Deciparticle Everolimus: Reviving mTOR Inhibition for Neuroendocrine Prostate Cancer?

Sapu-003, a nanoparticle-formulated version of everolimus delivered via a new platform (Deciparticle) has received approval for first-in-human Phase 1 testing in breast cancer patients, representing a major advance in intravenous oncology drug delivery. Unlike the standard oral everolimus tablet, which achieves only 10-20% bioavailability due to extensive first-pass metabolism and gastrointestinal degradation, the Deciparticle platform creates stable sub-20 nm nanoparticles that enable near-complete (80-100%) systemic absorption when administered intravenously. Recent pharmacokinetic studies demonstrate that this formulation reduces gastrointestinal drug accumulation by over 60% compared to oral dosing while maintaining prolonged circulation and enhanced tumor penetration in preclinical models. The upcoming Phase 1 trial will establish safety, tolerability, and optimal dosing in humans, with initial data expected later in 2026.

Why is this relevant to prostate cancer?

Everolimus works by selectively inhibiting mTORC1, a key kinase in the PI3K/AKT/mTOR pathway that cancer cells exploit to drive uncontrolled growth, protein synthesis, lipid metabolism, and resistance to apoptosis. In prostate cancer, mTOR signaling becomes hyperactive as tumors adapt to androgen deprivation therapy, particularly through PTEN loss (seen in up to 40-50% of cases) and cross-talk with the androgen receptor axis. This pathway fuels the metabolic reprogramming and survival signals that enable castration-resistant progression, making sustained mTOR blockade a logical but historically underachieved target. Oral everolimus has shown modest single-agent activity in clinical trials due to inconsistent drug levels, but the Deciparticle platform’s ability to deliver full therapeutic doses predictably could finally realize mTOR inhibition’s potential in advanced disease.

This development carries great promise for neuroendocrine prostate cancer (NEPC), an aggressive subtype that emerges in some men after prolonged exposure to potent AR pathway inhibitors like enzalutamide or abiraterone. NEPC represents an AR-independent escape mechanism where tumors dedifferentiate into small cell-like carcinomas, losing androgen receptor expression and becoming refractory to hormonal therapies while retaining dependency on alternative survival pathways, including mTOR. These cancers spread rapidly, respond poorly to platinum-based chemotherapy and express elevated neuroendocrine markers like neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP).

Retrospective clinical data from two independent series, one with 7 patients and another with 11, provide compelling proof-of-concept for everolimus in pathologically confirmed NEPC. In these heavily pretreated patients, oral everolimus (10 mg daily) produced biochemical responses in 70-75% of cases, with median NSE reductions of 67% and pro-GRP drops of 65%. The larger cohort achieved 24-month progression-free and overall survival rates of 57%, dramatically outperforming historical chemotherapy benchmarks and suggesting that mTOR inhibition can suppress neuroendocrine tumor biology even without AR targeting. Responses were not universal, likely limited by oral bioavailability variability, but the consistency across small datasets underscores a real signal.

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