nesuparib (JPI-547)

In vitro, JPI-547 and olaparib more effectively reduced cell survival in PTEN-deficient cells, and combined treatment with olaparib and the TNKS inhibitor XAV-939 induced synergistic cytotoxicity with elevated DNA double-strand breaks. PTEN knockdown further showed enhanced vulnerability to combined targeting. These findings show that JPI-547 enhances antitumor efficacy in PTEN-deficient EC by disrupting DNA repair pathways and Wnt signalling, supporting dual PARP/TNKS inhibition as a potential therapeutic strategy and providing a rationale for further clinical evaluation.

The recent ONC201 FDA approval, however, suggests DIPG therapy is tractable...A proof-of-concept in vivo mouse xenograft experiment demonstrated a reduction in tumor volume beyond antibody treatment alone. The work here represents an important milestone in preclinical development of a novel deruxtecan-based ADC agent for an intractable pediatric brain cancer, concurrent with other ADC agents demonstrating real-world clinical efficacy and gaining approvals in multiple disease indications.

DU145 and PC3 AIPC cells were treated with ONC201 (parent compound), ONC206, or ONC212...Imipridones induced a time-dependent cell-cycle redistribution with increased sub-G1 accumulation and modulated mitochondrial membrane potential and mass in a context-dependent manner. Collectively, these findings position ONC212 as a leading imipridone candidate in AIPC models, combining potent inhibition of tumor and stem-like cell functions with a coherent stress-response signature that supports further translational evaluation.

These results suggest the scientific rationale for further clinical development of JPI-547 for treating both PARP inhibitor-sensitive patients and those resistant to first-generation PARP inhibitors in BRCA-mutated cancers.

P1, N=36, Not yet recruiting, Onconic Therapeutics Inc.

Among these are histone deacetylase inhibitors (HDACis), receptor tyrosine kinase inhibitors, and novel agents such as ONC201 and unesbulin that target metabolic and epigenetic pathways respectively...Despite these advances, challenges such as drug delivery across the blood-brain barrier and therapeutic resistance persist, necessitating the development of combination therapies and innovative delivery methods. Ongoing research is focused on refining these strategies and exploring additional molecular and immunological targets to improve outcomes for children with DMG.

P1/2, N=71, Recruiting, Onconic Therapeutics Inc. | Phase classification: P1 --> P1/2 | N=30 --> 71 | Trial completion date: Jun 2026 --> Apr 2030 | Trial primary completion date: Mar 2026 --> Apr 2030

Ovarian cancer has a poor clinical prognosis due to chemoresistance following carboplatin/paclitaxel treatment...The therapeutic efficacy of these combinations was also proved in patient-derived tumor organoid models (PDTO), leading to their structural disintegration and reduced viability. Collectively, our study highlights that ABT-737, through BCL-xL inhibition and synergy with ER stress inducers, triggers ovarian cancer death, offering promising strategies for overcoming chemoresistance in relapsed ovarian cancer.

P2, N=81, Not yet recruiting, Onconic Therapeutics Inc.

P1/2, N=49, Not yet recruiting, Onconic Therapeutics Inc.

We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines...By contrast, cells treated with the cell cycle inhibitor and senescence inducer, abemaciclib rapidly regained p-Rb and Myc expression and cell proliferation following washout...Combining a ClpP agonist with a PARP inhibitor (olaparib) produced an additive effect. In summary, we show that ClpP activators stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells.

JPI-547 outperformed most PARP inhibitors, with a half-maximal inhibitory concentration approximately 10-fold lower than that of olaparib. PDAC cells reliant on Wnt signaling due to pathogenic RNF43 mutations showed increased susceptibility to JPI-547 without altering homologous recombination repair efficiency. JPI-547 disrupts the Wnt/β-catenin pathway in RNF43-mutated cells and inhibits the oncogenic YAP pathway, highlighting its multifaceted therapeutic potential in PDAC with HRD or Wnt-addiction.