- |||||||||| LB-100 / Lixte Biotech
Journal: The cellular protein phosphatase 2A is a crucial host factor for Marburg virus transcription. (Pubmed Central) - Sep 18, 2024
The regulatory subunit B56 of PP2A facilitates VP30 dephosphorylation, and hence transcription activation, via binding to NP. Our results, together with previous data, reveal a conserved mechanism of filovirus VP30 dephosphorylation by host factor PP2A at the NP interface and provide novel insights into potential pan-filovirus therapies.
- |||||||||| LB-100 / Lixte Biotech
Journal: The PP2A Inhibitor LB-100 Mitigates Lupus Nephritis by Suppressing Tertiary Lymphoid Structure Formation. (Pubmed Central) - Jul 1, 2024
The levels of chemokines inducing T cell infiltration were elevated in the kidneys of lupus mice, whereas LB-100 mitigated chemokines production and inhibited TLS formation. In summary, our study identified the role of PP2A in LN and highlighted the renal protective potential of the PP2A inhibitor LB-100 in two distinct lupus mouse models, suggesting its potential as a novel strategy for LN and other autoimmune diseases.
- |||||||||| LB-100 / Lixte Biotech
Review, Journal: Canonical and Noncanonical Functions of the BH3 Domain Protein Bid in Apoptosis, Oncogenesis, Cancer Therapeutics, and Aging. (Pubmed Central) - Jun 27, 2024
The unexpected upregulation of this Bid protein in cancer cells can also be instrumental in explaining the mechanisms behind acquired chemoresistance. The stable protein associations at the mitochondria between tBid and anti-apoptotic mitochondrial ATR play a crucial role in maintaining the viability of cancer cells, suggesting a novel mechanism to induce cancer cell apoptosis by freeing tBid from the ATR associations at mitochondria.
- |||||||||| LB-100 / Lixte Biotech, Jemperli (dostarlimab-gxly) / GSK
Trial completion date, Trial primary completion date: Safety and Efficacy of Targeting PP2A in Ovarian Clear Cell Carcinoma Using Dostarlimab and LB-100 (clinicaltrials.gov) - Mar 2, 2024
P1/2, N=21, Recruiting,
Our findings provide a potential explanation for the pre-clinical and clinical observations that LB-100 sensitizes cancer cells to immune checkpoint blockade. Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026
- |||||||||| LB-100 / Lixte Biotech, Jemperli (dostarlimab-gxly) / GSK
Enrollment open, Trial initiation date: Safety and Efficacy of Targeting PP2A in Ovarian Clear Cell Carcinoma Using Dostarlimab and LB-100 (clinicaltrials.gov) - Nov 21, 2023
P1/2, N=21, Recruiting,
Thus, the presented study provides insight into the bioactive molecules of probiotic yogurt and may be useful for both academia and industry in the development of new dairy-based functional products. Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Nov 2023
- |||||||||| LB-100 / Lixte Biotech
Trial completion, Enrollment change, Trial completion date, Trial primary completion date: Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma (clinicaltrials.gov) - Jul 13, 2023
P2, N=7, Completed,
The validated LC-MS/MS method enabled the accurate measurement of LB-100 and endothall in patient samples from an ongoing clinical trial (NCT04560972). Recruiting --> Completed | N=25 --> 7 | Trial completion date: Aug 2023 --> Aug 2022 | Trial primary completion date: Aug 2023 --> Aug 2022
- |||||||||| LB-100 / Lixte Biotech
Review, Journal: Targeting PP2A for cancer therapeutic modulation. (Pubmed Central) - Nov 8, 2022
Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies, including a phase I trial in extensive-stage small-cell lung cancer, a phase I/II trial in myelodysplastic syndrome, a phase II trial in recurrent glioblastoma, and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors. Herein, we review the development of LB100, the role of PP2A in cancer biology, and recent advances in targeting PP2A inhibition in immunotherapy.
- |||||||||| LB-100 / Lixte Biotech
Paradoxical activation of oncogenic signaling pathways as a cancer treatment strategy (Auditorium 2 + 3) - Apr 18, 2022 - Abstract #EACR2022EACR_54;
Conclusion These data show that the combination of LB-100 and WEE1 inhibition is lethal for a panel of colorectal cancer cells. Moreover, loss of oncogenic signaling is apparently a major escape route for treatments that are based on paradoxical activation of oncogenic signaling, supporting the prospect of “tumor-suppressive” acquired resistance to this type of therapy.
- |||||||||| LB-100 / Lixte Biotech
Journal: Serine/Threonine Protein Phosphatase 2A Regulates the Transport of Axonal Mitochondria. (Pubmed Central) - Apr 5, 2022
To resolve this discrepancy, we knocked down expression of the catalytic subunit of PP2A (PP2CA). This long-term inhibition of PP2A more than doubled retrograde transport of axonal mitochondria, confirming the importance of PP2A as a regulator of mitochondrial motility and as the likely mediator of cantharidin's effect.
- |||||||||| LB-100 / Lixte Biotech, Tecentriq (atezolizumab) / Roche
Trial completion date, Trial primary completion date, Combination therapy: LB-100, Carboplatin, Etoposide, and Atezolizumab for the Treatment of Untreated Extensive-Stage Small Cell Lung Cancer (clinicaltrials.gov) - Mar 24, 2022
P1, N=21, Recruiting,
This long-term inhibition of PP2A more than doubled retrograde transport of axonal mitochondria, confirming the importance of PP2A as a regulator of mitochondrial motility and as the likely mediator of cantharidin's effect. Trial completion date: Aug 2023 --> Mar 2026 | Trial primary completion date: Aug 2023 --> Mar 2026
- |||||||||| LB-100 / Lixte Biotech
Journal, Synthetic lethality: Targeting ribonucleotide reductase induces synthetic lethality in PP2A-deficient uterine serous carcinoma. (Pubmed Central) - Mar 8, 2022
While RNRi are not routinely used for uterine cancers, a retrospective analysis of patients treated with gemcitabine as a second or later line therapy revealed a trend for improved outcomes in USC patients treated with RNRi gemcitabine compared to patients with endometrioid histology. Overall, our data provide experimental evidence to support the use of ribonucleotide reductase inhibitors for the treatment of USC.
- |||||||||| LB-100 / Lixte Biotech, vosoritide (BMN 111) / BioMarin
Journal: Phosphatase inhibition by LB-100 enhances BMN-111 stimulation of bone growth. (Pubmed Central) - Feb 15, 2022
The combination treatment also reduced the abnormal elevation of MAP kinase activity in the growth plate of Fgfr3Y367C/+ mice and improved the skull base anomalies. Our results provide a proof of concept that a phosphatase inhibitor could be used together with an NPR2 agonist to enhance cGMP production as a therapy for ACH.
- |||||||||| LB-100 / Lixte Biotech
Enrollment status: Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma (clinicaltrials.gov) - Feb 14, 2022
P2, N=25, Recruiting,
Our results provide a proof of concept that a phosphatase inhibitor could be used together with an NPR2 agonist to enhance cGMP production as a therapy for ACH. Enrolling by invitation --> Recruiting
- |||||||||| LB-100 / Lixte Biotech, Tecentriq (atezolizumab) / Roche
Journal, PD(L)-1 Biomarker, IO biomarker: Protein phosphatase 2A as a therapeutic target in small cell lung cancer. (Pubmed Central) - Feb 11, 2022
Combining LB100 with atezolizumab increased the capacity of T cells to infiltrate and kill tumor spheroids and combining LB100 with carboplatin caused hyperphosphorylation of the DNA repair marker γH2AX, enhanced apoptosis while attenuating MET signaling and invasion through an endothelial cell monolayer. Taken together, these data highlight the translational potential of inhibiting PP2A with LB100 in combination with platinum-based chemotherapy and immunotherapy in SCLC.
- |||||||||| LB-100 / Lixte Biotech
Biomarker, Journal: PP2A phosphatase inhibition is anti-fibrotic through Ser77 phosphorylation-mediated ARNT/ARNT homodimer formation. (Pubmed Central) - Jan 27, 2022
In murine models of kidney fibrosis, and also of liver fibrosis, combinations of FK506 or GPI1046 (to induce ARNT expression) with LB100 (to enhance ARNT homodimerization) elicit additive anti-fibrotic activities. Our study provides additional evidence for the anti-fibrotic activity of ARNT-ARNT homodimers and reveals Ser77 phosphorylation as a novel pharmacological target to realize the therapeutic potential of increased ARNT transactivation activity.
- |||||||||| SCH-23390 / Boehringer Ingelheim
Journal: D1R/PP2A/p-CaMKIIα signaling in the caudate putamen is involved in acute methamphetamine-induced hyperlocomotion. (Pubmed Central) - Jan 11, 2022
In this study, SCH23390 (a D1R inhibitor) and LB100 (a PP2A inhibitor) were administered to examine the involvement of D1R and PP2A signaling in acute METH-induced hyperlocomotion in mice...Moreover, prior administration of 0.1 mg/kg LB100 attenuated hyperlocomotion induced by single METH administration and reversed the decrease in protein levels of p-CaMKII (Thr 286) in the PFC, NAc, and CPu. Collectively, these results indicate that the D1R/PP2A/p-CaMKIIα signaling cascade in the CPu may be involved in hyperlocomotion after a single administration of METH.
- |||||||||| LB-100 / Lixte Biotech
Journal: Allosteric Activation of PP2A Inhibits Experimental Abdominal Aortic Aneurysm. (Pubmed Central) - Dec 16, 2021
Mechanistically, modulation of PP2A activities in vivo functioned in part via alteration of the ERK1/2 and NFkB signaling pathways, known regulators of AAA progression. These studies, for the first time, demonstrate a role of PP2A in AAA etiology and demonstrate that PP2A activation may represent a novel strategy for the treatment of abdominal aortic aneurysms.
- |||||||||| LB-100 / Lixte Biotech
Journal: Cleavage and Polyadenylation Specificity Factor 6 Is Required for Efficient HIV-1 Latency Reversal. (Pubmed Central) - Nov 21, 2021
IMPORTANCE CPSF6 is a cellular factor that regulates cleavage and polyadenylation of mRNAs and participates in HIV-1 infection by facilitating targeting of preintegration complexes to the chromatin. Our observations reveal a second role of CPSF6 in the HIV-1 life cycle that involves regulation of viral transcription through controlling the stability of protein phosphatase 2A, which in turn regulates the phosphorylation/dephosphorylation status of critical residues in CDK9 and Pol II.
- |||||||||| LB-100 / Lixte Biotech
Enrollment status, Trial completion date, Trial primary completion date: Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma (clinicaltrials.gov) - Oct 26, 2021
P2, N=25, Enrolling by invitation,
This may provide new strategies for polyphyllin VII in the clinical treatment of ovarian cancer. Recruiting --> Enrolling by invitation | Trial completion date: Aug 2022 --> Aug 2023 | Trial primary completion date: Aug 2022 --> Aug 2023
- |||||||||| LB-100 / Lixte Biotech, Visudyne (verteporfin) / Novartis
Journal: Activation of Yes-Associated Protein/PDZ-Binding Motif Pathway Contributes to Endothelial Dysfunction and Vascular Inflammation in AngiotensinII Hypertension. (Pubmed Central) - Oct 20, 2021
The infusion of AngII (1.1 mg/kg/day by mini-pump) for 3 weeks induced the activation of YAP/TAZ, manifested by decreased cytosolic phosphor-YAP and phosphor-TAZ, and increased YAP/TAZ nuclear translocation, which were prevented by YAP/TAZ inhibitor verteporfin...Our results suggest that AngII induces YAP/TAZ activation via PP2A-dependent dephosphorylation, which may contribute to the impairment of endothelial function and the induction of vascular inflammation in hypertension. YAP/TAZ may be a new target for hypertensive vascular injury.
- |||||||||| Abraxane (albumin-bound paclitaxel) / BMS, Otsuka
Journal: Pharmacological Inhibition of PP2A Overcomes Nab-Paclitaxel Resistance by Downregulating MCL1 in Esophageal Squamous Cell Carcinoma (ESCC). (Pubmed Central) - Oct 14, 2021
Moreover, LB-100 pretreatment partially restored nab-PTX sensitivity in the resistant cell lines and synergistically inhibited the tumor growth of nab-PTX resistant xenografts with nab-PTX. In summary, our study identifies a novel mechanism whereby elevated PP2A activity stabilizes MCL1 protein, increases OXPHOS, and confers nab-PTX resistance, suggesting that targeting PP2A is a potential strategy for reversing nab-PTX resistance in patients with advanced ESCC.
- |||||||||| LB-100 / Lixte Biotech, Tecentriq (atezolizumab) / Roche
Trial completion date, Trial primary completion date, Combination therapy: LB-100, Carboplatin, Etoposide, and Atezolizumab for the Treatment of Untreated Extensive-Stage Small Cell Lung Cancer (clinicaltrials.gov) - Aug 18, 2021
P1, N=18, Recruiting,
Overall, combined PRMT5 and PP2A inhibition had significantly greater antitumor effects than PRMT5 inhibition alone. Trial completion date: Aug 2022 --> Aug 2023 | Trial primary completion date: Aug 2022 --> Aug 2023
- |||||||||| cisplatin / Generic mfg., paclitaxel / Generic mfg.
Journal: Targeting PP2A inhibits the growth of triple-negative breast cancer cells. (Pubmed Central) - May 26, 2021
Importantly, we found that LB-100 effectively inhibits the growth of MDA468 tumors in mice in vivo without apparent toxicity. Collectively, these data suggest that pharmacological inhibition of PP2A activity could be a novel therapeutic strategy for treating patients with TNBC in a clinical setting.
- |||||||||| LB-100 / Lixte Biotech
Trial completion date, Trial primary completion date: Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma (clinicaltrials.gov) - Dec 2, 2020
P2, N=25, Recruiting,
Initiation date: Nov 2020 --> Feb 2021 Trial completion date: Aug 2021 --> Aug 2022 | Trial primary completion date: Aug 2021 --> Aug 2022
- |||||||||| LB-100 / Lixte Biotech, Tecentriq (atezolizumab) / Roche
Enrollment change, Trial withdrawal, Combination therapy: LB-100, Carboplatin, Etoposide, and Atezolizumab for the Treatment of Untreated Extensive-Stage Small Cell Lung Cancer (clinicaltrials.gov) - Nov 2, 2020
P1, N=0, Withdrawn,
These results provide a new perspective on the treatment of MM. N=18 --> 0 | Not yet recruiting --> Withdrawn
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