Introduction

GLP-1 receptor agonists have transformed metabolism from a niche therapeutic area into one of biotechnology’s most commercially significant platforms. However, the story of metabolism in oncology began long before semaglutide and tirzepatide became household names. Cancer researchers have spent decades mapping the same biological systems that GLP-1s made commercially visible. Their work converged on a single pathway—the PI3K/AKT/mTOR pathway—that would become the focus of one of oncology’s most ambitious therapeutic experiments. What followed was a decade of success, repeated setbacks, and hard-earned lessons. The history of PI3K drug development revealed that compelling biology alone does not guarantee durable clinical or commercial success.

This article traces that journey — from the cancer metabolism research that anticipated the GLP-1 era, to the PI3K drug development story that defined a decade of oncology investment, to the programs now testing whether the field’s accumulated learning can finally be translated into durable clinical benefit. The answer will define whether metabolic oncology becomes a therapeutic category or remains a promising but incomplete biological idea.

Where Cancer and Metabolism Converged

Long before metabolism became a major investment theme, cancer researchers were investigating many of the same questions that GLP-1 therapies later brought to the forefront of biotechnology. How do nutrients shape cellular behavior in cancer? What role does insulin play beyond glucose regulation? Can systemic metabolism influence disease outcomes? Researchers studying tumor metabolism had been exploring these questions for decades.

Much of that work converged on the PI3K/AKT/mTOR pathway. Cancer biologists studying tumor growth and scientists investigating insulin signaling were approaching the same molecular architecture from different directions. In cancer, PI3K emerged as one of the most frequently altered pathways driving tumor growth and survival. In metabolism, it was recognized as a central mediator of insulin’s effects on glucose uptake, nutrient sensing, and cellular metabolism.

The convergence carried an important implication. A tumor harboring a PI3K alteration and a patient with chronically elevated insulin were both acting on the same growth-promoting signaling network. The mutation activated the pathway from within the tumor. Systemic insulin signaling reinforced it from outside.

The Great PI3K Experiment

The PI3K/AKT/mTOR pathway entered drug development with exceptional credentials. Mutations affecting the pathway occurred across a broad range of solid tumors, the biology was well characterized, and advances in medicinal chemistry had made selective small-molecule inhibition a realistic therapeutic strategy. What followed was more than a decade of clinical development. Each generation of PI3K inhibitors revealed something new about the pathway, its therapeutic potential, and its limitations.

The figure below (Figure 1) maps the major PI3K programs across two dimensions that shaped their clinical trajectories:

Figure 1. Strategic mapping of PI3K inhibitors by metabolic disruption and unmet clinical need. Programs that better managed the physiological consequences of pathway inhibition achieved the greatest clinical success, whereas those in which these effects remained uncontrolled often struggled despite compelling biology. The upper-right quadrant—high unmet need with managed metabolic complexity—represents the direction in which the field continues to evolve.

The horizontal axis reflects how severely each program disrupted glucose regulation and triggered insulin signaling. The vertical axis reflects the level of unmet clinical need, ranging from diseases with established treatment options to those with few effective therapies and poorer outcomes. Viewed through this framework, the evolution of PI3K inhibitors can be understood as four distinct phases, each reflecting a different attempt to balance pathway inhibition with clinical reality:

1. Proof of Concept:

• Hematologic malignancies provided the first proof of concept for PI3K inhibition. Agents including idelalisib, duvelisib, and copanlisibdemonstrated that selective pathway inhibition could produce meaningful clinical benefit when matched to the appropriate disease biology.
• Although copanlisib was later withdrawn for commercial reasons, these approvals collectively established that PI3K was a druggable target in the right setting.

2. Progress Zone:

• Alpelisib and later inavolisib validated PI3K inhibition in solid tumors, particularly PIK3CA-mutated breast cancer.¹⁸⁻¹⁹
• These programs demonstrated that the pathway could be successfully targeted in solid tumors but also highlighted ongoing challenges related to hyperglycemia, resistance, and patient selection.

3. Historical Limitations:

• Earlier broad-spectrum inhibitors such as buparlisib, pictilisib, and taselisib, as well as attempts to extend successful hematologic programs into solid tumors, struggled with toxicity and limited clinical benefit.
• Collectively, these programs illustrated the difficulty of balancing pathway suppression with metabolic tolerability.

4. The Frontier:

• Newer approaches such as gedatolisib and PIKTOR are attempting to address the remaining challenges through deeper pathway control or direct management of the metabolic consequences of inhibition.
• Gedatolisib combines PI3K and mTOR inhibition within a single molecule and is being evaluated in Phase 3 studies in HR+/HER2− breast cancer.
• PIKTOR combines dual PI3K/mTOR inhibition with an insulin-suppressing intervention and is being evaluated in advanced and recurrent endometrial cancer.
• Together, these programs represent the field’s latest effort to translate two decades of biological insight into durable clinical benefit.

Yet despite these advances, the same fundamental challenge persisted. Pathway inhibition could be refined, made more selective, and deployed in new settings. Whether it could be made truly durable remained unanswered. Understanding why required a closer look at the biology.

The Insulin Rebound — How PI3K Drugs Undermined Themselves

For years the challenges facing PI3K inhibitors were framed primarily as a tolerability problem. The drugs caused hyperglycemia. Patients struggled to remain on treatment. The solution appeared straightforward: develop more selective molecules, reduce metabolic side effects, and clinical outcomes would improve. That framing turned out to be incomplete.

In 2018, Hopkins and colleagues published a finding that fundamentally changed how the field interpreted PI3K inhibitor development. Hyperglycemia was not simply an unfortunate side effect of treatment. It was evidence of a systemic physiological response. When PI3K signaling is inhibited in normal tissues such as the liver and skeletal muscle, glucose uptake declines and blood glucose levels rise. In response the pancreas releases a compensatory surge of insulin. That insulin surge then reactivates PI3K signaling throughout the body — including within tumor cells — even while the inhibitor remains present.

The clinical experience across PI3K programs reflected this biology. Rates of severe hyperglycemia varied substantially across successive generations of inhibitors, providing a window into how different strategies managed the metabolic consequences of pathway inhibition (Figure 2).

Figure 2. Grade 3+ hyperglycemia rates across representative PI3K inhibitor programs. Earlier broad-spectrum inhibitors were frequently associated with severe hyperglycemia, whereas newer approaches demonstrated improved metabolic tolerability. PIKTOR incorporates an insulin-suppressing intervention as part of its therapeutic strategy, and Grade 3+ hyperglycemia rates have not yet been reported from the ongoing Phase 2 study.

Subsequent clinical evidence strengthened the hypothesis. Noch EK and colleagues identified insulin feedback as an independent resistance factor in patients receiving PI3K-directed therapy, demonstrating that the phenomenon was not confined to laboratory models but was operating in real patients. Programs associated with the greatest metabolic disruption generally produced the poorest outcomes, while successive generations of inhibitors improved tolerability through greater selectivity, refined pharmacology, or alternative dosing strategies.

Hyperglycemia alone does not determine therapeutic success, and the relationship is far from perfectly linear. Yet these experiences forced researchers to reconsider what they were treating. The tumor could no longer be viewed in isolation from the physiological environment in which it existed. Systemic metabolism had become part of the therapeutic equation.

That realization set the stage for a different way of thinking about cancer—one that considered not only the tumor itself, but also the environment that supports it.

The Seed, Soil, and Fertilizer

If the tumor is the seed and the metabolic environment is the soil, then insulin is the fertilizer. Every prior PI3K inhibitor program treated that fertilizer as a side effect to manage. None treated it as a resistance mechanism to solve. That distinction between managing the consequences of insulin feedback and preventing it altogether may be what every prior program missed.

The figure below (Figure 3) shows what high versus low systemic insulin means for the tumor environment.

Figure 3. The Soil and Seed Paradigm of Metabolic Oncology. Traditional cancer therapies focus primarily on eliminating tumor cells (the “seed”). The insulin-feedback hypothesis suggests that the systemic metabolic environment (the “soil”) also influences therapeutic response. Elevated insulin can promote tumor growth and survival through PI3K signaling, whereas reducing insulin-mediated signaling may create a less favorable environment for tumor progression. This framework underlies emerging strategies that combine pathway inhibition with metabolic intervention.

For years, this way of thinking remained largely confined to cancer metabolism researchers. The biology was compelling, but the evidence was fragmented and the commercial implications were unclear. What changed was not the underlying science, but it was the scale at which metabolism could be observed.

Why Investors Are Paying Attention Now

The widespread adoption of GLP-1 receptor agonists created an unprecedented natural experiment. For the first time, millions of individuals were receiving therapies designed to modify systemic metabolism, generating population-scale datasets that extended far beyond diabetes and obesity. Three studies published between October 2025 and June 2026 brought that evidence directly into oncology:

• First, the signal emerged in lung cancer. A study published in JCI Insight reported that GLP-1 receptor agonist use was associated with improved survival outcomes among overweight and obese patients with non-small cell lung cancer following surgical resection and during immunotherapy treatment. Preclinical experiments suggested that these effects might be mediated through changes in the immune tumor microenvironment rather than direct effects on cancer cells.
• Second, the signal extended to colorectal cancer. At the 2026 ASCO Gastrointestinal Cancers Symposium, a real-world analysis involving more than 281,656 individuals with obesity and type 2 diabetes found that patients receiving GLP-1 receptor agonists were 36% less likely to develop colorectal cancer compared with those receiving aspirin.
• Finally, the signal reached breast cancer. At the 2026 ASCO Annual Meeting, a retrospective analysis involving more than 110,000 women found that GLP-1 receptor agonist use was associated with a lower incidence of breast cancer across both unmatched and matched cohorts.

These findings are observational and do not establish causality. But the emergence of independent signals across lung, colorectal, and breast cancer — three separate tumor types, three separate research groups, within a twelve-month window — provides population-scale observations broadly consistent with a long-standing hypothesis in cancer metabolism. The specific mechanisms may differ by disease. But the pattern across three independent tumor types is consistent: a drug class developed for metabolic disease is generating measurable signals in oncology. That consistency moved the conversation forward. The question is no longer simply whether metabolism matters, but whether it can be deliberately controlled—and what therapies built around that premise might look like.

From Pathway Inhibition to Metabolic Control

If insulin-mediated feedback was contributing to resistance, the implications for drug development were profound. Improving PI3K inhibitors alone might not be enough. The challenge was no longer simply how to inhibit the pathway, but how to do so without triggering the physiological responses that undermined treatment. Rather than converging on a single solution, companies in this field started pursuing several distinct strategies (Figure 4):

Figure 4. Emerging approaches to PI3K pathway control. While all three programs aim to improve the therapeutic index of PI3K inhibition, they do so through fundamentally different strategies. RLY-2608 seeks greater molecular precision through mutant-selective inhibition, gedatolisib pursues broader pathway control through dual PI3K/mTOR inhibition, and PIKTOR incorporates metabolic intervention to address insulin-mediated feedback directly.

• One focused on greater selectivity. Programs such as Relay Therapeutics’ RLY-2608 were designed to more precisely target mutant PI3Kα while sparing normal tissues, reflecting the view that toxicity remained the primary barrier to unlocking the pathway’s potential.
• A second approach pursued deeper pathway suppression. Gedatolisib combines dual PI3K and mTOR inhibition with an intermittent dosing strategy intended to maintain anti-tumor activity while allowing metabolic recovery between treatment cycles. Preclinical studiesdemonstrated that this dual-node approach achieved more durable suppression of PI3K/AKT/mTOR signaling and greater anti-tumor activity than single-node inhibitors in breast cancer models. Positive Phase 3 results in HR+/HER2− breast cancer suggest that more comprehensive pathway control may improve outcomes in selected settings.
• A third approach focused on controlling the insulin feedback loop. Rather than asking only how to inhibit the pathway more effectively, it asked whether the physiological response to pathway inhibition could be managed directly. If insulin-mediated feedback was helping tumors evade therapy, then suppressing that feedback might itself become part of the treatment strategy. This hypothesis reframed metabolism from an unintended consequence of treatment into a therapeutic variable that could potentially be manipulated to improve outcomes. This question eventually became the foundation of PIKTOR.

PIKTOR: Building a Therapy Around Metabolism

PIKTOR was built around a simple premise: if insulin-mediated feedback contributes to resistance, then controlling that feedback may improve the effectiveness of PI3K pathway inhibition. Rather than viewing hyperglycemia and insulin rebound as unavoidable consequences of treatment, the program incorporates metabolic control directly into its therapeutic design. PIKTOR combines serabelisib, a PI3Kα inhibitor, with sapanisertib, an mTORC1/2 inhibitor, alongside a structured insulin-suppressing dietary intervention intended to minimize the compensatory metabolic response that follows pathway inhibition. This approach differs from previous generations of PI3K-directed therapies. Earlier programs focused primarily on the drug itself—improving selectivity, optimizing dosing schedules, or pursuing broader pathway suppression. PIKTOR instead treats the host response as part of the therapeutic problem. The objective is not simply to inhibit signaling within the tumor, but also to limit the systemic signals that may reactivate it.

Early clinical data from the Phase 1 study suggested that dual PI3K/mTOR inhibition could be delivered safely while demonstrating encouraging anti-tumor activity in heavily pretreated patients. Although these findings remain preliminary and require confirmation in larger studies, they provided an early signal that a treatment strategy informed by the biology of insulin feedback could be prospectively tested in patients. That hypothesis has now advanced into prospective evaluation through the GOG-3111 study in advanced and recurrent endometrial cancer. The remaining question was no longer whether the concept was biologically plausible, but whether it could generate meaningful clinical benefit in a setting where biology, unmet need, and commercial opportunity converged.

The Opportunity Landscape

The next question was where this strategy might matter most. Endometrial, breast, and ovarian cancers each combine compelling biology with meaningful unmet need, making them natural testing grounds for metabolic oncology approaches (Table 1).

                                      
Table 1. Strategic opportunity landscape for metabolic oncology approaches targeting PI3K-associated cancers. Endometrial cancer offers the most biologically compelling initial proving ground, breast cancer represents the largest validated commercial opportunity, and ovarian cancer provides a potential future expansion market.

• Endometrial Cancer: The First Proving Ground: Endometrial cancer represents the most immediate opportunity to test the metabolic oncology hypothesis. More than 80% of tumors harbor alterations in the PI3K pathway, while obesity and metabolic dysfunction are among the strongest risk factors for disease development. Despite this convergence of the pathway biology and systemic metabolism, no PI3K-directed therapy has yet achieved regulatory approval in the disease. Combined with a market projected to exceed $31 billion by 2035, the indication offers a rare combination of biological rationale, commercial scale, and an open competitive space.
• Breast Cancer: The Largest Validated Opportunity: Breast cancer presents a different opportunity. Here, the biology has already been clinically validated. Approvals of alpelisib and inavolisib established proof of concept that targeting PI3K can improve outcomes in solid tumors. Yet those approvals also highlighted the limitations of pathway inhibition alone, including resistance, hyperglycemia, and restricted patient eligibility. Because current therapies primarily address PIK3CA-mutated disease, a substantial portion of the market remains beyond the reach of existing PI3K-directed approaches. With the HR+/HER2-negative breast cancer market projected to exceed $30 billion in 2034, even incremental improvements in pathway inhibition could create significant value.
• Ovarian Cancer: Future Expansion Potential: Ovarian cancer represents a longer-term opportunity. PI3K pathway alterations are common, treatment options remain limited, and outcomes for recurrent disease continue to be poor. While the pathway is less clinically validated than in breast cancer, the combination of biological relevance and persistent unmet need makes ovarian cancer an attractive future setting for metabolic oncology approaches. The global ovarian cancer therapeutics market is projected to exceed $4 billion by 2031, providing additional expansion potential beyond the initial indications.

Viewed individually, these opportunities are meaningful. Viewed collectively, they suggest something larger. Endometrial cancer offers a biologically compelling proving ground. Breast cancer provides a validated commercial market. Ovarian cancer represents future expansion potential. The opportunity is not simply to develop another PI3K inhibitor. It is to determine whether controlling the metabolic environment can unlock clinical benefit—and therapeutic value—that previous generations of pathway-directed therapies were unable to achieve.That convergence of biology, unmet need, and commercial opportunity helps explain why investors have begun revisiting metabolic oncology—and why the Sensei–Faeth transaction attracted attention.

The Sensei–Faeth Deal: Financing the Next Test of Metabolic Oncology

By the time Sensei Biotherapeutics and Faeth Therapeutics announced their transaction in February 2026, two decades of PI3K drug development had transformed insulin-mediated feedback from an obscure biological observation into a clinically relevant explanation for why promising therapies sometimes failed. What the deal provided was something different: the capital to test whether those lessons could finally translate into better outcomes for patients.

The accompanying $200 million PIPE financing transformed metabolic oncology from a field supported primarily by academic research and private investment into a publicly traded investment thesis. Importantly, investors were not financing a purely theoretical construct. Faeth had already generated early clinical proof-of-concept data supporting the feasibility of combining pathway inhibition with metabolic intervention, while the larger studies needed to test the hypothesis required substantially greater capital than private financing alone could provide. The size and composition of the financing syndicate—including RA Capital Management, Cormorant Asset Management, Fairmount, Logos Capital, Vivo Capital, Balyasny Asset Management, Columbia Threadneedle, and others—suggested that institutional investors remained willing to fund oncology programs built around differentiated biological hypotheses despite the mixed history of PI3K-directed therapies.

The scientific pedigree behind Faeth is also notable. The company’s founding network includes Lewis Cantley, whose laboratory first identified PI3K as a key signaling enzyme in cancer biology, alongside leaders in cancer genetics and metabolism including Siddhartha Mukherjee, Karen Vousden, Scott Lowe, and the late Greg Hannon, whose work fundamentally shaped modern understanding of cancer genetics and RNA biology. Their involvement underscored that metabolic oncology was not a new idea, but rather the continuation of decades of research now reaching prospective clinical testing.

Viewed strategically, the transaction accomplished three things:

• First, it reset the pipeline hierarchy. PIKTOR moved from being the lead asset within a venture-backed private company to the central focus of a publicly traded oncology company.
• Second, it re-priced the risk. For decades, metabolic oncology had been supported by compelling biology but uneven clinical outcomes. The willingness of sophisticated healthcare investors to commit substantial capital suggested a growing belief that the field had learned enough from earlier generations of PI3K development to justify another test.
• Third, it consolidated ownership around a new thesis. For Sensei, the transaction represented a strategic reset rather than an incremental pipeline expansion. Prior to the PIPE financing, pre-transaction Sensei shareholders would have retained approximately 10.7% ownership of the combined company following the merger; after the financing, that stake fell to approximately 4.9%. The resulting ownership structure reflected the extent to which investors were underwriting a new therapeutic proposition. In practical terms, the future of the combined company became largely tied to a single question: can controlling the metabolic environment improve the effectiveness of pathway-directed cancer therapy? The timing was notable. The rise of GLP-1 receptor agonists had brought metabolism to the center of healthcare investing, while cancer researchers had spent years uncovering the role of insulin signaling in therapeutic resistance. Although these developments emerged from different disciplines, both pointed toward a common conclusion: systemic metabolism may influence disease outcomes more profoundly than previously appreciated.

In many ways, the Sensei–Faeth transaction represents the convergence of two stories that developed independently for years. One emerged from cancer researchers studying insulin signaling, nutrient sensing, and therapeutic resistance. The other emerged from the rapid rise of metabolic medicine in the GLP-1 era. The upcoming clinical studies will begin to determine whether those two stories are ultimately part of the same future for oncology.

Conclusion & Future Outlook

For much of the past three decades, oncology operated on a simple premise: find the mutation, drug the pathway, eliminate the tumor. The emerging lessons from PI3K development suggest that this framework may be incomplete. A complementary approach—modifying the metabolic environment in which tumors exist—could become an important component of therapeutic design.

If the answer is yes, the implications could extend far beyond PI3K. Therapies that trigger compensatory host responses may increasingly be paired with interventions designed to modify those responses. Clinical trials may incorporate metabolic variables alongside genomic ones, and dietary interventions may evolve from supportive measures into components of treatment itself.

The gedatolisib FDA decision on July 17 and the PIKTOR Phase 2 readout later this year will not resolve every question surrounding metabolic oncology. But they may provide the field’s first real indication of whether these ideas can translate into durable clinical benefit. For decades, cancer metabolism remained largely a scientific discipline. The next chapter will determine whether treating the seed and the soil as a single therapeutic problem can finally establish metabolic oncology as a therapeutic one.

Written By: Shruti Nagaraja (Postdoctoral Fellow in the Department of Oncology and Cancer Biology, University of Michigan Medical School)

Edited By:  Xingyu (Jasmine) Hu (PhD student in the Department of Biomedical Engineering, Boston University)