Torisel (temsirolimus)

P1, N=87, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2026

In this study, we conducted screens across different cancer cell lines and FDA-approved drugs, leading to the identification of temsirolimus in combination with the GPX4 inhibitor RSL3 as a potent inducer of ferroptosis in liver cancer cells. This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis. In conclusion, our findings underscore the potential of combining multi-target ferroptosis-inducing agents to circumvent resistance to ferroptosis in liver cancer cells and highlight temsirolimus as a promising FSP1 inhibitor and ferroptosis inducer, which also deserves further investigation in translational medicine.

P2, N=3791, Recruiting, American Society of Clinical Oncology | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Jun 2026

Taken together, there is a great potential for HOXC6 to become a prognosis biomarker and contribute to develop treatment strategies for LUAD patients. Further mechanism exploration and drug development for HOXC6 are needed.

Despite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker-directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2-mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi-responders, and describe distinct transcriptional characteristics and co-occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL.

CPNE1 could be a predictive biomarker and a potential target for biological therapy in STAD.

Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.

P1, N=249, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2025 --> Aug 2026 | Trial primary completion date: Aug 2025 --> Aug 2026

For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation...Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins...Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins within the RAS upstream and downstream signaling pathways in cancer.

For commonly used targeted drugs in RCC, including axitinib, pazopanib, temsirolimus, and sunitinib, LRG had lower IC50 values, indicating increased sensitivity. In summary, these data confirmed that tumor-infiltrating M0 cells play a key role in the prognosis and treatment of patients with ccRCC. This discovery offers new insights and directions for the prognostic prediction and treatment of ccRCC.

P1, N=12, Recruiting, Nader Sanai | Trial completion date: Apr 2025 --> Apr 2026 | Trial primary completion date: Apr 2024 --> Apr 2025

This study has important implications for the metabolic requirements of innate immune cells during bacterial infection as well as the clinical use of mTOR inhibitors.IMPORTANCESirolimus, everolimus, temsirolimus, and similar are a class of pharmaceutics commonly used in the clinical treatment of cancer and the anti-rejection of transplanted organs. Specifically, we observed that mTOR activity is required for phagocytes to produce antimicrobial free radicals. These results have important implications for immune responses during clinical treatments and in disease states where mTOR is suppressed.

P1, N=278, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2024 --> Apr 2026 | Trial primary completion date: Apr 2024 --> Apr 2026

P1, N=155, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Mar 2024 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Mar 2026

Two clusters of ccRCC were identified using the "ConsensusClusterPlus" package, cluster 1 exhibited a worse survival rate and was resistant to chemotherapeutic drugs of Axitinib, Erlotinib, Pazopanib, Sunitinib, and Temsirolimus, but not Sorafenib. In conclusion, our study offers valuable insights into the molecular mechanisms underlying ccRCC, identifying potential prognostic genes and molecular subtypes associated with the G2M checkpoint. These findings hold promise for guiding personalized treatment strategies in the management of ccRCC.

When the tumors have metastasized, systemic therapy with protein-tyrosine kinase antagonists including sorafenib, sunitinib, pazopanib, and tivozanib that target vascular endothelial, platelet-derived, fibroblast, hepatocyte, and stem cell factor growth factor receptors (VEGFR, PDGFR, FGFR, MET, and Kit) were prescribed after 2005. The monoclonal antibody immune checkpoint inhibitor nivolumab (targeting PD1) was approved for the treatment of RCCs in 2015. It is usually used now in combination with ipilimumab (targeting CTLA-4) or cabozantinib (a multikinase blocker). Other combination therapies include pembrolizumab (targeting programed cell death protein 1) and axitinib (a VEGFR and PDGFR blocker) or lenvatinib (a multikinase inhibitor). Since the KEYNOTE-426 clinical trial, the use of immune checkpoint inhibitors in combination with protein-tyrosine kinase inhibitors is now the standard of care for most patients with metastatic renal cell carcinomas and monotherapies are used only in those individuals who cannot receive or tolerate immune checkpoint inhibitors.

P3, N=236, Active, not recruiting, National Cancer Institute (NCI)

P2, N=349, Active, not recruiting, National Cancer Institute (NCI)

P1, N=22, Active, not recruiting, National Cancer Institute (NCI)

P1, N=20, Not yet recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=14, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

P2, N=137, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Jan 2024 --> Dec 2024

The disease progressed despite palliative radiation, lenvatinib, and nivolumab/ipilimumab therapy. However, no clear association between the efficacy of mTOR inhibitors and specific histologies or genetic mutations has been established. Future studies are warranted to elucidate these associations.

P1, N=18, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

These preclinical findings highlight the promise of marinopyrrole MP1 as a novel MYC inhibition approach for MYC-amplified MB.

Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis)...The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.

Besides, compared to the low-risk group, there were higher expressions of most immune checkpoint genes and HLA genes in the high-risk group, and the high-risk patients showed higher sensitivity to the chemotherapy and targeted drugs (axitinib, dasatinib, pazopanib, saracatinib, sunitinib and temsirolimus). The novel CRG signature may act as a reliable, efficient tool for prognostic prediction and treatment guidance in future clinical practice.

P1, N=140, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

Based on the m6A/m5C/m1A-related genes in LUAD, LUAD patients were divided into 2 subtypes, and a m6A/m5C/m1A-related LUAD prognostic model was constructed to provide a reference for the prognosis prediction of LUAD.

P1, N=249, Active, not recruiting, M.D. Anderson Cancer Center | Unknown status --> Active, not recruiting | Trial completion date: May 2021 --> Aug 2025 | Trial primary completion date: May 2020 --> Aug 2025

Finally, the combinational treatment of temsirolimus and bazedoxifene synergistically suppressed osteosarcoma development in vitro and in vivo. Our findings suggest that bazedoxifene directly prompts the deactivation of GP130 and inhibits the osteosarcoma progression in vitro and in vivo. Therefore, bazedoxifene could be effectively applied as a therapeutic drug for human osteosarcoma in the future.

Temsirolimus exhibited potent immunosuppressive effects, emerging as a strong candidate to mitigate organ transplant rejection.

Interestingly, pacritinib exhibited synergistic effects when combined with temsirolimus and sunitinib, but antagonistic effects when combined with doxorubicin, in a panel of RCC cell lines. Mechanistic studies indicated that the inhibition of JAK2, but not IRAK, was the main contributor to the anti-RCC activity of pacritinib. Our study is the first to demonstrate that pacritinib shows promise as a treatment option for RCC and underscores the therapeutic potential of targeting the JAK2/STAT signalling pathway in RCC.

Furthermore, we demonstrated that temsirolimus-induced neutrophil transendothelial migration was mediated by platelet endothelial cell adhesion molecule-1 (PECAM-1) in both in vitro and in vivo experiments. Collectively, these findings highlight that temsirolimus induces endothelial barrier dysfunction via PECAM-1-dependent pathway both in vitro and in vivo, ultimately leading to neutrophil infiltration and subsequent pulmonary injury.

P2, N=137, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Sep 2023 --> Jan 2024

In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration...For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7RALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3KALT)...Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%)...A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL.

P3, N=321, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2024 --> Jun 2023

Single cell RNA sequencing analysis demonstrated a strong shift in global gene expression with upregulation of mTOR signaling in resistant MCL PDX samples. Targeted blockade of mTORC1 with temsirolimus overcame the PRMT5 inhibitor resistant phenotype, displayed therapeutic synergy in resistant MCL cell lines, and improved survival of a resistant PDX.

P1/2, N=228, Completed, University Hospital Heidelberg | Recruiting --> Completed | N=350 --> 228 | Trial completion date: Sep 2024 --> Feb 2023 | Trial primary completion date: Sep 2023 --> Feb 2023

The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue 1 (Akt)/mammalian target of the rapamycin (mTOR) signaling pathway plays a critical role in a variety of cellular processes, such as cell proliferation and survival. This review is mainly focused on the PI3K/v-akt/mTOR pathway-related oncogenic mechanisms in B cell NHLs with an emphasis on common B cell lymphoma types [diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)]. Furthermore, it summarizes the literature regarding the clinical applications of the mTOR inhibitors temsirolimus and everolimus in B cell NHLs, which have been tested in a range of clinical trials enrolling patients with B cell malignancies, either as monotherapy or in combination with other agents or regimens.