PFK-158 / Advanced Cancer Therap - LARVOL DELTA

Inhibiting glycolysis for the treatment of HGF/MET/TWIST1 driven NSCLC brain metastases (AACR 2025) - "Interestingly, TWIST1 OE in H1993 cells increased HK2 levels, leading to 2DG resistance but increased sensitivity to the downstream glycolytic inhibitor, PFK158 with similar or decreased sensitivity to oxidative phosphorylation (OXPHOS) inhibitors...Remarkably, H1993 CR cells which were resistant to glycolytic inhibition in vitro were sensitive to 2DG ex vivo. These findings suggest that MET-driven glycolytic dependency plays a significant role in BM, highlighting glycolysis as a potential therapeutic target."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET • TWIST1

Repression of PFKFB3 sensitizes ovarian cancer to PARP inhibitors by impairing homologous recombination repair. (PubMed, Cell Commun Signal) - "Our findings demonstrate that PFKFB3 is crucial for PARPi resistance in OC. Inhibiting PFKFB3 sensitizes HR-proficient OC cells to PARPis by impairing HR repair, leading to increased DNA damage and apoptosis. PFKFB3 represents a promising therapeutic target for overcoming PARPi resistance and improving outcomes in OC patients."

Journal • Gynecologic Cancers • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • HRD • PFKFB3 • RPA3

The significance of upper glycolytic components in regulating retinal pigment epithelial cellular behavior. (PubMed, Sci Rep) - "Specific inhibitors used included WZB117 for Glut1 inhibition, Lonidamine for Hexokinase inhibition, PFK158 for PFKFB3/PFK axis inhibition, and TDZD-8 for Aldolase inhibition...Specifically, it highlights the critical roles of Glut1 and Aldolase in preserving barrier integrity and promoting RPE cell adhesion and spreading. Such understanding will guide the development of safe interventions to treat RPE cell dysfunction in various retinal disorders."

Journal • Age-related Macular Degeneration • Diabetic Macular Edema • Macular Degeneration • Ophthalmology • Retinal Disorders • PFKFB3 • SLC2A1

Hypoxia activates macrophage-NLRP3 inflammasome promoting atherosclerosis via PFKFB3-driven glycolysis. (PubMed, FASEB J) - "In addition, we administered the PFKFB3 inhibitor PFK158 during atherosclerosis modeling...Our study demonstrated that the HIF-1α/PFKFB3/NLRP3 axis serves as a crucial mechanism for macrophage inflammation activation in the emergence of atherosclerosis. The therapeutic potential of PFKFB3 inhibition may represent a promising strategy for atheroprotection."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • APOE • HIF1A • IL1B • NLRP3 • PFKFB3 • TNFA

PFKFB3 regulates breast cancer tumorigenesis and Fulvestrant sensitivity by affecting ERα stability. (PubMed, Cell Signal) - "Finally, growth of ER-positive breast cancer cells in vivo was more potently inhibited by fulvestrant combined with the PFKFB3 inhibitor PFK158 than for each drug alone. In conclusion, these data suggest that PFKFB3 is identified as an adverse prognosis factor for ER-positive breast cancer and plays a previously unrecognized role in the regulation of ERα stability and activity. Our results further explores an effective approach to improve fulvestrant sensitivity through the early combination with a PFKFB3 inhibitor."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER • PFKFB3

Targeting a novel TWIST1-Hexokinase II pathway to overcome MET TKI resistance in NSCLC (AACR 2024) - "Furthermore, LUAD cell lines with high MET expression demonstrated increased expression and activity of glycolytic enzymes, as well as increased susceptibility to glucose deprivation and glycolytic inhibitors (2DG, PFK158, AT-101, V-9302). Conversely, treatment of MET amplified cells with MET TKI, capmatinib, reduced glycolysis and oxidation phosphorylation to the levels observed in MET wild type LUAD lines...These findings suggest that continued upregulation of the TWIST1-HK2 axis is required for acquired MET TKI resistance. In summary, these studies suggest a targetable, metabolic reprogramming in MET altered LUAD BM mediated through a novel TWIST1-HK2 pathway."

IO biomarker • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET • TWIST1

Silencing of necroptosis related genes in endocrine-resistant breast cancer cells causes PFKFB3 induced arrest of necroptosis and contributes to resistance (AACR 2024) - "In this study, we showed that silencing of RIPK1 and MLKL, genes involved in necroptosis, by siRNAs followed by inhibition of PFKFB3 by PFK158 did not induce necroptosis in endocrine-resistant BC cells. Furthermore, we further confirmed that phosphorylation of MLKL and RIPK occurs with PFKFB3 inhibition. In summary, this study reveals that necroptosis induced by PFKFB3 inhibition contributes to resistance by arresting necroptosis in endocrine-resistant BC cells after silencing of necroptosis-related genes."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • PFKFB3 • RIPK1

Upper glycolytic components contribute differently in controlling retinal vascular endothelial cellular behavior: Implications for endothelial-related retinal diseases. (PubMed, PLoS One) - "This study illustrates the unique impacts of components within upper glycolysis on HREC functionality, emphasizing the crucial role of the PFKFB3/PFK axis in regulating HREC behavior. Understanding the specific contributions of each glycolytic component in preserving normal REC functionality will facilitate the development of targeted interventions for treating endothelial cell dysfunction in retinal disorders while minimizing effects on healthy cells."

Journal • Diabetic Macular Edema • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • PFKFB3 • SLC2A1

6-Phosphofructo-2-kinase in regulating DNA damage and repair in EGFR-driven lung cancer (AACR 2023) - "Moreover, a PFKFB3 inhibitor, PFK-158, increases oxidative stress in mutEGFR lung cancer cell lines and, as a result, promotes DNA damage. Importantly, we found that PFKFB3 plays an important role in the chromatin binding of scaffold proteins regulating the assembly of DNA repair complex.Our studies suggest that PFKFB3 plays an important role in DDR and provide a clear rationale to propose the use of PFKFB3 inhibitors in combination with EGFR inhibitors to increase the efficiency and/or overcome resistance to EGFR-TKIs."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • PFKFB3 • RRM2

PFKFB3 Increases IL-1β and TNF-α in Intestinal Epithelial Cells to Promote Tumorigenesis in Colitis-Associated Colorectal Cancer. (PubMed, J Oncol) - "In addition, PFK158, the PFKFB3 inhibitor, could reduce the CRC cell viability, migration, and invasion caused by PFKFB3 overexpression. In conclusion, overexpression of PFKFB3 promoted tumorigenesis in CAC by inducing phospho-p65 and expression of IL-1β and TNF-α. Our study suggested that PFKFB3 acted as a potential treatment target for CAC."

Journal • Colorectal Cancer • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Solid Tumor • IL1B • PFKFB3 • TNFA

Gene-dosage effect of Pfkfb3 on monocyte/macrophage biology in atherosclerosis. (PubMed, Br J Pharmacol) - "Collectively, these findings suggest the existence of a double-edged sword effect of myeloid PFKFB3 on the pathogenesis of atherosclerosis, and highlight the need for caution in developing anti-atherosclerotic strategies that target PFKFB3."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • APOE • PFKFB3

PFKFB3 regulates cancer stemness through the hippo pathway in small cell lung carcinoma. (PubMed, Oncogene) - "We found that PFK158 treatment and PFKFB3 knockdown enhanced the ABCG2-interacting drugs doxorubicin, etoposide, and 5-fluorouracil in reducing cell viability under conditions of enriched cancer stem cells (CSC). PFKFB3 knockdown and PFK158 treatment in a H1048 SCLC cancer stem cell-enriched mouse xenograft model showed significant reduction in tumor growth and weight with reduced expression of cancer stem cell markers, ABCG2, and YAP/TAZ. Our findings identify that PFKFB3 is a novel target to regulate cancer stem cells and its associated therapeutic resistance markers YAP/TAZ and ABCG2 in SCLC models."

Journal • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • ABCG2 • ALDH1A1 • CD133 • CD44 • PFKFB3 • SOX2

PFKFB3 works on the FAK-STAT3-SOX2 axis to regulate the stemness in MPM. (PubMed, Br J Cancer) - "This study confers a comprehensive and mechanistic function of PFKFB3 in CSC maintenance that may foster exceptional opportunities for targeted small molecule blockade of the TICs in MPM."

Journal • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Movement Disorders • Oncology • Solid Tumor • CD133 • CD44 • CDKN1A • PFKFB3 • SKP2 • SOX2 • STAT3

Therapeutic targeting of PFKFB3 and PFKFB4 in multiple myeloma cells under hypoxic conditions. (PubMed, Biomark Res) - "The combined treatment of myeloma cells with carfilzomib and PFK158 or 5MPN was more cytotoxic than either drug alone. In addition, the combined treatment was effective in the bortezomib-resistant cell line. Our data also suggest that administration of PFKFB3 and PFKFB4 inhibitors may be a powerful strategy against myeloma cells and to enhance the cytotoxic effects of proteasome inhibitors in hypoxic conditions."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • CASP3 • CASP7 • PFKFB3 • PFKFB4

PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer. (PubMed, Front Oncol) - "3PO, a PFKFB3 inhibitor, reduced lactate level and sensitized A2780CP cells to cisplatin treatment, along with the modulation of inhibitors of apoptosis proteins (c-IAP1, c-IAP2 and survivin) and an immune modulator CD70. PFK158, another potent inhibitor of PFKFB3, impaired the stemness of ALDH+CD44+ cells in vitro and in vivo, whereas ectopic expression of PFKFB3 had the opposite results. Overall, PFKFB3 was found to mediate metabolic reprogramming, chemoresistance, metastasis and stemness in ovarian cancer, possibly via the modulation of inhibitors of apoptosis proteins and the NF-κB signaling pathway; thus, suggesting that PFKFB3 may be a potential therapeutic target for ovarian cancer."

Journal • Immune Modulation • Inflammation • Oncology • Ovarian Cancer • Solid Tumor • BIRC3 • BIRC5 • CD44 • CD70

Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer. (PubMed, Cancer Metab) - "Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients."

Journal • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • MYC

Synergistic Activity and Biofilm Formation Effect of Colistin Combined with PFK-158 Against Colistin-Resistant Gram-Negative Bacteria. (PubMed, Infect Drug Resist) - "The biofilm formation assay and scanning electron microscopjihy showed that colistin with PFK-158 can effectively suppress the formation of biofilm and reduce the cell arrangement density of biofilm against most experimental strains. The results of the performed experiments suggest that the combination of colistin and PFK-158 may be a potential new choice as a new antibiofilm group for the treatment of infections caused by the colistin-resistant GNB."

Journal • Infectious Disease • Pneumonia

Group III phospholipase A2 downregulation attenuated survival and metastasis in ovarian cancer and promotes chemo-sensitization. (PubMed, J Exp Clin Cancer Res) - "Taken together, our study for the first time emphasizes the role of PLA2G3 in regulating the OC metastasis. This study further suggests the therapeutic potential of targeting phospholipases and/or restoration of PC for future OC treatment and the critical role of PLA2G3 in regulating ciliary function by coordinating interface between lipogenesis and metastasis."

Journal • Metabolic Disorders • Oncology • Ovarian Cancer • Solid Tumor

[VIRTUAL] 6-phosphofructo-2-kinase enhances cytotoxicity of the EGFR inhibitor erlotinib via regulation of cell cycle in non-small lung cancer cell lines (AACR 2021) - "Importantly, dual treatment caused only minor changes in glycolytic flux when compared to the effects of PFK-158 or erlotinib alone suggesting that glucose metabolism did not contribute to the observed effect. Taken together, our findings suggest that a non-metabolic function of PFKFB3 limits the usefulness of EGFR-TKI in vitro and that targeting of PFKFB3 can be a promising approach to improve clinical efficacy of FDA-approved EGFR-TKIs in lung cancer patients."

Preclinical • Lung Cancer • Oncology • Solid Tumor • FDG PET

[VIRTUAL] Autophagy-dependent therapeutic targeting of group III phospholipase A2 attenuates ovarian cancer metastasis (AACR 2021) - "PLA2G3 knockout OVCAR5 xenograft in combination with carboplatin on tumor growth and metastasis was assessed in vivo. Taken together, this will be the first comprehensive study that emphasizes the in depth crucial role of PLA2G3 in regulating the OC metastasis and further suggests the therapeutic potential of targeting phospholipases and/or restoration of primary cilia in cancer cells for future treatment. Thus, the elucidation of pathways and molecular inhibitors towards ciliogenesis in cancer cells will be of interest to forge forward to be tested in a novel clinical setting."

Oncology • Ovarian Cancer • Solid Tumor

Design, synthesis, and antibacterial evaluation of PFK-158 derivatives as potent agents against drug-resistant bacteria. (PubMed, Bioorg Med Chem Lett) - "Compounds A1, A3, A14, A15 and B6 exhibited potent antibacterial effect against both clinical drug sensitive and resistant Gram-positive bacteria, and they are 2-8 folds more potent than levofloxacin against Methicillin-resistant staphylococcus epidermidis (MRSE). A significant synergistic effect of these compounds and polymyxin against drug-resistant Gram-negative bacteria, which is similar to PFK-158 was also observed. The result can provided a new and broader prospect for the development of new medicine against drug-resistant bacteria."

Journal

Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets. (PubMed, Cancers (Basel)) - "We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options."

Journal • Review • Oncology

Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer. (PubMed, Oncogene) - "Pharmacological inhibition of PFKFB3 with PFK158 and or genetic downregulation of PFKFB3 dramatically suppressed cell proliferation and enhanced the sensitivity of EC cells to carboplatin (CBPt) and cisplatin (Cis). More importantly, PFK158 treatment, either as monotherapy or in combination with CBPt, led to a marked reduction in tumor growth in two chemoresistant EC mouse xenograft models. These data suggest that PFKFB3 inhibition alone or in combination with standard chemotherapy may be used as a novel therapeutic strategy for improved therapeutic efficacy and outcomes of advanced and recurrent EC patients."

Journal • Endometrial Cancer • Oncology • Solid Tumor • RAD51

Inhibition of PFKFB3 Hampers the Progression of Atherosclerosis and Promotes Plaque Stability. (PubMed, Front Cell Dev Biol) - "Here, we analyzed the expression of PFKFB3 in human atherosclerotic lesions and investigated the therapeutic potential of pharmacological inhibition of PFKFB3 in experimental atherosclerosis by using the glycolytic inhibitor PFK158...In mice, high PFKFB3 expression is also associated with a vulnerable plaque phenotype, whereas inhibition of PFKFB3 activity leads to plaque stabilization. This data implies that inhibition of inducible glycolysis may reduce inflammation, which has the ability to subsequently attenuate atherogenesis."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Immunology • Inflammation

PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses. (PubMed, Cell Death Dis) - "Finally, PFK158 alone and in combination with carboplatin-inhibited tumorigenesis of EMMeso xenografts in vivo. Since most cancer cells exhibit an increased glycolytic rate, these results provide evidence for PFK158, in combination with standard chemotherapy, may have a potential in the treatment of MPM."

Journal • Lung Cancer • Mesothelioma • Oncology • Sarcoma • Solid Tumor • Thoracic Cancer