In normal human tissues, levels of p16 and PR55α proteins were inversely correlated and mutually exclusive. Collectively, these results describe a novel function of PR55α/PP2A in blocking p16/RB signaling and IR-induced cellular senescence.

P1/2, N=21, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

Targeting the LASS2 and β-catenin pathways may be an effective strategy to overcome cisplatin resistance and inhibit tumor growth in bladder cancer patients.

The steadiness and tightness of lapatinib with CIP2A inside the stem domain disclosed glutamic acid-318 as the culprit amino acid with the highest electrostatic energy. These results provide clear information on the CIP2A domain capable of ligand binding and validate lapatinib as a promising CIP2A inhibitor in TNBC carcinogenesis.

Analysis of the difference between these cell lines revealed that Myc activity plays a pivotal role in SET KD-mediated Bmi-1 degradation. Our data added new insights into the molecular mechanism of the SET-regulated colony-forming ability, in which Akt-mediated activation of mTORC1/p70S6K and Bmi-1 signaling.

P1, N=87, Recruiting, Institut Curie | Active, not recruiting --> Recruiting | N=56 --> 87 | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Nov 2023 --> Dec 2024

One of the mediators of progressive MASLD is environmental toxins. In this research report, we show for the first time a novel mechanism where microcystin-LR, an environmental toxin, advances MASLD to MASH by triggering the release of Hsp70 as a DAMP to activate TLR4-induced inflammation in the liver.

P1/2, N=21, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Nov 2023

Mice injected with PP2A-KO tumor survived longer than WT, and had the highest expression of both calreticulin gamma-H2AX when compared to WT tissue. In conclusion, PP2A-deficiency and inhibition via LB-100 is demonstrated to induce immunogenic cell death in tumors, thus being a promising target for immunotherapy.

SAC inactivation is common in BRCA2-deficient prostate cancer patients, but PP2A inhibitors could reactivate the SAC and achieve BRCA2-deficient prostate tumor synthetic lethality. Our research reveals the survival adaptation mechanism of BRCA2-deficient prostate tumor cells and provides different angles for exploring synthetic lethal inhibitors in addition to targeting DNA damage repair pathways.

P1, N=43, Not yet recruiting, The Netherlands Cancer Institute

P1, N=56, Active, not recruiting, Institut Curie | Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2023 --> Nov 2023

P1/2, N=21, Not yet recruiting, M.D. Anderson Cancer Center

In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154, and DBK-1160...Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors.

P1, N=37, Not yet recruiting, The Netherlands Cancer Institute

P2, N=7, Completed, National Cancer Institute (NCI) | Recruiting --> Completed | N=25 --> 7 | Trial completion date: Aug 2023 --> Aug 2022 | Trial primary completion date: Aug 2023 --> Aug 2022

Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). DT-061 inhibited the growth of wild type and Bax/Bak double knockout multidrug resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug resistant CLL cells in patients, and validated a pharmacologically tractable pathway to deplete this reservoir.

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

This review establishes the concept that inhibition of PP2A activity is a common mechanism of human cancer progression and activation of PP2A activity leads to effective anticancer therapy.

In addition, we found that p53 mutants in NSCLC cells increased Cip2a expression by inhibiting the activity of wild-type p53. Our findings provide new insights into the mechanisms of Cip2a in promoting tumor progression and suggest that Cip2a represents a potential therapeutic target for treating NSCLC.

We have compared specific features related to the mechanism-of-action of PEP-010 in sensitive (MDA-MB-231, IGROV1) and not sensitive cell models of different tumor origins and in tissue sections derived from Patient-Derived Xenografts models of breast cancer treated or not with PEP-010. Widely used techniques as immunofluorescent staining and immunohistochemistry were employed, making these results easily transferable in clinical routine.Taken together, our pre-clinical data showed the potential of PEP-010 as an anti-cancer peptide on a wide variety of malignancies and enabled the identification of pharmacodynamic biomarker candidates, important to ease the clinical development.

CIP2A expression could be a novel therapeutic strategy for chemoresistance in GC.

Collectively, we discover a unique multi-step hijack and mute protein complex regulation mechanism resulting in tumour suppressor PP2A-B56α inhibition. Further, the results unfold a structural determinant for the oncogenic activity of CIP2A, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.

This discovery stemmed from our finding that Survivin expression is downregulated upon treatment of pancreatic cancer cells with the KRAS inhibitor Sotorasib...CIP2A, by inhibiting protein phosphatase 2A (PP2A), helps to maintain MYC phosphorylation at Ser 62, thereby ensuring its cooperation with oncogenic KRAS in driving cancer progression. Overall, these findings highlight a novel role for Survivin in mediating the cooperative actions of KRAS and MYC during malignant transformation and raise the possibility that targeting Survivin may offer therapeutic benefits against KRAS-driven cancers.

Interestingly, the review focused on the role of PP2A inhibitors, focusing on CIP2A inhibition, as CIP2A participated in tumor cell growth by stimulating cell-renewal survival, cellular proliferation, evasion of senescence and inhibition of apoptosis. This review suggested CIP2A inhibition as a promising strategy in oncology target therapy.

The above results demonstrated that Eth inhibited the proliferation, induced the apoptosis, and activated the autophagy of SGC7901/DDP cells by targeting CIP2A and then down-regulating PP2A/mTORC1 signaling pathway. This study provided a new target for the treatment of cisplatin-resistant gastric cancer.

FC-A treatment of TNBC cells leads to the increased association of CIP2A with 14-3-3. We show that the composite interface between 14 and 3-3 and CIP2A's C-terminus can be targeted by the PPI stabilizer FC-A, providing a new interface that could potentially be exploited to modulate CIP2A's activity.

Furthermore, it was verified that prodigiosin inhibited the KIAA1524/PP2A/Akt axis in vivo in the LN229 xenograft model. These data improve the understanding of the anticancer effects of prodigiosin and further highlight the potential of prodigiosin for the development of anti-glioma drugs.

In conclusion, in vitro, in vivo and patient ex vivo data demonstrate ASAH1 is a novel, clinically relevant and tractable target for the treatment of PI-resistant MM. Future studies to develop novel and potent ASAH1 inhibitors for the treatment resistant MM, in combination with current standard of care therapies are on-going and we believed warranted based on our emerging data.

Importantly, inhibition of PP2A activity by genetic silencing of PPP2R5A resulted in a growth advantage, which can be largely compromised by the addition of the glycolysis inhibitor 2-Deoxy-D-glucose, suggesting a glycolysis-dependent effect of PP2A in gastric cancer...Ectopic expression of a phosphorylation-mutant c-Myc resistant to PP2A (MycT58A) restored the inhibitory effect of FTY-720 and DT-061 on lactate production and glucose uptake. Furthermore, there was a close association between SET and CIP2A expression and c-Myc gene signatures in gastric cancer samples. Collectively, this study provides strong evidence of the involvement of PP2A in the Warburg effect and indicates that it could be a novel antitumor strategy to target tumor metabolism in gastric cancer.

Moreover, GKI-1, the first-in-class small molecule inhibitor of MASTL kinase, phenocopied MASTL depletion in enhancing the outcome of cisplatin treatment in OSCC cells, at a dose substantially lower than that needed to disrupt mitotic entry. Finally, GKI-1 exhibited promising efficacy in a mouse tumor xenograft model, in conjunction with cisplatin therapy.

In conclusion, B7-H3 was found to be upregulated in malignant meningiomas. The PP2A inhibitor LB-100 increased the phosphorylation of STAT1 and B7-H3 expression, which could increase the sensitivity of malignant meningiomas to B7-H3 targeted immunotherapy.

Our findings indicate that PP2A may serve as a potential therapeutic target in BLCA through regulating p21 stability.

TP53TG1 interacts with cancerous inhibitor of protein phosphatase 2A (CIP2A) and triggers its ubiquitination-mediated degradation, resulting in the inhibition of PI3K/AKT pathway. These results suggest that TP53TG1 plays an important role in inhibiting the progression of GC and provides a crucial target for GC treatment.

The reduction of CIP2A expression also enhanced the sensitivity of PCa cells toward Enzalutamide treatment...In summary, our data showed the existence of a novel regulation between CIP2A and AR protein levels, which is critical for promoting PCa malignancy. Thus, CIP2A could serve as a therapeutic target for PCa.

Notably, for PP2A activation, we used the highly specific activator DT-061, that also reduces leukemic burden in peripheral blood, spleen and bone marrow in the Eµ-TCL1 adoptive transfer model of CLL, with a concomitant decrease in N1-ICD expression. Overall, we identify in GSK3β a key component of the network regulating N1-ICD stability in CLL, and in AKT and PP2A new druggable targets for disrupting NOTCH1 signaling with therapeutic potential.

Activation of PP2A with FTY720 or Ad-PP2A reduced phosphorylated AKT and inhibited ZEB1 transcription, thereby further downregulating the expression of MMP-2, VE-cadherin, and VEGFR-2, whereas inhibition of PP2A with okadaic acid (OA) or Ad-dn-PP2A exerted the opposite effect...This study indicated that PP2A could regulate VM formation in NSCLC through the PI3K/AKT/ZEB1 axis. PP2A reactivation or combination with PI3K inhibitor might be a more effective treatment against advanced NSCLC by inhibiting VM formation.

Dasatinib, a kinase inhibitor used in relapsed/refractory NB, and OP449 synergized, decreasing activating AKT phosphorylations. In summary, concomitantly reactivating phosphatases and inhibiting kinases with a combination of OP449 and dasatinib are promising novel therapeutic approaches to NB.

In multivariate analysis, CIP2A overexpression was an independent adverse prognostic factor that negatively affected DFS and OS (p<0.001, HR:2.8,95%CI:1.7-4.7 and p=0.002, HR:1.8; 95%CI:1.2-2.65, respectively). CIP2A overexpression is a useful prognostic marker in AML.

Our study suggests that PP2A activation is an effective strategy for SCSC treatment and the CD-3 and mTORi combination may serve as a promising treatment for SCSC.