AKR1C3 expression

P2, N=39, Recruiting, SWOG Cancer Research Network | Trial completion date: Aug 2027 --> Aug 2032 | Trial primary completion date: Aug 2026 --> Aug 2028

To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent...ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL.

Gratifyingly, concomitant degradation of ARv7 was observed with a DC50 = 70 nM, along with degradation of the AKR1C3 isoforms AKR1C1 and AKR1C2 to a lesser extent. This compound represents a highly useful chemical tool and a promising strategy for prostate cancer intervention.

Moreover, AKR1C3 expression was correlated with the infiltration of several immune cell types, and AKR1C3 was predicted to interact with several clinical drugs. Dysregulated AKR1C3 expression is related to gastric carcinogenesis and immunotherapy response and is a promising biomarker and effective biotherapy target in GC.

The in vivo results suggested that AKR1C3 knockdown inhibited the development of subcutaneous TPC-1 tumors in nude mice and inactivated the ERK signaling. Collectively, AKR1C3 silencing inhibited autophagy-dependent glycolysis in thyroid cancer by inactivating ERK signaling.

P2, N=39, Recruiting, SWOG Cancer Research Network | Active, not recruiting --> Recruiting

We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib. In summary, our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α, and suppression of PTGFR limited HCC growth. Therefore, targeting the AKR1C3-PGF2α-PTGFR axis may be a new strategy for the treatment of HCC.

AKR1C3 inhibitor 2j significantly suppressed 5α-Adione-induced AR and ELK1 upregulation, as did an AR antagonist apalutamide. Immunohistochemical staining in surgical specimens further revealed that strong expression of AKR1C3 was associated with significantly higher risks of tumor progression and cancer-specific mortality in patients with muscle-invasive bladder cancer. These results suggest that AKR1C3 inhibitors as adjunctive agents enhance the efficacy of GC therapy for bladder cancer.

In conclusion, we constructed an optimal model that was derived from single cell RNA-seq and bulk RNA-seq to predict the survival probability of HNSCC patients. Among this model, AKR1C3 higher expression in cancer associated fibroblasts (CAFs) of HNSCC has been confirmed by preliminary experiments.

ACHM-025 was designed to improve drug specificity and minimize toxicity observed with currently used DNA alkylating agents, such as cyclophosphamide (CPM), a prodrug which is activated systemically via liver enzymes...For the consolidation therapy comparison, ACHM-025 (IP Days 0, 7) or CPM (IP Days 0, 7) combined with cytarabine (Ara-C; IP Days 0-4, 7-11) and 6-mercaptopurine (6MP; IP Days 0-4, 7-11) were assessed against a T-ALL PDX derived from a patient at relapse... ACHM-025 exerted profound in vivo efficacy against T-ALL PDXs and eradicated the disease in 7 aggressive T-ALL PDXs. ACHM-025 was significantly more effective than CPM both as a single agent and when used in combination with Ara-C/6MP. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo.

In sum, we found that AKR1C3 can bind with Keap1 leading to reduced ubiquitination level of Nrf2, causing upregulation of Nrf2 expression and providing new insights into PCa radiotherapy resistance.

AST-3424 had a promising effect against HCC in PDTX model and orthotopic model with good safety. It could promote the sensitivity of other drugs without increasing toxicity. Clinical trials are warranted to further certify its antitumor effect and safety.

Resistant cell sublines generated from C4-2B cells resistant to enzalutamide (MDVR), apalutamide (ApalR), darolutamide (DaroR), or abiraterone (AbiR) were treated with LX-1 or their respective antiandrogen and cell number was determined. We generated novel small molecule inhibitors that concurrent target AR/AR-variant and AKR1C3. These compounds, specifically LX-1, effectively reduce CRPC growth and synergize with antiandrogens including enzalutamide in vitro and in vivo, suggesting potential for treating advanced prostate cancer.

Notably, elevated ERRα portends poor prognosis for prostate cancer and cholesterol is an ERRα agonist. Considering that statin can diminish ERRα activity (PMID 26777690) and AKR1C3 inhibitors are in clinical trials, this novel axis revealed from our study may be actionable for the clinical interception of the progression in SULT2B-low advanced prostate cancer.

In addition, the molecular docking results suggested that the genistein had a strong affinity with the AKR1C3, and that it could be a promising AKR1C3 inhibitor. Genistein inhibits the progression of CRPC via the suppression of AKR1C3.

In a validated experiment, we demonstrated that PCNP and CINP were up-regulated, and TERF2 and TP53 were down-regulated by western blotting. We concluded that siAKR1C3@PPA may arrest the cell cycle and affect cell proliferation.

AKR1C3-dependent LD accumulation protects HCC cells from sorafenib-induced mitochondrial lipotoxicity by regulating lipophagy. Targeting AKR1C3 might be a promising therapeutic strategy for HCC tumors.

Finally, we provide evidence that these effects require the expression of the antioxidant response sensor, nuclear factor erythroid 2-related factor 2 (Nrf2). Our findings identify an interconnection between conventional fatty acid metabolism and steroid metabolism that has broad relevance to androgen physiology and inflammatory regulation.

AKR1C3-EXO is associated with patient prognosis regarding OS and ABI-PFS and can be used as a biomarker in mCRPC.

In our experiments, ZAN inhibited the AKR1C3-mediated inactivation of daunorubicin (DAUN) at both the recombinant and cellular levels. Finally, in accumulation assays, ZAN was found to interfere with the DAUN efflux mediated by the ABCB1, ABCG2, and ABCC1 transporters, which might further contribute to the reversal of ANT resistance. In summary, our data provide the rationale for ZAN inclusion in ANT-based therapy and suggest its potential for the treatment of tumours expressing AKR1C3 and/or the above-mentioned ABC transporters.

AST-3424 is a prodrug of a potent nitrogen mustard, which targets the tumor by its specific and selective mode of activation and results in the concentration of the drug in the tumor and plays a higher intensity of antitumor effect with reduced side effects...The inhibition of AST-3424 was significantly higher than OXA, 5-Fu, Sor (sorafenib), and Apa (apatinib) in both HCC cells...The in-vitro studies revealed that AST-3424 in combination with both OXA and 5-Fu showed an increased antitumor effect, and the combination with OXA resulted in a synergistic effect. Together with the in-vitro results, additional in-vitro and in-vivo studies are warranted to further certify its antitumor effects and explore more potential antitumor mechanisms.

Further, AKR1C3 stabilized PARP1 by decreasing its ubiquitination, which resulted in HCC cell proliferation and low sensitivity of Cisplatin. Moreover, we discovered that the tumorigenic role of AKR1C3 was non-catalytic dependent and the NRF2/MAFG-AKR1C3-PARP1 axis might be one of the important proliferation pathways in HCC. In conclusion, blockage of AKR1C3 expression provides potential therapeutic benefits against HCC.

The detected plasma and tissue AKR1C3 expression levels were analyzed for patients' overall survival (OS) and progression-free survival under first-line abiraterone use (ABI-PFS)...In patients with worse baseline blood tests (including higher alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) level and lower hemoglobin (HB) level), and lower ISUP/WHO group (<4), their OS was significantly worse when showing AKR1C3-EXO positive. Conclusions AKR1C3-EXO is associated with patient prognosis regarding OS and ABI-PFS and can be used as a biomarker in mCRPC.

The AKR1C3 expression in peripheral blood by Protein Wes and RT-qPCR showed concordance in relapsed/refractory and/or minimal residual T-ALL cases. Sigma/Millipore Anti-AKR1C3 antibody and mouse monoclonal, clone NP6.G6.A6 can be used to aid in AKR1C expression of T-ALL and in cases of relapsed/refractory and/or minimal residual disease.

TFX05-01 is a novel selective AKR1C3-activated prodrug, which is different from traditional non-selective alkylating agents for cancer therapy. Preclinical studies have shown profound in vivo efficacy of TFX05-01 in AKR1C3 overexpressed mouse tumor xenograft models without marked toxicity. TFX05-01 represents a novel treatment option for AKR1C3 expressing solid cancers.

The AKR1C3 inhibitor PB was modified from celecoxib...The effects of the AKR1C3 inhibitor on enzalutamide sensitivity were characterized by growth assay and colony formation assay. Eight PDX models have been developed from prostate cancer patients with high Gleason score and/or at the castration-resistant stages... PS1172 and castration-resistant 1172CR cells are novel models with significant characteristics such as AR-V7 and AKR1C3. These novel prostate cancer models are ideal for small molecule testing and resistant mechanism investigating.

Downregulation of AKR1C3 by HEXIM1 influenced E2 and DHT production, estrogen- and androgen-dependent gene expression, and cell proliferation. Our studies indicate that HEXIM1 has the unique ability to inhibit both the transcriptional activity of the ER and AR and the synthesis of the endogenous ligands of these receptors.

from the Slovenian Research Agency. Ethical Issues The study was approved by the National Medical Ethics Committee of the Republic of Slovenia (0120-701/2017-6).

Based on the predictive factors in multivariate analysis, we developed two risk stratification tools to select candidates for corticosteroid switching. Detection of serum ALP level, PSA level, and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.

In the combination therapy, we showed that 3424 could enhance the efficacy of the standard care of chemotherapy in the CDX models. The results described here highlight that 3424 exhibits AKR1C3-dependent cytotoxicity in vitro and anti-tumor activity in vivo in a wide range of human cancer types, which support further development of 3424 as an anti-cancer agent for treating different types of cancers and the use of AKR1C3 as a biomarker to profile cancer patients and further guide patient selection for therapy with 3424.

High AKR1C3 nuclear expression in NSCLC is related to radiation resistance. The higher the AKR1C3 nucleus expression, the worse short-term curative effects after radiotherapy. High β-catenin nuclear expression is related to radiation resistance, and the higher the β-catenin nuclear expression, the worse the short-term curative effects after radiotherapy. The nuclear aggregation of AKR1C3 during radiation resistance of non-small cell lung cancer (NSCLC) may have some synergistic relationship with nuclear aggregation of β-catenin.

Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.

DDHD1 expression is associated with depth of tumor invasion in CRC tissues and may be involved in tumor progression.

Altogether, our study identifies a novel signaling regulation of miR-379-5p/AKR1C3/EKR axis in regulating IM resistance in CML cell, and provides a scientific base for exploring AKR1C3 as a biomarker in impeding IM resistance in CML.