Nampt Inhibitors: The Latest Advancement In Cancer Therapy

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NAMPT, also known as visfatin or PBEF, is a ubiquitous enzyme responsible for the rate-limiting step in NAD biosynthesis. As a key regulator of cellular NAD+ levels, NAMPT plays an important role in modulating several pathways involved in cancer initiation and progression. Nicotinamide phosphoribosyltransferase inhibitors work by blocking the enzymatic activity of NAMPT, thereby depleting intracellular NAD+ levels and disrupting NAD+-dependent processes like metabolism and DNA repair.

There are multiple mechanisms by which NAMPT Inhibitors leads to cancer cell death. Depletion of NAD+ levels impair aerobic glycolysis and ATP generation in cancer cells, causing metabolic dysfunction. Since cancer cells rely more on glycolysis even in the presence of oxygen, they are more sensitive to decreases in NAD+ levels compared to normal cells. Additionally, reduced NAD+ availability disrupts poly ADP-ribose polymerase (PARP) activity which is crucial for DNA damage response and repair. This induces synthetic lethality in cancer cells with homologous recombination deficiencies like BRCA1/2 mutations. NAMPT inhibition has also ...
... been shown to induce Endoplasmic Reticulum (ER) stress pathways leading to apoptosis in various cancer models.

Preclinical Studies With NAMPT Inhibitors

Early studies with the non-specific Nicotinamide phosphoribosyltransferase inhibitors APO866 showed potent anti-tumor activity in a wide range of preclinical cancer models including leukemia, lymphoma, multiple myeloma, melanoma, lung, breast, ovarian and pancreatic cancers. Treatment with APO866 as a single agent led to marked tumor growth inhibition and regressions. Combining APO866 with chemotherapy or PARP inhibitors produced synergistic anti-tumor effects and increased survival in mice bearing human tumor xenografts.

Other selective small molecule Nicotinamide phosphoribosyltransferase inhibitors that have advanced into clinical studies include FK866, CHS-828, and STF-118804. FK866 demonstrated efficacy as monotherapy as well as in combinations with radiation, chemotherapy or cancer immunotherapy in preclinical models of hematological and solid tumors. Research with STF-118804 revealed activation of ER stress-induced cell death pathways in addition to inhibition of glycolysis contributing to its anti-cancer activity. Preclinical and mechanism of action studies with Nicotinamide phosphoribosyltransferase inhibitorscontinued to provide scientific rationale for their clinical development.

Clinical Trials With NAMPT Inhibitors

APO866 was the first Nicotinamide phosphoribosyltransferase inhibitors tested clinically but its development was halted due to formulation issues leading to suboptimal exposure levels. However, clinical trials carried out with the second-generation Nicotinamide phosphoribosyltransferase inhibitors FK866 have shown encouraging anti-tumor responses both as monotherapy and in combinations.

In an early phase I study, single-agent FK866 showed an acceptable safety profile and signs of clinical activity in patients with advanced hematological malignancies. Dose-dependent increases in NAD+ depletion along with lymphocyte count reductions were observed as on-target effects. Stable diseases were reported in a few patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.

Combination trials with FK866 have demonstrated improved clinical outcomes. In a phase Ib study combining FK866 with carboplatin and paclitaxel in patients with advanced solid tumors, the triplet was well tolerated with no unexpected toxicities observed. Partial responses were seen in patients with ovarian cancer, non-small cell lung cancer and melanoma. Ongoing combination trials are assessing FK866 with immune checkpoint inhibitors and radiation therapy.

Another phase I study evaluated the novel NAMPT inhibitors STF-118804 in patients with advanced hematological or solid tumors. STF-118804 displayed a manageable safety profile up to the highest dose levels tested. Preliminary anti-tumor activity was observed even at low doses, including partial response in a patient with endometrial cancer. Biomarker analysis revealed dose-dependent NAD+ depletion and ER stress activation validating the mechanism of action.

While clinical experience with the new Nicotinamide phosphoribosyltransferase inhibitors is presently limited, initial results indicate a favorable safety margin which has permitted evaluation of combination regimens. Correlative studies are providing insights into the mechanism of action and its relationship to anti-tumor responses observed. Further clinical investigation of Nicotinamide phosphoribosyltransferase inhibitors alone as well as in rational combinations holds promise to yield new therapies for cancer. Patient selection based on tumor genetic profiles may help optimize clinical outcomes with these agents.

Get more insights on this topic:https://fortunetelleroracle.com/news/nampt-inhibitors--a-promising-new-class-of-anti-cancer-drugs-928737

Author Bio:

Alice Mutum is a seasoned senior content editor at Coherent Market Insights, leveraging extensive expertise gained from her previous role as a content writer. With seven years in content development, Alice masterfully employs SEO best practices and cutting-edge digital marketing strategies to craft high-ranking, impactful content. As an editor, she meticulously ensures flawless grammar and punctuation, precise data accuracy, and perfect alignment with audience needs in every research report. Alice's dedication to excellence and her strategic approach to content make her an invaluable asset in the world of market insights. (LinkedIn: www.linkedin.com/in/alice-mutum-3b247b137 )

*Note:
1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it