Multi-Node PI3K Inhibition for Cancer: Optimizing Efficacy and Safety While Broadening the Patient Population

Metabolism has always been a crucial pillar in cancer treatment, but clinical considerations have been limited to general diet and nutrition advice, minimizing the potential therapeutic impact of targeting relevant metabolic pathways. Groundbreaking research on the PI3K/AKT/mTOR signaling pathway has revealed that cancer has a sweet tooth: high glucose levels instigate the release of insulin, required by tumors to maintain their overactive metabolic processes.

Targeting cellular metabolism is complex due to the inherent importance of the same mechanisms in healthy cells as cancerous ones. But the PI3K/AKT/mTOR pathway is one of the most frequently dysregulated pathways in cancer, with mutations occurring in approximately 50% of solid tumors. Initial efforts to target the pathway have had modest efficacy, with single-node inhibition leading to approved products. Unfortunately, they have been accompanied by relatively high toxicity and emergence of multiple treatment resistance mechanisms.

Two alternative approaches to drugging the pathway have recently been gathering momentum in clinical development. Notably, these approaches adopt diverging strategies; one seeks to push single-node targeted therapy to a further, exquisite level of selectivity, by only targeting the mutant form of proteins. But the other seeks to leverage targeted specificity with broader effects, hitting multiple pathway nodes simultaneously. The aim is greater pathway inhibition while side-stepping resistance mechanisms, thereby developing therapies with the potential to treat a larger patient population.  

The case for multi-node inhibition

The leading mutant-specific, single-node approaches target mutated forms of PI3Kα, a common upstream oncogenic mutation in the PI3K/AKT/mTOR pathway across solid tumors. There are three main contenders in clinical development, the most mature of which is Relay Therapeutics’s zovegalisib (RLY-2608), which is nearing a Phase 3 trial. But the competition is fierce: earlier this year, Eli Lilly acquired STX-478 from Scorpion Therapeutics for $2.5 billion, and OnKure recently raised significant capital to advance OKI-219, currently in Phase 1.

The critical challenge with single-node inhibitors is that the PI3K pathway is highly adaptable and interconnected, with numerous feedback loops and alternative routes of activation. Blocking just one node often leads to rapid reactivation of the pathway through compensatory mechanisms. For example, alternative kinases can reactivate the pathway, and mutations in other pathway members like PTEN or AKT activate signaling downstream of PI3K.

A different approach, now in Phase 2 and Phase 3 trials, is multi-node inhibition. Celcuity recently shared topline data in the VICTORIA-1 trial for its intravenous multi-node inhibitor, gedatolisib. Multi-node approaches like this target upstream and downstream PI3K pathway proteins simultaneously, typically inhibiting PI3K and mTOR (mTORC1 and mTORC2 complexes), and aim to overcome the resistance mechanisms common to single-node inhibitors.

An important question in the multi-node field is exactly how broad the target set should be. Gedatolisib is a pan-PI3K, pan-mTOR inhibitor. That means in addition to wild-type and mutant forms of PI3Kα and mTOR, gedatolisib inhibits PI3Kβ, γ, and δ. The latter two in particular play critical roles in immune cells. Given the potential utility of combining PI3K inhibition with immunotherapy, immunosuppressive effects may be detrimental for treating certain cancers, and risk additional side effects.

Optimised multi-node inhibition

A novel multi-node approach is combining selective inhibitors of PI3Kα, mTORC1 and mTORC2, and simultaneously reducing overall pathway activity by decreasing insulin binding to PI3K, which initiates the pathway cascade. A recent British Journal of Cancer publication demonstrated preclinical evidence supporting this rationale, now in Phase 2 clinical testing itself. Robust therapeutic target engagement of the triad – and adding in a precision nutrition component that reduces insulin resistance – translates to superior anti-tumor efficacy in xenograft models, inducing deeper, more durable responses. This approach comprehensively shuts down pathway signaling and prevents the tumor from escaping through feedback reactivation.

Importantly, this enhanced efficacy is achieved with a manageable toxicity profile, such as lower rates of hyperglycemia compared with single-node inhibitors. Hitting multiple nodes achieves a greater degree of pathway suppression at lower drug exposures, potentially improving the therapeutic index. Landing in this “Goldilocks zone” could prove to be a key differentiator, applicable to many forms of PI3K pathway mutation, not just a select few.

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