^
    3d
    mTOR inhibition enhances the antitumor efficacy of pan-RAF-MEK blockade by inhibiting the ATF4-MTHFD2 pathway. (PubMed, Cell Death Dis)
    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.
    Journal
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • ATF4 (Activating Transcription Factor 4) • MTHFD2 (Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2)
    |
    BRAF mutation
    |
    Cotellic (cobimetinib) • sapanisertib (CB-228) • belvarafenib (RG6185)
    7d
    Spatially resolved ex vivo drug response profiling in SMARCB1-deficient sinonasal carcinoma. (PubMed, EMBO Mol Med)
    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.
    Preclinical • Journal
    |
    MSLN (Mesothelin) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • ALDH1A1 (Aldehyde Dehydrogenase 1 Family Member A1) • TP63 (Tumor protein 63)
    |
    sapanisertib (CB-228)
    9d
    Sapanisertib and Serabelisib (PIKTOR) in Various Combinations in Patients With HR+/HER2- Advanced/Metastatic Breast Cancer (clinicaltrials.gov)
    P1/2, N=32, Recruiting, Faeth Therapeutics
    New P1/2 trial
    |
    HER-2 (Human epidermal growth factor receptor 2)
    |
    HER-2 negative
    |
    fulvestrant • sapanisertib (CB-228) • serabelisib (MLN1117)
    19d
    RMC-5552 Monotherapy in Adult Subjects With Recurrent Glioblastoma (clinicaltrials.gov)
    P1, N=7, Terminated, Nicholas Butowski | N=48 --> 7 | Trial completion date: Apr 2030 --> Dec 2025 | Recruiting --> Terminated | Trial primary completion date: Apr 2030 --> Dec 2025; Drug no longer provided by sponsor
    Enrollment change • Trial completion date • Trial termination • Trial primary completion date
    |
    EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)
    |
    RMC-5552
    2ms
    SARC046: A Phase II Trial of Nab-Sirolimus in Patients With Progressing or Symptomatic Epithelioid Hemangioendothelioma (clinicaltrials.gov)
    P2, N=41, Recruiting, Sarcoma Alliance for Research through Collaboration | Not yet recruiting --> Recruiting
    Enrollment open
    |
    Fyarro (nanoparticle albumin-bound rapamycin)
    2ms
    A Phase I Trial of Combination Gemcitabine and Nab-Sirolimus in Advanced Leiomyosarcomas or Advanced Soft-Tissue Sarcomas With TSC2 or TSC1 Loss-of-function Mutations or Deletions (clinicaltrials.gov)
    P1, N=18, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting
    Enrollment open
    |
    TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)
    |
    gemcitabine • Fyarro (nanoparticle albumin-bound rapamycin)
    3ms
    Coexistent PTEN and PIK3CA alterations hyperactivate mTORC1 signaling in endometrial cancers and cause their selective sensitivity to mTORC1 inhibition. (PubMed, bioRxiv)
    These findings are consistent with a phase I trial of bi-steric mTORC1 inhibitor RMC-5552, showing anti-tumor activity in patients with EC. PDXs with KRAS co-mutations regrew after RMC-6272 treatment, which was prevented by the addition of the RAS(ON) multi-selective inhibitor RMC-7977...Single mutant tumors are sensitive to PI3K inhibition but those with both mutations are insensitive to PI3K or AKT inhibition but are exquisitely dependent on mTORC1 kinase. This provides strong preclinical rationale for targeting mTORC1, alone or combined with RAS inhibition (in RAS co-mutant tumors), as an effective therapeutic strategy.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog)
    |
    KRAS mutation • PIK3CA mutation • RAS mutation
    |
    RMC-7977 • RMC-5552
    3ms
    A Phase I Trial of Combination Gemcitabine and Nab-Sirolimus in Advanced Leiomyosarcomas or Advanced Soft-Tissue Sarcomas With TSC2 or TSC1 Loss-of-function Mutations or Deletions (clinicaltrials.gov)
    P1, N=18, Active, not recruiting, M.D. Anderson Cancer Center | N=12 --> 18
    Enrollment change
    |
    TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)
    |
    gemcitabine • Fyarro (nanoparticle albumin-bound rapamycin)
    4ms
    mTORC1/2 Inhibitor AZD2014 or the Oral AKT Inhibitor AZD5363 for Recurrent Endometrial and Ovarian (clinicaltrials.gov)
    P1, N=159, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Dec 2025 --> Jun 2026
    Trial completion date • Trial primary completion date
    |
    ER (Estrogen receptor) • PGR (Progesterone receptor) • BRCA (Breast cancer early onset) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    BRCA mutation
    |
    Lynparza (olaparib) • Truqap (capivasertib) • vistusertib (AZD2014)
    5ms
    Combining brigatinib with mTOR inhibition to effectively treat NF2-SWN-associated and sporadic NF2-deficient meningiomas. (PubMed, Cancer Res Commun)
    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.
    Journal
    |
    EGFR (Epidermal growth factor receptor) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NF2 (Neurofibromin 2)
    |
    Alunbrig (brigatinib) • sapanisertib (CB-228)
    5ms
    EVERLAST: Everolimus Aging Study (clinicaltrials.gov)
    P2, N=106, Active, not recruiting, University of Wisconsin, Madison | Recruiting --> Active, not recruiting | Trial completion date: Dec 2026 --> Sep 2026 | Trial primary completion date: Dec 2025 --> Sep 2026
    Enrollment closed • Trial completion date • Trial primary completion date
    |
    everolimus
    5ms
    Sapanisertib in Treating Patients With Locally Advanced or Metastatic Bladder Cancer With TSC1 and/or TSC2 Mutations (clinicaltrials.gov)
    P2, N=17, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2025 --> Nov 2026
    Trial completion date
    |
    TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)
    |
    sapanisertib (CB-228)