LB-100

LNP-siPP2Ac efficiently silenced PP2Ac in vitro and, when delivered locally in vivo, prolonged survival in a CD8+ T cell-dependent manner. Together, these findings identify PP2A as a regulator of immunogenic senescence in MB and support PP2Ac targeting as a therapeutic strategy.

Variation in experimental platforms, sample representation, and data integration across public datasets is a recognised study limitation. Nonetheless, LB-100 may provide a novel therapeutic avenue in CML, provided further preclinical functional and clinical validation is performed in patient-derived samples to confirm translational applicability of the findings.

Importantly, using a drug-repurposing approach, we found that inhibition of CA5B, PPP3CA, and PP2A by acetazolamide, tacrolimus, and LB-100, respectively, showed high toxicity toward KMT2A::AFF1+ leukemic blasts and reduced leukemia burden in vivo...This study highlights how the unique microRNA expression signature of patients with KMT2A::AFF1+ BCP-ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing. It also indicates potential new drug combinations for less toxic chemotherapy.

P1, N=3, Active, not recruiting, City of Hope Medical Center | Trial completion date: Mar 2026 --> Jan 2027 | Trial primary completion date: Mar 2026 --> Jan 2027

P1/2, N=21, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2026 --> Oct 2027 | Trial primary completion date: Jan 2026 --> Oct 2027

This study also preliminarily validated the effect of the combination of the two drugs on other subtypes of CTCL. Overall, these findings provide potential new therapeutic strategies for CTCL (especially SS), although further clinical evaluation is required to validate these results.

We found that in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC) cells, CIP2A degradation via ubiquitination enhanced PP2A phosphatase activity, leading to the dephosphorylation of ATR at Ser428 in the cytoplasm...These findings reveal a novel mechanism of resistance to DNA damage-based cancer drugs and introduce a new action mechanism of LB-100, which works through mtATR-tBid complex-mediated apoptotic dormancy triggered by CIP2A degradation-mediated PP2A activation. Disrupting the mtATR-tBid complex may represent a promising strategy to restore or sensitize resistant cancer cells to apoptosis.

P1/2, N=152, Active, not recruiting, Grupo Espanol de Investigacion en Sarcomas | Recruiting --> Active, not recruiting

Altogether, we delineated NLRP4's unexplored facets and discovered an NLRP4-driven anti-tumor ecosystem composed of TIGIT+TNFA+ NK and iNOS+ M1. Finally, targeting PP2A by its inhibitor successfully mimicked the anti-tumor capacity of the overexpression of NLRP4.

P1, N=3, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting | N=21 --> 3

P1, N=37, Recruiting, The Netherlands Cancer Institute | Not yet recruiting --> Recruiting

Furthermore, oral administration of 28a and TMZ was well tolerated to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft model. Collectively, these results implicate 28a could be a drug candidate by reversing TMZ resistance with a selective PP5 inhibition manner.