unesbulin (BMIi-1)

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

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

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

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

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

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.

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.

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.

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.

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.

Moreover, UNC1999 and a selective Akt inhibitor TAS-117 synergistically inhibit the growth of MM cells through epigenetic mechanisms...Interestingly, a microtubule polymerization inhibitor PTC596 cooperatively downregulates BMI1 protein with proteasome inhibitors, exhibiting in-vitro and in-vivo cytotoxicity in MM cells. Finally, our mouse model with concurrent loss of the histone demethylase Utx and the activating mutation of Braf V600E in post germinal center B cells demonstrates mature B-cell malignancies including plasma cell neoplasms. Our ongoing analyses will reveal the pathogenesis of MM induced by somatic mutations, and this model is a useful tool for the development of novel molecular-targeted therapies for MM patients.

We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.

The combination of PTC596 and S63845 may be an effective treatment in CD34+ adverse risk AML with elevated MN1 gene expression and MCL1 protein levels, while PTC596 and trametinib may be more effective in CD34+ adverse risk AML with elevated BMI1 gene expression and MEK protein levels.

Treatment with a related but more specific BMI1 inhibitor resulted in tumor regression and maintenance of cell identity. We conclude that inhibition of BMI1 alone is efficient at inducing GBM regression, and that dual inhibition of BMI1 and EZH2 using PTC596 may be also beneficial but only in specific contexts.

The novel small molecule PTC596 directly binds tubulin, inhibits microtubule polymerization, downregulates MCL-1, and induces p53-independent apoptosis in acute myeloid leukemia cells...PTC-028 synergized with hypomethylating agents, such as decitabine and azacitidine, to inhibit growth and induce apoptosis in MDS cells...PTC-028 prolonged the survival of mice in xenograft models. The present results suggest a chemotherapeutic strategy for MDS through the disruption of microtubule dynamics in combination with DNA hypomethylating agents.

Treatment of DIPG stem-like cells with PTC596, a BMI-1 modulator, and IR, impairs the kinetics of DNA damage response (DDR)...At the single-cell level, the analysis reveals that BMI-1 pathway is upregulated in undifferentiated cells and positively correlates with stemness in DIPG tumors. Implications: Together, our findings indicate that BMI-1 modulation is associated with mitotic abnormalities, impaired DDR and cell death, supporting the combination of BMI-1 modulation and radiation as a promising novel therapy for children with DIPG.

Moreover, we observed a complete eradication of MM after PTC596 treatment in the 5TGM.1 in vivo model and define epigenetic compounds and B cell leukaemia/lymphoma 2 homology domain 3 (BH3) mimetics as promising combination partners. These results bring into question the postulated role of BMI-1 as an essential MM gene and confirm BMI-1 modulators as potent anti-mitotic agents with encouraging pre-clinical activity that supports their rapid translation into clinical trials.

Treatment with a related but more specific BMI1 inhibitor resulted in tumor regression and maintenance of cell identity. We conclude that inhibition of BMI1 alone is efficient at inducing GBM regression, and that dual inhibition of BMI1 and EZH2 using PTC596 may be also beneficial but only in specific contexts.