in drug discovery and development.