Taltorvic (ridaforolimus) / Takeda, Merck (MSD) - LARVOL DELTA

IGF/PI3K–mTOR axis and PRRX1-driven stemness cooperate to promote chemoresistance in CIC-DUX4 sarcoma (Sarcoma-RC 2026) - "PRRX1 knockdown reduced proliferation and increased doxorubicin sensitivity, whereas PRRX1 overexpression induced resistance in vitro and expanded the tumor-initiating cell population with a ∼7-fold increase in stem cell frequency by in vivo limiting-dilution analysis...Combined IGF blockade (Xentuzumab) and mTOR inhibition (Ridaforolimus) significantly suppressed growth of chemotherapy-experienced tumors...Legal entity responsible for the study McGill University. Funding Terry Fox Foundation."

Ewing Sarcoma • Sarcoma • Solid Tumor • DUX4 • IGF1 • IGF2 • KLF4 • PRRX1 • SOX2

PMEPA1 promotes mTOR inhibitor resistance in triple-negative breast cancer: Targeting the TGF-β/PMEPA1 axis as a therapeutic strategy to overcome resistance. (PubMed, Biochem Pharmacol) - "To model acquired resistance, we established two mTORi-resistant TNBC cell lines, MDA-MB-231/DREVE and MDA-MB-231/DRRIDA through chronic exposure to everolimus and ridaforolimus, respectively...Pharmacological inhibition of upstream TGF-β signaling with galunisertib suppressed PMEPA1 and synergistically restored sensitivity to mTORi in both invitro and xenograft models, resulting insignificant tumor regression...Collectively, these findings establish PMEPA1 as a dual modulator of canonical and non-canonical TGF-β signaling and a critical mediator of mTORi resistance in TNBC. Targeting the TGF-β/PMEPA1 axis represents a promising strategy to overcome resistance and improve clinical outcomes in mTORi-refractory TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • KRAS • PMEPA1 • PTEN • TGFB1

Maintenance therapy-a potential strategy to prolong the survival of advanced soft tissue sarcoma patients. (PubMed, Ther Adv Med Oncol) - "The LMS-04 trial demonstrated improved outcomes with doxorubicin plus trabectedin induction followed by trabectedin maintenance in leiomyosarcoma patients...Switch maintenance strategies, such as ridaforolimus and regorafenib, have limitations in efficacy and tolerability, preventing their widespread adoption. Pegylated liposomal doxorubicin (PLD), a liposome-encapsulated formulation of doxorubicin, offers a potential continuation maintenance option. With a similar mechanism of action to free-form anthracycline but reduced cumulative cardiac toxicity, PLD may be both effective and better tolerated in STS patients who have derived benefit from anthracycline-based chemotherapy. A clinical trial investigating continuation maintenance PLD in this patient population is warranted."

Journal • Review • Cardiovascular • Leiomyosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Targeting mTOR Kinase for Cancer Treatment: A Comprehensive Review With Clinical Insights. (PubMed, Drug Dev Res) - "Key mTOR inhibitors, including rapalogs (e.g., sirolimus, everolimus) and ATP-competitive inhibitors (e.g., MLN0128, PP242), are discussed in detail, along with their clinical applications and limitations. Additionally, we summarize the findings from major clinical trials, including FDA-approved mTOR inhibitors like everolimus and temsirolimus, and non-FDA-approved inhibitors such as sapanisertib and ridaforolimus. The review underscores the importance of understanding mTOR signaling and its role in cancer progression, offering insights into the future of mTOR-targeted therapies in oncology."

Journal • Review • Genito-urinary Cancer • Hematological Malignancies • Multiple Myeloma • Oncology • Renal Cell Carcinoma • Solid Tumor

Transcriptomic analysis reveals Streptococcus agalactiae activation of oncogenic pathways in cervical adenocarcinoma. (PubMed, Oncol Lett) - "In general, the MAPK and mTORC1 signaling pathways were identified as the main pathways associated with GBS and AC cells. The combination of binimetinib and ridaforolimus could be a potential AC treatment."

Journal • Cervical Cancer • Gynecology • Infectious Disease • Oncology • Solid Tumor

Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation. (PubMed, Biochem J) - "We identified 13 compounds - ABT-578, AR-A014418, AZD1480, AZD5363, Idelalisib,  Ipatasertib, LJ1308, PHA-793887, Rapamycin, Ridaforolimus, SMI-4a,  Temsirolimus and Tideglusib - each of which inhibits mTOR signalling or regulators thereof, and blocked constitutive cell death executed by R30E MLKL. Our study implicates mTOR signalling as an auxiliary factor in promoting transport of activated MLKL oligomers to the plasma membrane, where they accumulate into hotspots that permeabilise the lipid bilayer to cause cell death."

IO biomarker • Journal

Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review. (PubMed, Front Pharmacol) - "Rapamycin, an established mTOR inhibitor in clinical practice, is widely recognized for its therapeutic efficacy...These trials employed diverse drug combinations, incorporating agents such as ponatinib, bicalutamide, dalotuzumab, MK-2206, MK-0752, and taxanes...Our review encompassed analyses of signaling pathways, ridaforolimus as a single therapeutic agent, its compatibility in combination with other drugs, and an assessment of adverse events (AEs). We conclude by recommending further research to advance our understanding of ridaforolimus's clinical applications."

Journal • Review • Breast Cancer • Endometrial Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor

Gene signatures to therapeutics: Assessing the potential of ivermectin against t(4;14) multiple myeloma. (PubMed, World J Clin Oncol) - "Collectively, the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14) MM diagnosis and treatment, with ivermectin emerging as a potential therapeutic alternative."

Gene Signature • Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Hematological Malignancies • Metabolic Disorders • Multiple Myeloma • Oncology • CCL3 • CCR2 • CD48 • CXCL12 • NCAM1 • PTPRC • VCAM1

Dual inhibition of FGFR4 and HER2/EGFR with Lapatinib improves targeting of Erk and Akt signaling in HER2+ breast cancer cells (SABCS 2023) - "Ridaforolimus (mTOR inhibitor) was used in combination with either BLU554 or Lapatinib to assess MAPK/ERK and PI3K/AKT pathway crosstalk in MB-453 cells. Dual treatment simultaneously blocks MAPK/ERK and PI3K/AKT signaling and yields decreases of mTOR downstream effectors pS6RP and p4EBP1. These effects are maintained even when challenged with FGF19, suggesting that dual inhibition of FGFR4 and HER2 could prevent pathway activation from external stimuli."

Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EGFR • EIF4EBP1 • FGF19 • FGFR4 • HER-2

Three Layers of Personalized Medicine in the Use of Sirolimus and Its Derivatives for the Treatment of Cancer. (PubMed, J Pers Med) - "A review of the current literature was conducted to identify enzymes involved in the metabolism of Sirolimus, Everolimus, Ridaforolimus, and Temsirolimus along with characteristics of tumors that predict the efficacy of these agents. Current evidence suggests that tumors with mutations in the mTOR signal transduction pathway are sensitive to rapalogue treatment; the rapalogues are metabolized by cytochromes such as CYP3A4, CYP3A5, and CYP2C8 and transported by ABC transporters that are known to vary in activity in individuals; and that tumors can express these transporters and detoxifying enzymes. This results in three levels of genetic analysis that could impact the effectiveness of the mTOR inhibitors."

Journal • Review • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CYP3A4 • CYP3A5

The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches. (PubMed, Curr Mol Med) - "Although mTOR inhibitors rapamycin and rapamycin rapalogs (everolimus, rapamycin, temsirolimus, deforolimus, etc.) and new generation mTOR inhibitors (Rapalink, Dual PI3K/mTOR inhibitors, etc.) are used in cancer treatments, mTOR resistance mechanisms may inhibit the efficacy of these drugs. Since mTOR resistance mechanisms prevent the effects of mTOR inhibitors used in cancer treatments, new inhibition strategies should be developed. Inhibition approaches are created using nanoparticles, and one of them offers a promising treatment option with evidence supporting its effectiveness."

Journal • Oncology

Targeting NFE2L2 Mutations in Advanced Squamous Cell Lung Cancers with the TORC1/2 Inhibitor TAK-228 (IASLC-WCLC 2018) - P2; "Method Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells harboring an NFE2L2 E79K mutation treated with TAK-228, everolimus, rapamycin, or deforolimus with requisite vehicle controls. The trial has met its first-stage endpoint and has expanded to N=10 patients. The trial has also expanded to included patients with KRAS mutant lung cancers harboring co-alterations in NFE2L2 or KEAP1. "

Non Small Cell Lung Cancer

Why is rapamycin not a rapalog? (PubMed, Gerontology) - "Rapamycin and its analogs (everolimus, temsirolimus, ridaforolimus) inhibit the mammalian target of rapamycin (mTOR) kinase by binding to FK506-binding proteins (FKBP) and have a similar chemical structure that only differs in the functional group present at carbon-40. Analogs of rapamycin were developed to improve its pharmacological properties, such as low oral bioavailability and a long half-life. The analogs of rapamycin are referred to as 'rapalogs.' Rapamycin is the parent compound and should there with not be called a 'rapalog.'"

Journal • FKBP5

Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2. (PubMed, J Clin Invest) - "Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved as mTOR inhibitors for the treatment of human diseases, including cancer and autoimmunity. In rodent models of infection, injection of rapamycin prior to and after virus exposure resulted in elevated SARS-CoV-2 replication and exacerbated viral disease, while ridaforolimus had milder effects. Overall, our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating lysosome-mediated suppression of intrinsic immunity."

Journal • Immunology • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • TFEB

CDH6 as a prognostic indicator and marker for chemotherapy in gliomas. (PubMed, Front Genet) - "Potential drugs associated with high CDH6 expression were also predicted, including AMG-22, rutin, CCT128930, deforolimus, bis(maltolato)oxovanadium, anagrelide, vemurafenib, CHIR-98014, and AZD5582. Thus, this study showed that CDH6 correlates with glioma immune infiltration, it is expressed mainly in AC-like malignant cells, and it may act as a new target for glioma therapy."

Biomarker • Journal • Brain Cancer • CNS Tumor • Glioma • Infectious Disease • Oncology • Solid Tumor • CD8

Select Rapamycin Analogs Promote VSV-G-Mediated Cell Entry by Activating TFEB-Dependent Microautophagy (ASGCT 2022) - "Rapamycin and its analogs everolimus and temsirolimus, but not ridaforolimus, activate the nuclear translocation of transcription factor EB (TFEB) and trigger the induction of an endosomal remodeling pathway known as microautophagy. Our findings suggest that they act at the level of cell-intrinsic immunity to undermine the cell's first line of antiviral defenses. The development of rapamycin analogs that lack this activity may reduce unintended immunosuppression in human subjects."

Infectious Disease • TFEB

Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew (Cryptotis parva). (PubMed, Front Pharmacol) - "With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block the activity of one of the two mammalian targets of rapamycin (mTOR) complexes, mTORC1...We then determined the broad-spectrum antiemetic potential of a 20 mg/kg (i.p.) dose of temsirolimus against diverse emetogens, including selective and nonselective agonists of 1) dopaminergic D receptors (apomorphine and quinpirole); 2) serotonergic 5-HT receptors [5-HT (serotonin) and 2-methyl-5-HT]; 3) cholinergic M receptors (pilocarpine and McN-A-343); 4) substance P neurokinin NK receptors (GR73632); 5) the L-type calcium (Ca) channel (LTCC) (FPL64176); 6) the sarcoplasmic endoplasmic reticulum Ca ATPase inhibitor, thapsigargin; 7) the CB receptor inverse agonist/antagonist, SR141716A; and 8) the chemotherapeutic cisplatin...The mechanisms underlying the pro- and antiemetic effects of temsirolimus evaluated by immunochemistry for c-fos expression demonstrated a..."

Journal • Oncology • FOS

RAPALOGS DOWNMODULATE INTRINSIC IMMUNITY AND PROMOTE CELL ENTRY OF SARS-CoV-2 (CROI 2022) - "Rapamycin and rapamycin analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved for use as mTOR inhibitors in multiple clinical settings, including cancer and autoimmunity, but a common side effect of these drugs is immunosuppression and increased susceptibility to infection. In the hamster model of SARS-CoV-2 infection, injection of rapamycin four hours prior to virus exposure resulted in elevated virus titers in lungs, accelerated weight loss, and decreased survival. Our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating a lysosome-mediated suppression of intrinsic immunity."

Human Immunodeficiency Virus • Immunology • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • TFEB

mTOR inhibitors and risk of ovarian cysts: a systematic review and meta-analysis. (PubMed, BMJ Open) - "Ovarian cyst development is a common adverse event during immunosuppression treatment with mTORi. These cysts are benign conditions, but they require pelvic ultrasound follow-up and in some cases hospital admission and surgery."

Journal • Retrospective data • Review • Gynecology

Targeting NFE2L2 mutations in advanced squamous cell lung cancers with the TORC1/2 inhibitor TAK228. (ASCO 2018) - P2; " Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells harboring an NFE2L2 E79K mutation treated with TAK228, everolimus, rapamycin, or deforolimus. TAK228 is well-tolerated w/ evidence of pre-clinical and clinical activity in NFE2L2 mutant SQCLC. The trial has met its first-stage endpoint and has expanded to N = 10 patients."

Non Small Cell Lung Cancer

[VIRTUAL] Phase II study of TAK228 in patients with advanced non-small cell lung cancer (NSCLC) harboring NFE2L2 and KEAP1 mutations. (ASCO 2020) - P2 | " Cell line and xenograft experiments were performed using LK-2 LUSC (NFE2L2 E79K mut), A549 ADCL (KRAS G12S + KEAP1 loss), and SK-MES-1 LUSC cells (NFE2L2/KEAP1 WT) treated with TAK-228, everolimus, rapamycin, or deforolimus. TAK228 is tolerable with differential activity in NFE2L2 (primary endpoint met) and KEAP1 mutant LUSC. A randomized phase 2 trial of TAK228 + docetaxel vs. SoC chemotherapy in advanced LUSC pts with NFE2L2/KEAP1 mut is in development (LungMAP S1900D) as is an NCI CTEP phase 1/1b trial of TAK228 + CB-839 in advanced NSCLC patients with NFE2L2/KEAP1 mut (NCI #10327)."

Clinical • P2 data • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • KEAP1 • KRAS • NFE2L2

Targeting NFE2L2/KEAP1 mutations in advanced NSCLC with the TORC1/2 inhibitor TAK-228. (ASCO 2019) - P2; " Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells (NFE2L2 E79K mut) treated with TAK-228, everolimus, rapamycin, or deforolimus. TAK228 is tolerable with evidence of pre-clinical activity, radiographic responses, and prolonged DOR in biomarker-selected NSCLC pts. Accrual is ongoing. Clinical trial information: NCT02417701"

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer. (PubMed, Proc Natl Acad Sci U S A) - "mTORC1 inhibition with rapamycin analog Ridaforolimus suppresses TRIM28 phosphorylation, hTERT expression, and cell viability. This study may lead to hTERT-directed cancer therapies with reduced effects on normal progenitor cells."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • TERT • TRIM24

Advances in targeted therapy for osteosarcoma based on molecular classification. (PubMed, Pharmacol Res) - "Therefore, we indicated the importance of molecular classification on the targeted therapy for osteosarcoma. And the stratification of patients based on the genetic characteristics of osteosarcoma will help to obtain a better therapeutic response to targeted therapies, bringing us closer to the era of personalized medicine."

Journal • Review • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Structural Aspects of mTOR Inhibitors: In Progress to Search Potential Compounds. (PubMed, Anticancer Agents Med Chem) - "It plays a crucial role in various fundamental cell processes like cell proliferation, metabolism, survival, cell growth, etc. Various first line mTOR inhibitors such as Rapamycin, Temsirolimus, Everolimus, Ridaforolimus, Umirolimus, Zotarolimus have been used popularly. Whereas, several mTOR inhibitors such as Gedatolisib (PF-05212384) are under phase 2 clinical trials studies for the treatment of triple-negative breast cancer. The mTOR inhibitors bearing heterocyclic moieties such as quinazoline, thiophene, morpholine, imidazole, pyrazine, furan, quinoline are under investigation against various cancer cell lines (U87MG, PC-3, MCF-7, A549, MDA-231). In this review, we summarized updated research related to mTOR inhibitors, their structure-activity relationship which may help scientists for the development of potent inhibitors against cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer