Targeting constitutively active <scp>STAT3</scp> in chronic lymphocytic leukemia: A clinical trial of the <scp>STAT3</scp> inhibitor pyrimethamine with pharmacodynamic analyses

Brown, Jennifer R.; Walker, Sarah R.; Heppler, Lisa N.; Tyekucheva, Svitlana; Nelson, Erik A.; Klitgaard, Josephine L.; Nicolais, Maria; Kroll, Yasmin; Xiang, Michael; Yeh, Jennifer; Chaudhury, Mousumi; Giaccone, Zachary T.; Fernandes, Stacey M.; Jacobsen, Eric; Fisher, David C.; Freedman, Arnold S.; Davids, Matthew S.; Supko, Jeffrey G.; Wu, Catherine J.; Frank, David A.

doi:10.1002/ajh.26084

Cited by 22 publications

(26 citation statements)

References 9 publications

(12 reference statements)

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“…Recently, the antileukemic activity of pyrimethamine was investigated and it substantially decreased the viability of chronic lymphocytic leukemia (CLL) cells through the induction of apoptosis. Interestingly, pyrimethamine displayed marginal activity towards peripheral blood mononuclear cells (PBMCs) collected from healthy individuals, and these observations are in agreement with the previously reported safety profile of this drug 61 . Further investigation revealed that STAT3 is constitutively activated in CLL cells and they identified pyrimethamine as a STAT3 inhibitor through chemical biology approach 61 .…”

Section: Antineoplastic Effects Of Pyrimethaminesupporting

confidence: 82%

The multifaceted antineoplastic role of pyrimethamine against human malignancies

et al. 2022

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Cancer accounted for nearly 10 million deaths in 2020 and is the second leading cause of death worldwide. The chemotherapeutic agents that are in clinical practice possess a broad range of severe adverse effects towards vital organs which emphasizes the importance of the discovery of new therapeutic agents or repurposing of existing drugs for the treatment of human cancers. Pyrimethamine is an antiparasitic drug used for the treatment of malaria and toxoplasmosis with a well‐documented excellent safety profile. In the last 5 years, numerous efforts have been made to explore the anticancer potential of pyrimethamine in in vitro and in vivo preclinical models and to repurpose it as an anticancer agent. The studies have demonstrated that pyrimethamine inhibits oncogenic proteins such as STAT3, NF‐κB, DX2, MAPK, DHFR, thymidine phosphorylase, telomerase, and many more in a different types of cancer models. Moreover, pyrimethamine has been reported to work in synergy with other anticancer agents, such as temozolomide, to induce apoptosis of tumor cells. Recently, the results of phase‐1/2 clinical trials demonstrated that pyrimethamine administration reduces the expression of STAT3 signature genes in tumor tissues of chronic lymphocytic leukemia patients with a good therapeutic response. In the present article, we have reviewed most of the published articles related to the antitumor effects of pyrimethamine in malignancies of breast, liver, lung, skin, ovary, prostate, pituitary, and leukemia in in vitro and in vivo settings. We have also discussed the pharmacokinetic profile and results of clinical trials obtained after pyrimethamine treatment. From these studies, we believe that pyrimethamine has the potential to be repurposed as an anticancer drug.

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Section: Antineoplastic Effects Of Pyrimethaminesupporting

confidence: 82%

The multifaceted antineoplastic role of pyrimethamine against human malignancies

et al. 2022

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“…A key translational question is whether the anticancer effects of pyrimethamine are mediated solely by STAT3 inhibition or whether STAT3-independent effects of DHFR inhibition are playing a significant role. In clinical trials for both its antimicrobial and anticancer effects, pyrimethamine has shown essentially no toxicity at therapeutic levels ( 10 ), suggesting that it is not generally cytotoxic at these concentrations. This is in sharp contrast to methotrexate, which can cause a variety of toxicities with continued use.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, the therapeutic relevance of pyrimethamine in cancers characterized by frequent STAT3 activation is becoming more apparent. Pyrimethamine showed on-target activity, as assessed by inhibition of expression of STAT3-dependent genes, in a clinical trial of chronic lymphocytic leukemia ( 10 ), a disease in which the leukemia cells are nearly always driven by increased STAT3 transcriptional activity. Thus, understanding the mechanistic properties of pyrimethamine that underlie its effects on STAT3 inhibition may suggest opportunities to further potentiate its therapeutic effects.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we use a proteome-wide approach coupled with a metabolomic analysis to identify the direct molecular targets of pyrimethamine and further elucidate the mechanism by which pyrimethamine inhibits STAT3 transcriptional activity. As an Food and Drug Administration–approved compound, pyrimethamine is already being tested in the clinic and has shown activity in the treatment of several STAT3-driven malignancies, including chronic lymphocytic leukemia ( 10 ), breast cancer, and intermediate-risk to high-risk myelodysplastic syndrome. Therefore, an understanding of the mechanism of action of pyrimethamine may have major clinical implications regarding both the rational design of combination therapies and patient stratification.…”

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confidence: 99%

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The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase

Heppler

Attarha

Persaud

et al. 2022

Journal of Biological Chemistry

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Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.

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“…A published clinical trial suggested that at the maximum tolerated dose (500 mg TID), only 1/3 of the patients reach 163.5 ng/mL. 134 Scientist thought of improving the delivery system and several nanobased-agents were invented, which may improve its bioavailability. 135 In the future, scientists may explore these agents in clinical trials.…”

Section: Dark Side: Limitations and Future Directionsmentioning

confidence: 99%

Progress in Redirecting Antiparasitic Drugs for Cancer Treatment

Huang¹,

He²,

Bing-hua³

et al. 2021

DDDT

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Drug repurposing is a feasible strategy in developing novel medications. Regarding the cancer field, scientists are continuously making efforts to redirect conventional drugs into cancer treatment. This approach aims at exploring new applications in the existing agents. Antiparasitic medications, including artemisinin derivatives (ARTs), quinine-related compounds, niclosamide, ivermectin, albendazole derivatives, nitazoxanide and pyrimethamine, have been deeply investigated and widely applied in treating various parasitic diseases for a long time. Generally, their pharmacokinetic and pharmacodynamic properties are well understood, while the side effects are roughly acceptable. Scientists noticed that some of these agents have anticancer potentials and explored the underlying mechanisms to achieve drug repurposing. Recent studies show that these agents inhibit cancer progression via multiple interesting ways, inducing ferroptosis induction, autophagy regulation, mitochondrial disturbance, immunoregulation, and metabolic disruption. In this review, we summarize the recent advancement in uncovering antiparasitic drugs’ anticancer properties from the perspective of their pharmacological targets. Instead of paying attention to the previously discovered mechanisms, we focus more on newly emerging ones that are worth noticing. While most investigations are focusing on the mechanisms of their antiparasitic effect, more in vivo exploration in clinical trials in the future is necessary. Moreover, we also paid attention to what limits the clinical application of these agents. For some of these agents like ARTs and niclosamide, drug modification, novel delivery system invention, or drug combination are strongly recommended for future exploration.

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Targeting constitutively active STAT3 in chronic lymphocytic leukemia: A clinical trial of the STAT3 inhibitor pyrimethamine with pharmacodynamic analyses

Cited by 22 publications

References 9 publications

The multifaceted antineoplastic role of pyrimethamine against human malignancies

The multifaceted antineoplastic role of pyrimethamine against human malignancies

The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase

Progress in Redirecting Antiparasitic Drugs for Cancer Treatment

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