David Frank, MD, PhD, on Targeting STAT3 in CLL

In an interview with Oncology Learning Network, David Frank, MD, PhD, Associate Professor of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, spoke on the findings and significance of a clinical trial on the STAT3 inhibitor pyrimethamine in chronic lymphocytic leukemia (CLL; Am J Hematol. 2021;96[4]:E95-E98).

What existing data led you and your co-investigators to conduct this research?

CLL is the most prevalent form of leukemia in the United States, though it remains incurable. New therapeutic approaches are clearly needed that target molecular vulnerabilities of these leukemia cells. In previous work, we had shown that CLL cells in essentially all patients displayed activation of the transcription factor STAT3 (J Clin Invest. 1997;100:3140-8). STAT3 regulates genes controlling central cellular processes such as proliferation, survival, and self-renewal, and can directly contribute to cancer pathogenesis when activated inappropriately.

Therefore, we used a chemical biology approach to identify drugs that block the function of STAT3 and could rapidly be introduced into clinical trials. From this approach, we identified the FDA-approved anti-parasitic drug pyrimethamine as a STAT3 inhibitor (Human Mol Gen. 2011; 20:4143-54). We showed that at concentrations that are routinely achieved in human patients, and maintained safely for months on end, pyrimethamine effectively inhibits STAT3 transcriptional activity. With our goal of quickly translating laboratory advances into clinical trials for our patients, we therefore initiated a clinical trial of pyrimethamine in patients with CLL that had progressed despite standard therapies.

Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?

Several notable findings emerged from this study.

First, although CLL is ultimately a progressive disease, 50% of patients treated with pyrimethamine achieved stable disease, 1 of whom was maintained on this drug for 12 months. This is particularly unusual and encouraging for a single agent non-toxic drug.

Second, we obtained blood samples from the patients on the trial to carefully measure the drug levels we were achieving in these patients as well as the effects on STAT3-dependent gene expression in the leukemia cells. We found that the blood levels of pyrimethamine were a little lower than our target, suggesting that it might be possible to use a higher dose of pyrimethamine in future trials. In addition, we developed an assay to measure STAT3-dependent gene expression in the CLL cells. This allowed us to correlate changes in STAT3 inhibition with therapeutic effects of pyrimethamine.

What are the possible real-world applications of these findings in clinical practice?

Further research is needed to determine how beneficial pyrimethamine, and other STAT3 inhibitors being developed, will ultimately be in CLL. However, abundant evidence suggests that STAT3 can be inhibited in people for long periods of time with little toxicity. Knowing that we may have a greater therapeutic effect with slightly higher doses of pyrimethamine also provides an opportunity to improve upon these results.

Do you and your co-investigators intend to expand upon this research? If so, what are/will be your next steps?

There are several areas where we hope to expand this work.

First, since the time that we conducted this clinical trial, additional agents have been approved for the treatment of CLL, which inhibit pathways complementary to STAT3, such as BTK and PI3 kinase. Given that STAT3 increases the expression of several pro-survival proteins, we believe that combinations of pyrimethamine with these drugs may show even greater efficacy, though that remains to be evaluated in a clinical trial.

Second, we have found that inhibition of STAT3 by pyrimethamine or other drugs decreases the ability of leukemia cells to evade recognition and killing by the immune system (Cancer Immunology and Immunotherapy. 2018; 67:13-23). This is particularly notable, as CLL is a cancer that has not shown significant susceptibility to immune-based therapies. Thus, combinations of pyrimethamine and treatments like immune checkpoint inhibitors may be a very promising approach to be tested in subsequent clinical trials.

Is there anything else pertaining to your research and findings that you would like to add?

Transcription factors have long been considered very difficult proteins to target therapeutically. One important aspect of this work is the proof of concept in humans that one can successfully target STAT3 pharmacologically. Pyrimethamine was identified through a chemical biology approach. We have also taken computational approaches based on transcriptional signatures to identify other clinically-applicable STAT3 inhibitors (Blood. 2016;128:1845-1853), which have now also entered clinical trials.

These types of small, focused clinical trials testing the effects of a novel signaling inhibitor are critical to advancing promising therapies from the lab to the clinic, particularly for academic-based researchers. Unfortunately, it is often difficult to obtain NIH funding for these types of studies. Thus, it is notable that the majority of funding for this clinical trial and associated laboratory studies were obtained through a peer-reviewed grant from the Lymphoma Research Foundation. This is a great example of how disease-focused foundations, which are looking to fill a niche in the development of new therapies, can have a powerful impact in developing new treatments for our patients.

Finally, it should be noted that inappropriate activation of STAT3 is a common finding in many other cancers beyond CLL. Thus, the findings of studies like this can have wide impact well beyond this one disease.