Our study reveals mechanisms whereby Bmi1 preserves renal structure and function during aging by suppressing DDR and p53/TGFβ1-mediated EMT. These pathways represent potential targets for detecting and attenuating age-related renal decline.

Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

P1, N=21, Active, not recruiting, St. Jude Children's Research Hospital

Here, we demonstrate the utility of AP3 for the identification of a key druggable resistance mechanism to ACR-368 and how to overcome that with low dose gemcitabine (gem), providing OncoSignature negative patients with a new potential therapeutic option. These data supported a dose escalation Phase 1b/2 clinical study of low dose gem with ACR-368 to evaluate the efficacy and safety of the combination in ACR-368 OncoSignature negative patients (NCT05548296). This shows the potential of AP3 for unbiased elucidation of actionable drug resistance mechanisms and rapid clinical implementation in our trials, which have recently confirmed clinical activity.

Higher CHK2 expression was associated with poorer treatment responses and disease outcomes. Higher CHK2 expression and positive p53 together with a TP53 deletion could be a prognostic marker of unfavorable disease outcomes in patients with germline truncating mutations in CHEK2.

The upregulation of lncRNA AFAP1-AS1, which increases TSCC cell viability, migration, proliferation and invasion via the AFAP1-AS1/miR-133a-5p/ZIC2 axis, aids in the progression of TSCC.

Furthermore, 25 mutations in Chk1, 189 in Chk2, and 14 in Wee1 were highly conserved, possessing deleterious effect and also influencing the protein structure and function. These identified mutations may provide underlying genetic intricacies to serve as potential targets for therapeutic inventions and clinical management.

Study Design and Combination effects of simultaneous versus sequential treatment of PHI-101 with other agents, including daunorubicin, cytarabine, venetoclax (Ven), and azacytidine (Aza) were tested using human leukemia cell lines harboring FLT3-ITD mutations (MV4-11, Molm13, Molm14) or FLT3-wild type as controls...The GI 50 of the gilteritinib was 5... Treatment of AML cells with the combination of Ven or Aza with PHI-101 in vitro induced rapid induction of apoptosis and inhibition of cell growth that showed significant synergy. In vivo data showed improved efficacy for the combination treatment with these agents. In vitro and in vivo data from the preclinical AML models provides a rationale to evaluate the activity of PHI-101 in combination for patients who are ineligible for more intensive chemotherapeutic induction therapy.

"Acrivon Therapeutics, Inc...announced the U.S. Food and Drug Administration (FDA) has granted Breakthrough Device designation for the ACR-368 OncoSignature assay, a multiplex immunofluorescence assay for the identification of ovarian cancer patients who may benefit from ACR-368 treatment. The designation reflects FDA’s determination that the device is reasonably expected to provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions."

P1/2, N=390, Recruiting, Acrivon Therapeutics | Phase classification: P1b/2 --> P1/2

In conclusion, we developed a precise gene editing strategy of human HSCs to identify prexasertib as a promising therapy for SF3B1m myeloid neoplasms, and implicate the mitotic function of CHK1 as a SF3B1m sensitivity. The safety and toxicity profiles displayed in early phase clinical trials make prexasertib a suitable agent for further clinical investigation in SF3B1m MDS and its advanced stages.

P1/2, N=21, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

This subtype tended to metastasize and was resistant to respond to immunotherapy. Pharmacogenomics analysis showed three therapeutic agents (NVP-BEZ235, LY2606368, and rutin) were potential interventions for MNG-4.

No abstracts available

No abstracts available

P2, N=10, Completed, Baylor Research Institute | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Nov 2022

P1, N=36, Recruiting, Seoul National University Hospital | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2023

Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models...BRCA reversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC.

Mechanistically, LINC00173 bound with checkpoint kinase 2 (CHK2) in nucleus, and impaired the irradiation-induced CHK2 phosphorylation, then suppressed the activation of P53 signalling pathway, which eventually inhibiting apoptosis and leading to radioresistance in NPC cells. In summary, LINC00173 decreases the occurrence of apoptosis through inhibiting the CHK2/P53 pathway, leads to NPC radioresistance and could be considered as a novel predictor and therapeutic target in NPC.

Collectively, our data suggest the possible involvement of innate immunity in modulating CHK1i response. Increasing peripheral immunosuppressive cells and lower immunocompetence of the innate immune system may contribute to CHK1i resistance, whereas the functionality of DCs may be involved in the response. Enhancing innate immunity may represent a strategy to increase CHK1i response in this hard-to-treat population.

P2, N=10, Active, not recruiting, Baylor Research Institute | Trial completion date: Dec 2022 --> Dec 2023

Our results suggest that the mitochondrial-related risk model could be a reliable prognostic biomarker for personalized treatment of STAD patients.

In addition, effective therapeutic responses to olaparib-Ga and cisplatin combination or olaparib-Ga and carboplatin combination were observed in SKOV3-cis tumor-bearing animal models. Altogether, the present findings demonstrate that olaparib-Ga has therapeutic implications in platinum-resistant OC cells, and the combination of olaparib-Ga with cisplatin or carboplatin may be promising for treating patients with OC who exhibit resistance to both PARPi and platinum.

Moreover, treatment with SFN inhibited CD34-positive neovascularization with decreased VEGF expression and GEM-induced EMT in iCCA-derived xenografted tumors. In conclusion, these results suggest that combination therapy with SFN with GEM is a potential novel option for iCCA treatment.

CHK1i yields promising clinical benefit in BRCAwt, PR-HGSOC, hard-to-treat population. Our preliminary biomarker analyses suggest that tumoral upregulation of IGF1/insulin and DNA repair pathways as well as a systemic increase of immunosuppressive cells, e.g., M-MDSCs may negatively impact CHK1i response.

Additionally, the phosphorylation of ERK, JNK, and p38 MAPK was suppressed when the cells were treated with their respective inhibitors (U0126, SP600125, and SB203580)...These data demonstrate that BPA interferes with the proliferation, migration, and invasion capacities of VSMCs. Therefore, our findings suggest that overexposure to BPA can lead to cardiovascular damage due to dysregulated VSMC responses.

All the results suggest that baicalein has another novel growth inhibitory effect on highly invasive ovarian cancer cells, which is partly related to G/M cell cycle arrest through the ROS-mediated DNA breakage damage and CHK2 activation. Collectively, our findings provide a molecular basis for the potential of baicalein as an adjuvant therapeutic agent in the treatment of metastatic ovarian cancer.

Here we show that human lung or mammary cells strikingly undergo SQM with polyploidisation when they are exposed to genotoxic or mitotic drugs, such as Doxorubicin or the cigarette carcinogen DMBA, Nocodazole, Taxol or inhibitors of Aurora-B kinase or Polo-like kinase. The results show that DNA damage has the potential to drive SQM via mitotic checkpoints, thus providing novel molecular candidate targets to tackle lung SCC. Our findings might also explain why SCC is frequent in the lung, but not in the mammary gland and why chemotherapy often causes complicating skin toxicity.

FFGL can inhibit cervical cancer cell proliferation. Furthermore, it can increase CDK1 phosphorylation, block the cell cycle by causing DNA damage, and inhibit HeLa cell proliferation.

Cellular evaluation indicated that AO/854-suppressed tumor growth and metastasis in PC3 cells by enhancing DNA damage, phosphorylating Chk1/Chk2, and altering the p53 signaling pathway. Collectively, the study highlights the potential of BLM as a therapeutic target in PCa and reveals a distinct mechanism by which AO/854 competitively inhibits the function of BLM.

In conclusion, we detected germline CHEK2 variants in 7.7% of all pediatric cancer patients, of which a minority but still relevant fraction of approximately 20% had a profound impact on protein expression or its phosphorylation after irradiation-induced DNA damage. Accordingly, we conclude that CHEK2 variants increase the risk for not only adult-onset but also pediatric cancer.

In general, the decrease in the expression of DNA damage repair genes in tumor tissue indicates that these genes may have a role in the development of BC. Our study results also suggest that CHK2 may be a candidate marker in the molecular classification of breast cancer.

Repression of the miR-34a-5p-c-MYC-CHK1/CHK2 axis contributes to the acquisition of radioresistance in HCC cells. In summary, the miR-34a-5p-c-MYC-CHK1/CHK2 axis counteracts cancer stem cell-like properties and enhances radiosensitivity in hepatocellular cancer through repression of the DNA damage response.

In the form of an NCA-chitosan nanoformulation, the efficacy was enhanced by about 8 times compared to free form of NCA towards selective killing of CHK2-null HCT116 cells as compared to HCT116 cells. The chitosan-based nanoformulation for NCA was developed to augment the efficacy of the NCA for enhanced cell death of colorectal cancer cells having CHK2 defects.

We finally demonstrated the crucial role of p53 for OH-ME triggered cell death as evidenced by reduced pro-apoptotic gene expression, strongly attenuated Bax activation and cell death inhibition upon genetic knockdown or pharmacological inhibition of p53. Taken together, our study demonstrates for the first time that ME-derived DNA damage causes replication stress and triggers mitochondrial apoptosis via the p53-Bax pathway.

Furthermore, we show that the glutathione-targeted Cys8E nanoparticles we synthesized, which have high drug-loading capacity, remarkable stability, and satisfactory release efficiency, enhanced the therapeutic efficacy of this treatment and reduced the required dosages of these drugs both in vitro and in vivo. Overall, we propose combination therapy of cisplatin and AZD7762 for PCa and facilitate it using Cys8E nanoparticles, which allow for better drug loading release, higher release efficiency, and more accurate tumor-targeting efficacy.

Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.