P1/2, N=52, Recruiting, Bold Therapeutics Inc. | N=38 --> 52

Moreover, the combination of San with copper ionophores (Elesclomol-CuCl 2) exhibits synergistic effects in promoting cuproptosis...Surface plasmon resonance experiments and cellular thermal shift assay confirm that San strongly interacts with FDX1 and markedly enhances the thermostability of FDX1. In conclusion, our findings indicate that San substantially inhibits the progression of HCC by targeting FDX1/LIAS/DLAT/HSP70 axis-dependent cuproptosis.

To mitigate the off-target toxicity of verteporfin, a YAP1 inhibitor, we develop macrophage-membrane-camouflaged hollow mesoporous silica nanoparticles (M@O-VNPs) co-loaded with verteporfin and oxaliplatin...By inducing immunogenic cell death, M@O-VNPs remodel the tumor microenvironment and enhance ICB efficacy while minimizing systemic toxicity. The therapeutic potential of this strategy is supported by synergistic antitumor effects of M@O-VNPs combined with anti-PD-1 therapy in genetically engineered and syngeneic GC models.

Here, through a small-molecule compound screening, we identify elesclomol, a potent copper ionophore, which sensitizes BRCA-proficient ovarian cancer cells to PARPi by inhibiting activation of the ATR-CHK1 pathway...Importantly, we reveal a secondary metabolic vulnerability in PARPi-resistant ovarian cancer associated with de novo pyrimidine synthesis, suggesting that targeting this pathway as an effective strategy to eradicate drug-adaptive residual tumors and resistant patient-derived xenograft models following ATR and PARP co-inhibition. These findings propose de novo pyrimidine synthesis as an adaptive metabolic vulnerability that can be therapeutically targeted to overcome PARPi resistance in BRCA-proficient ovarian cancer.

P=N/A, N=15, Recruiting, Aura Biosciences

To overcome this, we screened various metalloporphyrins and identified Cu-based verteporfin as an effective YAP inhibitor, so that a tumor-targeted nanosystem termed CuVP-F127-IKE-Mem is developed, which integrates the YAP inhibitor copper-verteporfin metalloporphyrin and the ferroptosis inducer imidazole ketone erastin (IKE) into cancer cell membrane-coated nanoparticles. In pancreatic cancer, CuVP-F127-IKE-Mem significantly enhances ferroptosis sensitivity, suppresses YAP/SLC7A11 signaling, and exhibits potent tumor growth inhibition in vivo. This YAP-targeted transcriptional regulation strategy establishes a new paradigm for overcoming ferroptosis resistance.

In this study, we designed and synthesized Photodegradation-Targeting Chimeras (PDTACs) by conjugating a clinically approved photosensitizer, verteporfin, to a PD-L1-targeted peptide...In mouse models with immune cold tumors, PPA-VPF elicited robust adaptive antitumor immunity and effectively inhibited the growth of both primary and distant tumors. This PD-L1-targeted PDTAC achieved immune checkpoint blockade and ICD induction in a single therapeutic mode using one molecular species, presenting a novel strategy for combinational immunotherapy, particularly in immune cold tumors.

P1, N=5, Terminated, Roswell Park Cancer Institute | Active, not recruiting --> Terminated; low accrual

YAP1 and tumor-like CAFs (tCAFs) play a pivotal role in driving desmoplasia in PDAC. YAP1 mediates the conversion of mCAFs to tCAFs and remodels the extracellular matrix (ECM), while high YAP1 activity in tCAFs regulates EMT induction to propel disease progression. Targeting the YAP1-tCAF axis can suppress desmoplasia and improve therapeutic outcomes. Magnetic resonance elastography (MRE) holds significant potential for non-invasive monitoring of stromal mechanics, offering a new perspective for stromal therapies in PDAC.

In this study, elesclomol (ES) or disulfiram (DSF)/Cu was used to induce cuproptosis, and bathocuproine disulfonic acid (BCS) was used to inhibit it. In vivo, the role of the ALKBH5-ATOX1 axis in AML progression has also been confirmed. In Conclusion, The demethylase ALKBH5 downregulates ATOX1 by reducing its m⁶A levels, thereby modulating cuproptosis in AML-a mechanism that offers potential novel insights and therapeutic targets for AML treatment.

Using CRISPR/Cas9-mediated knockout and rescue experiments in EOC cell lines, we demonstrate that MED12 deficiency significantly enhances sensitivity to ferroptosis inducers (RSL3 and Erastin), as evidenced by reduced IC50 values...Pharmacological inhibition of YAP with verteporfin or siRNA-mediated TEAD1 knockdown reverses ferroptosis sensitivity in MED12-deficient cells, confirming pathway specificity. These findings establish MED12 as a modulator of the YAP-TEAD1-ferroptosis axis and suggest that targeting this pathway could overcome chemoresistance in MED12-deficient EOC. Our work provides a mechanistic foundation for exploiting ferroptosis induction as a therapeutic strategy in ovarian cancer.

Next, two gastric cancer cell lines (AGS, HGC27) were selected for in vitro experiments to assess the combined effects of PUN and the copper ionophore elesclomol (ES) (hereafter referred to as ES-Cu, representing the combination of ES and Cu2+)...In combination therapy strategies, PUN can work synergistically with chemotherapy drugs to suppress gastric cancer growth. Furthermore, PUN enhances its inhibitory effect on gastric cancer by working synergistically with cuproptosis through targeting FDX1.