We and others have shown that treatment with cytotoxic chemotherapy agents (e.g. Cisplatin, Carboplatin) induce Bmi-1 expression and increase the fraction of highly tumorigenic CSC in HNSCC. In vivo, Bmi-1 inhibition with PTC596 suppressed Cisplatin-mediated increase in the fraction of ALDHhighCD44high cells (cancer stemness). Collectively, these preclinical results demonstrate that Bmi-1 is a key mediator of head and neck cancer stemness and suggest that HNSCC patients might benefit from treatment with a Bmi-1 inhibitor combined with a conventional chemotherapeutic agent.

This work provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC-596 to improve the durability of remissions and extend survival of patients with treatment-refractory Group 3 MB.

PTC 209 utilizes the high affinity of modified hyaluronic acid nanoparticles for colorectal cancer to reverse CSC stemness in colorectal cancer...These strategies emphasize specificity, nanodelivery, and combination therapies to reduce toxicity and resistance, highlighting precision oncology potential. Clinical validation remains critical for translation.

In the present study, in vitro experiments were performed using the Wnt signaling agonist Wnt3a and the B lymphoma Mo‑MLV insertion region 1 homolog (Bmi1) small molecule inhibitor PTC209 to treat MSCs, and the roles and regulatory mechanisms of the Bmi1 and Wnt3a‑RhoA signaling pathways on the neural differentiation of MSCs were explored by MTT assay, immunofluorescence analysis and western blotting...The findings suggested that Bmi1 modulates the neural differentiation of MSCs through its regulatory effects on Wnt3a and RhoA expression, thereby influencing the reparative potential of MSCs in ischemic brain tissue. These findings highlight the therapeutic relevance of targeting Wnt3a‑RhoA activation and Bmi1 inhibition in MSC‑based interventions for IBI.

In our present study, the BMI1 inhibitors PTC-028 and PTC-209 exhibited selective antitumor activity against MYCN-amplified neuroblastoma. Significantly, PTC-028 also exhibited antitumor efficacy in a mouse xenograft model of human neuroblastoma. These results suggest that BMI1 inhibitors, particularly PTC-028, are promising therapeutic agents for the management of aggressive MYCN-amplified neuroblastomas.

Pharmacological inhibition of BMI1 using PTC-209 significantly attenuated cell proliferation, migration, and cell cycle progression in both SH-SY5Y neuroblastoma cells and primary enteric neural crest cells (ENCCs), whereas BMI1 overexpression produced the opposite effects...Molecular level probing revealed that BMI1 binds to the promoter region of Axin2, an inhibitor of the Wnt signaling pathway, and inhibited Axin2 transcription by increasing H2AK119ub and decreasing H3K4me3 in the Axin2 promoter, thereby hindering Wnt signaling. This study revealed that the BMI1/Axin2/Wnt axis may play an important role in the pathogenesis of HSCR.

BMI1 promotes angiogenesis in CRC by upregulating ANGPT2 expression. High BMI1 and ANGPT2 levels served as independent prognostic factors for tumor progression, highlighting their potential as therapeutic targets for CRC management.

Using a series of preclinical models in murine systems, we confirmed that PTC209@VNP-HA eliminated BMI1+ CSCs, and greatly inhibited the proliferation and metastasis of HNSCC when combined with cisplatin. This study investigated PTC209@VNP-HA as a novel and potentially transformative HNSCC treatment option that eliminates CSCs, prevents metastasis, and overcomes cisplatin resistance.

PTC209/MnO2@BSA (bovine serum albumin) nanoparticles (PMB NPs) synthesized via a facile and green process are reported, wherein the released manganese (Mn) ions under acidic tumor microenvironment significantly enhance cGAS-STING signals and facilitate the dendritic cells maturation to unleash the T-cell-mediated immune response...Both in vitro and in vivo experiments elucidate that PMB NPs function as designed, exerting powerful immunotherapeutic and chemotherapeutic impacts to impede HNSCC growth and metastasis as well as bolster anti-PD-1-based ICB. Collectively, our findings provide a promising therapeutic strategy against HNSCC by combinational CSCs elimination and STING activation via metalloimmunotherapy.

P2/3, N=360, Terminated, PTC Therapeutics | Active, not recruiting --> Terminated; Business decision

To date, there have been no reports on the combination of BMI1-targeted therapy and immunotherapy in cervical cancer. This review, therefore, elucidates the current state of research and explores the potential and perspectives of combining targeted therapy with immunotherapy for cervical cancer.

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