P1, N=64, Active, not recruiting, Nationwide Children's Hospital | Trial primary completion date: Mar 2024 --> Aug 2024

Cell lines were treated with SAHA, 5-Azacytidine, GSK-126, and PTC-209 individually and then RSM was used to find most effective combinations. Results showed that optimized combinations significantly reduce cell survival and induce cell cycle arrest and apoptosis in both cell lines. Expression of cyclin B1 and cyclin D1 were decreased while caspase3 increased expression.

P1, N=27, Completed, University of Oklahoma | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Mar 2024

Here we revealed how EGFR-mutant landscapes are affected at the single-cell resolution level during Unesbulin treatment. This novel drug, by targeting cancer cells and their interactions with crucial TME components, could be envisioned for future therapeutic advancements.

P1, N=41, Completed, PTC Therapeutics | Active, not recruiting --> Completed

Of particular interest is the observation that PTC596, alone or in combination with PRIMA-1 and etoposide, significantly reduced GSH levels, increased peroxide production, stimulated lipid peroxidation, and induced ferroptosis. Therefore, these findings suggest that PTC596, by inhibiting BMI-1 and triggering ferroptosis, could be a promising approach to fight chemoresistance.

P1, N=64, Active, not recruiting, Nationwide Children's Hospital | Recruiting --> Active, not recruiting | Phase classification: P1b --> P1

No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m IV DTIC q21d and 300 mg unesbulin BIW in a staggered regimen is well tolerated in patients with LMS.

P1, N=27, Active, not recruiting, University of Oklahoma | Trial completion date: Feb 2024 --> Dec 2024 | Trial primary completion date: Jan 2024 --> Jun 2024

P1, N=41, Active, not recruiting, PTC Therapeutics | Phase classification: P1b --> P1

P2/3, N=345, Active, not recruiting, PTC Therapeutics | Recruiting --> Active, not recruiting

The suppression of the radioresistant performance of LP(PTC-209) has been proved on radiosensitive and radioresistant Hepa1-6 CSC tumor models, respectively. Our study clarified the relationship between radiotherapy and cancer stemness and provided insights to achieve complete suppression of radioresistant HCC tumor by inhibiting cancer stemness.

P1, N=27, Active, not recruiting, University of Oklahoma | Phase classification: P1b --> P1

Additionally, HCC stem cell inhibitors can reverse intrinsic resistance by inhibiting HCC stem cells. Therefore, this study contributes to the application of DDS in combating drug resistance in HCC and enhances its potential for clinical implementation.

P1b, N=64, Recruiting, Nationwide Children's Hospital | Trial completion date: Jul 2028 --> Mar 2029 | Trial primary completion date: Jul 2023 --> Mar 2024

Ribociclib, PTC-209, and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells. This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.

In a phase 1b dose escalation study, unesbulin, an oral microtubule polymerization inhibitor, plus dacarbazine (DTIC), showed promising efficacy and tolerability in patients with advanced LMS. However, administering unesbulin with a low-fat diet is recommended as it reduces the inter-subject variability. Unesbulin is being evaluated in an ongoing randomized, placebo-controlled, phase 2/3 trial, SUNRISELMS (NCT05269355).

Therapeutic inhibition of Bmi-1 ablates chemoresistant CSCs and prevents ACC tumor relapse. Collectively, these results suggest that ACC patients might benefit from Bmi-1-targeted therapies.

Furthermore, α-tocopherol restored sperm count (Ctrl vs. PTC-209, p = 0.0034; Ctrl vs. PTC-209 + α-tocopherol, p = 0.7293) and normalized sperm malformation such as broken heads, irregular heads, lost and curled tails in vivo, as demonstrated by its antagonism with the BMI1 inhibitor PTC-209. Analysis demonstrated that α-tocopherol is a potent in vitro and in vivo modulator of BMI1, a transcription factor that plays an important role in in SSC proliferation and spermatogenesis. Our findings identify a new target and strategy for treating male infertility that deserves further pre-clinical investigation.

Our study demonstrates that BMI-1 affects the cellular activity, proliferation, migration, and invasion of GC cells. Silencing the BMI-1 gene significantly reduces the number of SP cells and the expression of drug-resistant proteins in ADR-treated GC cells. We speculate that inhibition of BMI-1 increases the drug resistance of GC cells by affecting GCSCs, and that EZH2, CBX8, CBX4, and SUZ12 may participate in BMI-1-induced enhancement of GCSC-like phenotype and viability.

Collectively, our results validate the use of ALX bis-biguanide to potentiate the action of conventional TKI treatment as a potential new therapeutic solution to eradicate CML LSCs.

Therefore, elucidating the functional role of Bmi-1 in CSC-mediated cancer progression may unveil an attractive target for mechanism-based, developmental therapeutics. In this review, we discuss the parallels in the role of Bmi-1 in stem cell biology of health and disease and explore how this can be leveraged to advance clinical treatment strategies for head and neck cancer.

Our results indicate that the relationship between BMI-1 and phosphatases involved in AKT regulation depends on the glucose concentration and insulin stimulation.

In conclusion, DSF/copper targets CSCs in DTCs by inhibiting c-Myc- or E2F1-mediated BMI1 expression. Therefore, DSF is a potential therapeutic agent for future therapy in DTCs.

Collectively, these results demonstrate that p53 defines the stemness of MEC and suggest that therapeutic activation of p53 might have clinical utility in patients with salivary gland mucoepidermoid carcinoma.

In this study, the BCL-XL inhibitor A1331852, MCL1-inhibitor S63845, dual PI3K-mTOR inhibitor bimiralisib (PQR309), BMI-1 inhibitor unesbulin (PTC596), MEK-inhibitor trametinib (GSK1120212), and STAT3 inhibitor C-188-9 were assessed as single agents and in combination with venetoclax, for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. For the venetoclax and bimiralisib combination treatment, responders were enriched for IDH2 and FLT3 mutations, whereas non-responders were associated with PTPN11 mutations. The combination of PI3K/mTOR dual pathway inhibition with bimiralisib and BCL2 inhibition with venetoclax has emerged as a candidate treatment in IDH2- and FLT3-mutated AML.

More importantly, we discovered that knockdown of CDKN2D/BRCA1 could promote cell proliferation and migration after repression by PTC-209. Our results reveal that BMI-1 transcriptionally suppressed BRCA1 in TNBC cell lines, whereas in luminal A cell lines, CDKN2D was the target gene. This provides a reference for the precise treatment of different types of breast cancer in clinical practice.

Moreover, the inhibitor of BMI1, PTC-209, displayed an excellent anti-HCC effect in vitro. Enrichment analysis of BMI1 downstream targets showed that BMI1 might be involved in tumor immunotherapy. Together, our overall analyses revealed that the 11-RNFs prognostic signature might provide us latent chances for evaluating HCC prognosis and developing novel HCC therapy.

She subsequently received 6 cycles of Docetaxel and gemcitabine followed by pelvic radiation...She was started on Doxorubicin and is currently under evaluation for dacarbazine and the PTC596 trial...EUS-FNA biopsy is the key to diagnosing and differentiating metastatic from new primary lesions. Given the rarity, the treatment for metastatic ULMS to the pancreas is situationally determined and non-standardized, generally is still the combination of surgery, hormonal, and chemotherapy.

BMI1 is an unfavorable prognostic biomarker of CCA. Our data depict a novel function of BMI1 in CCA tumorigenesis and metastasis mediated by exosomes. Besides, BMI1 inhibition may augment immune checkpoint blockade to inhibit tumor progression by activating cell-intrinsic immunity of CCA.

The BMI1 inhibitor, PTC-209, suppressed BMI1 expression in established canine glioma cell lines and resulted in antiproliferative activity when used alone and in combination with chemotherapeutic agents...PTC-209 targeting of BMI1 activated the RB pathway through downregulation of total and phosphorylated RB, independent of INK4A/ARF signaling, likely through BMI1-inhibition mediated upregulation of p21. These data support the rationale for targeting of BMI1 signaling and the use of canine glioma as a translational therapeutic model for human disease.

Our data demonstrate that ErbB3 regulates Bmi1 expression through PI3K/Akt and MAPK signaling in both human and mouse intestinal cells. Furthermore, BMI1 activity promotes LYZ1 expression. Together, these results support our hypothesis that ErbB3 regulates secretory cell differentiation through BMI1 in the intestinal epithelium.

The levels of MMP2, MMP7, MMP9, Rock1, RhoA and p53, p21, Bax protein in BMI1 overexpression group were significantly increased, while the levels of MMP2, MMP7, MMP9, Rock1, RhoA and p53, p21, Bax protein in BMI1 inhibitor group were significantly decreased. BMI1 is highly expressed in endometrial cancer tissues, and inhibiting BMI1 expression can reduce the proliferation, migration, and invasion of HEC-1B cells after ionizing radiation and promote apoptosis, which offers new insights into the clinical radiotherapy of tumors.

Downregulation of miR-218-5p or upregulation of BMI1 inhibited the inhibitory effect of silencing CCAT1 on Hep-2 and TU177 cell proliferation, invasion, and migration. In conclusion, our study elicited that lncRNA CCAT1 facilitated the proliferation, migration, and invasion of Hep-2 and TU177 cells by sponging miR-218-5p and regulating the downstream BMI1.

The molecular dissection of the CHD7-BMI1-MAPK regulatory axis in BMI1 High;CHD7 Low MB identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in G4 MB patients.

When average tumor volume reached 100 mm3, the mice were treated with phase 1 treatment of radiation (dose 30 Gy in 10 fractions daily) delivered through SAARP platform and cisplatin (2mg/kg, every 3rd day for 10 days) and then randomized to receive phase 2 treatments: 1). These results suggest that chemoradiation therapy leads to the activation of Bmi1 as a resistance mechanism, which in turn results in the activation of inhibitory immune checkpoint PD-L1 leading to immune escape and acquired resistance to immunotherapy. Treatment with PTC-596 demonstrated synergistic benefits to anti-PD-L1 immunotherapy after pre-chemoradiation treatment of preclinical mouse lung tumor model.

These results suggest that chemoradiation therapy leads to the activation of Bmi1 as a resistance mechanism, which in turn results in the activation of inhibitory immune checkpoint PD-L1 leading to immune escape and acquired resistance to immunotherapy. Treatment with PTC-596 demonstrated synergistic benefits to anti-PD-L1 immunotherapy after pre-chemoradiation treatment of preclinical mouse lung tumor model.

Blockade of IL-6R by lentiviral knockdown or pharmacologic inhibition with a humanized monoclonal antibody (Tocilizumab) is sufficient to inhibit Bmi-1 expression, secondary sphere formation, and to decrease the CSC fraction even in Cisplatin-resistant HNSCC cells. Altogether, these studies demonstrate that therapeutic blockade of IL-6R suppresses Bmi-1 function and inhibits cancer stemness. These results suggest therapeutic inhibition of IL-6R might be a viable strategy to overcome the CSC-mediated chemoresistance typically observed in HNSCC patients.

Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inhibitor PTC596, MEK-inhibitor trametinib, MCL1-inhibitor S63845, and BCL-2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Only the MCL1 inhibitor S63845 induced cell death with equal efficacy in the absence or presence of bone marrow stroma. The combination of the STAT5-inhibitor AC-4-130 and the MCL1 inhibitor S63845 may be an effective treatment targeting FLT3-mutated or TET2-mutated AML.

Dual EPS8 and ALDH7A1 knockdown had a synergistic effect on suppressing PADC cell proliferation in vitro and in vivo. In conclusion, this study revealed that EPS8 supports PADC growth by interacting with ALDH7A1 and inhibiting BMI1 mediated proteasomal degradation of ALDH7A1.