sapanisertib (CB-228)

Human and murine models resistant to combined belvarafenib and cobimetinib exhibited elevated levels of ATF4 and MTHFD2 and were sensitive to sapanisertib. This study provides promising treatment opportunities for patients with non-BRAF-mutant melanomas, or those who relapse following belvarafenib and cobimetinib combination therapy.

Ex vivo drug testing revealed a striking response: the mTOR inhibitor Sapanisertib induced extensive tumor necrosis and was associated with near-complete depletion of ALDH1A1+ and NTN4+ states, accompanied by strong stress/apoptosis signatures and reduced endothelial cells. In an additional retrospective cohort of 12 SDSC, ALDH1A1 was present in all cases with heterogeneous spatial patterns and higher levels in recurrences. Mesothelin was expressed in the index case and a subset of tumors, supporting mesothelin-directed therapeutic strategies.

P1/2, N=32, Recruiting, Faeth Therapeutics

We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers.

We previously generated an orthotopic, NF2-deficient meningioma model using the luciferase-expressing Ben-Men-1 cell line established from a sporadic tumor and identified the multi-kinase inhibitor brigatinib and the mTOR kinase inhibitor INK128 to potently impede tumor growth. As the first NF2-SWN-related meningioma cell line, AG-NF2-Men is a unique reagent for investigating meningioma biology and therapeutics. A clinical trial to evaluate the combination of brigatinib with an mTOR inhibitor in NF2-deficient meningiomas is warranted.

P2, N=17, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2025 --> Nov 2026

P1, N=22, Active, not recruiting, National Cancer Institute (NCI) | N=85 --> 22 | Trial completion date: Jun 2026 --> Nov 2026 | Trial primary completion date: Jun 2026 --> Nov 2025

Pharmaco-transcriptomic analysis revealed that IL3RA-high AML exhibited selective sensitivity to venetoclax and sapanisertib, suggesting potential synergistic opportunities. In conclusion, IL3RA overexpression defines a clinically and biologically distinct subgroup of AML, with unique therapeutic vulnerabilities. Continued research efforts are warranted to integrate CD123-directed therapies into the upfront AML treatment paradigm.

P1, N=50, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Oct 2026

Despite the advent of venetoclax-based regimens, resistance mechanisms remain a major clinical challenge, particularly in patients with high-risk mutations such as TP53, MUC4, HLA-B and FLT3. Here, we evaluate two rational combination therapies, LY3009120 (pan-RAF) plus sapanisertib (mTOR) (LS), and ruxolitinib (JAK1/2) plus ulixertinib (ERK) (RU), across ten AML cell lines and a zebrafish embryo xenograft model...Mutation response analyses and clustering highlighted TP53, MUC4, HLA-B and FLT3 as correlates of LS and RU sensitivity, supporting mutation-informed prioritization. Collectively, our results nominate LS and RU as promising candidates, particularly in AML with TP53, FLT3, HLA-B or MUC4 alterations, and motivate prospective validation in stratified AML cohorts.

Sapanisertib plus fulvestrant provided the greatest PFS benefit (HR 0.34, 95% CI 0.14-0.82) but had a high discontinuation rate (>15%). Among the approved therapies, ribociclib plus ET (HR 0.57, 95% CI 0.39-0.84), capivasertib plus fulvestrant (HR 0.62, 95% CI 0.51-0.75), and elacestrant (HR 0.70, 95% CI 0.55-0.89) demonstrated superior efficacy...Ipatasertib and alpelisib showed the greatest benefits in patients with PI3K/PTEN/AKT alterations. Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan and sacituzumab govitecan, outperformed standard chemotherapy, albeit with higher toxicity...Grant Assignment Decree No. 1369 adopted on 01.09.2023 by the Italian Ministry of University and Research (MUR).

P2, N=6452, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026