Oncology Drug Discovery Is Targeting The Wrong Problem
By Carsten Faltum, CEO, Celex Oncology
For decades, oncology drug discovery has been guided by a relatively consistent objective: reduce tumor burden. From cytotoxic chemotherapy to targeted therapies and immuno-oncology, success has often been measured by the ability to shrink tumors or delay their growth. These endpoints have shaped pipelines, regulatory pathways, and investor expectations alike.
Yet there is a growing tension between what we measure and what ultimately matters. Tumor shrinkage, while important, is not always synonymous with improved survival. In many advanced cancers, mortality is driven less by the primary tumor and more by metastatic spread and disease progression.1 This disconnect raises an uncomfortable but necessary question: are we targeting the right problem?
The Endpoint Problem
Objective response rate (ORR) and tumor size reduction remain central to early- and mid-stage development decisions. These metrics are relatively straightforward to measure and provide early signals of efficacy. However, they can fail to capture the biological processes that determine long-term outcomes.
Metastasis is responsible for 90% of cancer-related deaths.2 It is a complex, multistep process involving cellular invasion, migration, and colonization of distant tissues. Critically, these processes are not always reflected in changes in tumor size. A therapy may reduce tumor volume without meaningfully altering the underlying biology that enables dissemination.
As a result, pipelines optimized for tumor shrinkage may inadvertently deprioritize mechanisms that influence progression and metastatic potential. This has implications not only for clinical outcomes but also for how we allocate research and development resources.
The Limitations Of Downstream Targeting
The past two decades have seen significant investment in targeting downstream mutations and signaling pathways. Precision medicine has delivered important advances, particularly in genetically defined subpopulations. However, this approach also has inherent limitations.
First, mutation-specific targeting often results in narrow patient populations. While highly effective in some contexts, these therapies may lack scalability across tumor types. Second, tumors are adaptive systems. Targeting a single downstream node can lead to resistance through pathway redundancy or compensatory mechanisms.
Perhaps more fundamentally, downstream targets are often several steps removed from the initial drivers of tumor behavior. By the time these pathways are activated, key aspects of disease biology, such as invasiveness and metastatic potential, may already be established.
It is also fair to acknowledge that some existing modalities already engage aspects of progression biology. Adjuvant therapy aims to prevent metastatic recurrence; immune checkpoint inhibitors can produce durable disease control rather than mere cytoreduction; and antibody‑drug conjugates extend beyond simple proliferation killing. These advances are important, but they engage progression as a downstream consequence of other mechanisms rather than by targeting the upstream regulators of metastatic behavior directly.
The Case For Upstream Biology
An alternative approach is to focus on upstream regulators that sit earlier in the chain of events, governing tumor behavior. These mechanisms often control multiple downstream pathways simultaneously and may therefore offer broader and more durable effects.
One emerging area of interest is the role of bioelectric signaling in cancer. Voltage-gated sodium channels (VGSCs), traditionally associated with excitable tissues, such as nerves and muscles, are increasingly recognized as contributors to cancer cell behavior.3 Evidence suggests that VGSC activity is linked to processes such as invasion and metastasis.3 Notably, recent work indicates that Nav1.5 sits upstream of K‑Ras signaling, stabilizing the KRas–calmodulin complex and activating downstream MAPK pathways implicated in invasion and metastasis. This places VGSCs at a regulatory node above one of oncology’s most studied — and most difficult to drug — targets.
What makes upstream targets compelling is not only their position in the biological hierarchy but also their potential to influence multiple hallmarks of cancer. By modulating fundamental cellular processes, it may be possible to shift the trajectory of disease rather than simply responding to its later manifestations.
Implications For Drug Discovery
Reframing oncology drug discovery around progression and metastasis requires a shift in mindset across several dimensions.
Target selection
Greater emphasis should be placed on mechanisms that regulate tumor behavior, not just proliferation. This may involve integrating insights from fields such as systems biology and bioelectricity, which have historically been underrepresented in oncology.
Preclinical models
Traditional models often prioritize tumor growth inhibition. There is a need for models that better capture invasion, dissemination, and interaction with the tumor microenvironment, including patient‑derived xenografts (PDX), genetically engineered mouse models (GEMMs), three‑dimensional organoid and microfluidic invasion assays, and intravital imaging approaches that allow direct observation of metastatic dynamics.
Clinical endpoints
Overall survival should remain the primary endpoint, since it is the outcome that ultimately matters to patients. Within that frame, secondary endpoints that capture progression dynamics, such as time to new metastatic lesions or organ‑specific progression, can help illuminate anti‑metastatic activity and support translational interpretation.
Combination strategies
Upstream targeting may be particularly well suited to combination approaches. By addressing fundamental drivers of behavior, such therapies could enhance the effectiveness of existing treatments without competing directly with them.
Trial design and feasibility
A common concern is that focusing on metastasis biology demands longer, larger, or more costly trials. But this does not need to be the case; anti‑metastatic mechanisms can be evaluated within conventional trial architectures appropriate to the disease setting, keeping overall survival as the primary endpoint. The shift lies in target selection and translational rationale, not in trial scale.
A Broader Perspective On Success
None of this suggests that tumor shrinkage is unimportant. Rather, it highlights the need for a more balanced framework that aligns biological insight with clinical outcomes. Oncology is a field defined by complexity, and no single metric can capture all dimensions of therapeutic benefit.
What is becoming increasingly clear is that addressing the mechanisms of progression and metastasis is essential for meaningful advances in survival. By shifting attention upstream, the industry has an opportunity to complement existing approaches and potentially unlock new avenues for treatment.
The question is not whether current strategies are wrong, but whether they are incomplete. Recognizing and addressing that gap may be one of the most important steps in the next phase of oncology drug discovery.
References
- Gupta, G.P. and Massagué, J. (2006) Cancer metastasis: building a framework, Cell, 127(4), pp. 679–695
- Bogenrieder T, Herlyn M. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene. 2003;22(42):6524‐6536.
- Sanchez-Sandoval, L. et al. (2023) Voltage-gated sodium channels: from roles and mechanisms in metastatic cell behavior to clinical potential as therapeutic targets, Frontiers in Pharmacology
About The Author
Carsten Faltum is a seasoned executive in the life sciences sector, bringing over 25 years of leadership experience across research and development, commercialisation, and corporate strategy. As cofounder and CEO of Celex Oncology, Carsten has been instrumental in guiding the company from conceptual stages through clinical planning and capitalization. Under his leadership, Celex Oncology has successfully secured two financing rounds, established a comprehensive operational and advisory team, and developed a robust clinical and regulatory strategy. Carsten’s expertise is grounded in a strong scientific foundation, holding a Master of Science in chemical engineering.