everolimus

In the NEN cell lines BON-1, QGP-1, and MS-18, we applied cisplatin, etoposide, streptozotocin, 5-fluorouracil, temozolomide, and everolimus- all systemic agents used in highly proliferative NEN. These findings might have an impact on the optimal therapy sequence and patient selection for future CXCR4-targeted approaches. Further, the decreased CXCR4 expression could represent a new mechanism of action of the established drugs Cisplatin, Temozolomide, and Everolimus.

Despite extensive prior treatment, patients experienced clinical benefit from TT, particularly VEGFR-TKIs, after progression on belzutifan. These findings support the feasibility of sequencing TT following belzutifan-based regimens in advanced ccRCC, and highlight the need to further define optimal therapeutic sequencing strategies.

Our findings suggest efficacy of PI3K inhibition + tamoxifen beyond second-line treatment and after prior targeted therapies, including CDK4/6 inhibition in metastatic HR+/HER2- breast cancer although the magnitude of benefit did not outweigh the tolerability of this combination. Exploratory biomarker analysis indicates that tumor fraction determined in ctDNA differentiates patients based on prognosis and may help to optimize patient selection for targeted treatment strategies.

Isogenic PDX models of TNBC provide a powerful platform to define molecular mechanisms of acquired carboplatin resistance and uncover actionable therapeutic strategies. Our findings reveal multiple adaptive routes to platinum resistance, including restoration of homologous recombination and activation of alternative DNA repair programs. Synergistic interactions between SG and mTOR inhibition offer a promising avenue for overcoming resistance, supporting further clinical investigation of these combinations in TNBC.

P2, N=180, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2026 --> Jan 2028 | Trial primary completion date: Jan 2026 --> Jan 2028

Targeting mTOR signaling contributes to the regulation of Galectin-1 immune checkpoint activity in KMT2Ar-ALL. Inhibition of mTOR may represent a potential therapeutic strategy to overcome immune evasion in this leukemia subtype.

SRT-1720 induces oxidative stress and apoptosis in leukemic lymphocytes through SIRT1-independent pathway(s). In contrast, it enhances antioxidant defense in normal lymphocytes through a SIRT1-dependent pathway. These findings highlight the potential of SRT-1720 as an adjuvant to chemotherapy in T-ALL, particularly in drug combinations demonstrating strong synergism, which may allow dose reduction and decreased toxicity.

P1, N=104, Completed, Royal Marsden NHS Foundation Trust | Active, not recruiting --> Completed | Trial completion date: Jun 2025 --> Oct 2025 | Trial primary completion date: Jun 2025 --> Oct 2025

P1, N=396, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2026 --> Jun 2027

The individualized regimen comprised trametinib and everolimus for dual pathway inhibition, the tissue-agnostic agent dordaviprone (ONC201), metabolic modulation with 2-deoxy-D-glucose, and electric field-based therapy. The systematic integration of comprehensive molecular profiling with mechanistically rational treatment selection may contribute to meaningful radiological and clinical benefit in this otherwise uniformly fatal disease. These observations support further investigation of individualized, pathway-targeted approaches in prospective studies and N-of-1 trial frameworks.

P1, N=27, Recruiting, SAPU NANO (US) LLC

P4, N=336, Enrolling by invitation, Baylor Research Institute | Trial completion date: Jun 2024 --> Mar 2027 | Trial primary completion date: Jun 2024 --> Mar 2027 | Active, not recruiting --> Enrolling by invitation