P1, N=30, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P1/2, N=135, Recruiting, GlaxoSmithKline | Trial completion date: Nov 2025 --> Nov 2029 | Trial primary completion date: Jun 2025 --> Dec 2027

Moreover, the combination of POLQ inhibitor and ferroptosis inducer synergistically suppressed MGC-803 xenograft tumor growth and diminished metastasis. Our results identify a POLQ-mediated stemness and ferroptosis defense mechanism and provide a new therapeutic strategy for gastric cancer.

Cells were pretreated with simvastatin or lovastatin before GSK101...Herein, we showed that statins can modulate gliosis and TNF-α expression in Müller cells, protecting RGCs. These data further support the neuroprotective effect of statins, promoting them as a potential treatment for glaucoma.

P1/2, N=390, Active, not recruiting, Artios Pharma Ltd | Recruiting --> Active, not recruiting | Trial completion date: Aug 2025 --> Jan 2026 | Trial primary completion date: Mar 2025 --> Aug 2025

P1/2, N=135, Recruiting, GlaxoSmithKline | Phase classification: P1 --> P1/2

P1, N=30, Suspended, National Cancer Institute (NCI) | Initiation date: Oct 2023 --> Jul 2023

Thus, DNA/chromatin binding and TMEJ activity of PolΘ were restored upon PARG-mediated removal of PAR repressive marks on PolΘ. This process seems to play a critical role in protecting OTK-positive hematopoietic malignant cells from genotoxic effect of formaldehyde generated by altered serine/one-carbon cycle metabolism.

P1, N=112, Recruiting, GlaxoSmithKline | Not yet recruiting --> Recruiting | Phase classification: P1/2 --> P1

DNMT3A mutations promote resistance to anthracyclines (including daunorubicin, the component of standard "7+3" induction therapy), interferon alpha, and ABL1 kinase inhibitor imatinib...The combination of Polθis + quizartinib and Polθis + etoposide completely eradicated clonogenic activity of these cells while Polθis + cytarabine and Polθis + azacytidine exerted modest and weak effects, respectively, when compared to individual compound treatments...Median survival time of the mice will be recorded. Altogether, we discovered that Polθ protects OTK-positive DNMT3A-deficient myeloid malignant cells from the toxic effects of DSBs and identified Polθ as a novel therapeutic target.

P1/2, N=112, Not yet recruiting, GlaxoSmithKline

P1, N=30, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=30, Recruiting, National Cancer Institute (NCI) | Initiation date: Jul 2023 --> Oct 2023

P1/2, N=250, Recruiting, Artios Pharma Ltd | Not yet recruiting --> Recruiting

P1, N=30, Recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2023 --> Jul 2023

Small molecule inhibitor of Poltheta (Polthetai) when combined with PARP or RAD52 inhibitors (PARPi, RAD52i) caused accumulation of DSBs and exerted increased effect against HR-deficient leukemia and myeloproliferative neoplasm cells. Implications: In conclusion, we show that PARPi or RAD52i might improve therapeutic effect of Polthetai against HR-deficient leukemias.

P1/2, N=250, Not yet recruiting, Artios Pharma Ltd

Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to block tumor growth while simultaneously stimulating an immune response.

P1, N=30, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Depletion of CD8 T cells compromised the efficacy of POLθ inhibition, whereas antitumor effects were augmented in combination with anti-PD-1 immunotherapy. Collectively, our findings demonstrate that POLθ inhibition induces immune responses in a cGAS/STING-dependent manner and provide a rationale for combining POLθ inhibition with immune checkpoint blockade for the treatment of HR-deficient cancers.

In vitro, single-agent treatment with novobiocin or ART558 caused a significant cytotoxic effect at physiologically relevant concentrations in ATM-deficient cells and co-treatment of novobiocin or ART558 with AZD0156 was synergistic in killing ATM-proficient MCL cells. Importantly, POLQ inhibitors significantly decreased the cell viability of MCIR1, which is an ibrutinib-resistant MCL cell line... POLQ is a promising target in MCL, especially in ATM-deficient setting. In ATM-proficient MCL, targeting ATM and POLQ is synergistic. Our data has the potential to uncover novel biomarker-driven drug therapy of POLQ inhibitors in R/R MCL.

P1/2, N=290, Recruiting, Artios Pharma Ltd | N=206 --> 290

P1, N=30, Not yet recruiting, National Cancer Institute (NCI)

Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer-specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC.

Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLq inhibitor (POLqi) in vitro and in vivo. In conclusion, we demonstrated that POLq plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde and that it can be targeted to achieve therapeutic effect.

While the MRN complex nucleolytically processes ssDNA gaps, CDK6 promotes cell-cycle progression, thereby exacerbating replication stress, a feature of BRCA1-deficient cells that lack POLθ activity. Thus, ssDNA gap formation, modulated by cell-cycle regulators and MRN complex activity, underlies the synthetic lethality between POLθ and BRCA1, an important insight for clinical trials with POLθ inhibitors.

Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLθ inhibitor (POLθi) in vitro and in vivo...A scheme illustrating functional pathway where OTKs - reprogrammed serine/1C cycle – produced formaldehyde induces DPCs which are likely repaired by POLθ-mediated end-joining (TMEJ). OTKs also enhance the expression of POLθ by stimulating ERK1/2 serine/threonine kinases, which inhibit c-CBL E3 ligase-dependent ubiquitination of POLθ and its proteasomal degradation.

As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo...The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.

Peposertib is an inhibitor of DNA-dependent protein kinase (DNA-PK), which is a key driver of nonhomologous end-joining (NHEJ)...Consequently, the combination of peposertib plus novobiocin resulted in synthetic lethality in TP53-deficient tumor cell lines, organoid cultures, and patient-derived xenograft models. Thus, the combination of a targeted DNA-PK/NHEJ inhibitor with a targeted POLθ/MMEJ inhibitor may provide a rational treatment strategy for TP53-mutant solid tumors.

A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2 mouse tumor xenograft model.

Here, we show that even though Polθ deficiency does not fully prevent the development of pancreatic cancer, it significantly delays the onset of PanIN formation, prolongs the overall survival of experimental mice, and correlates with the overall survival of pancreatic cancer patients in the TCGA database. Our study clearly demonstrates the role of alt-EJ in the development of PDAC, and alt-EJ may be an attractive therapeutic target for pancreatic cancer patients.

We detected BRCA reversion mutations in at least ̃40% of breast and ̃20% of ovarian cancer pts following treatment with olaparib. A large proportion of these reversion mutations are likely to have been mediated by MMEJ repair, suggesting that POLθ inhibitors in combination with platinum or PARP inhibitors might prevent or delay emergence of PARP inhibitor resistance.

Collectively, our study revealed that POLQ may participate in the development of HCC, depletion of which may be a promising treatment strategy for HCC.

P1/2, N=206, Recruiting, Artios Pharma Ltd | Not yet recruiting --> Recruiting

The specific gain in expression of POLQ, encoding the error-prone DNA polymerase Theta (POLθ) involved in theta-mediated end joining (TMEJ), is associated with a characteristic mutational signature. To gain insight into the mechanistic regulation of POLQ expression, this review briefly presents recent findings on the regulation of POLQ in the claudin-low breast tumor subtype, specifically expressing transcription factors involved in epithelial-to-mesenchymal transition (EMT) such as ZEB1 and displaying a paucity in genomic abnormality.

P1/2, N=206, Not yet recruiting, Artios Pharma Ltd

Loss of POLQ and/or FANCD2 also resulted in the activation of cGAS and upregulation of interferon-stimulated genes (ISGs). Our results suggest that high abundance of POLQ in ESCC contributes to the malignant phenotype through genome instability and activation of the cGAS pathway.

Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. (151/150).