Repurposing Cancer Drugs for COVID-19

Treating COVID-19 with current cancer therapeutics is an investigational niche that has garnered attention of late, as oncologists try to balance effective patient care with the acuteness of a global pandemic.

“We're stuck with the current reality of not having bespoke, purpose-built strategies to directly counter SARS-CoV-2,” said Keith Flaherty, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, during the American Association for Cancer Research (AACR) Virtual Meeting: COVID-19 and Cancer in July. Therefore, “much of the focus has been on finding existing drugs we might be able to repurpose that target the mechanics of this virus's entry and replication or [that] mitigate the deleterious immune response it provokes.”

Like other coronaviruses and influenza viruses, SARS-CoV-2 relies on two proteins, TMPRSS2 and ACE2, to successfully infiltrate host cells. TMPRSS2 and ACE2 are both androgen-driven—in particular, the TMPRSS2 gene has a testosterone-activated response element and is strongly upregulated in prostate cancer, where it was first identified.

Less is known about TMPRSS2 in the context of the lungs—a key conduit for COVID-19—where it is also found, along with ACE2. Preclinically, however, researchers at the University of Pennsylvania in Philadelphia have observed decreased mRNA levels of both enzymes in the lung tissue of castrated mice. This finding was corroborated by protein expression analyses, reported Irfan Asangani, PhD; the team also showed that in a human lung cell line, TMPRSS2 and ACE2 are regulated by the androgen receptor.

Androgen involvement at the level of viral entry “may explain some of the sex differences seen with COVID-19 severity”—higher hospitalization and ICU admission rates among men versus women—said Catherine Marshall, MD, of Johns Hopkins University in Baltimore, MD. Several epidemiologic studies have suggested that hormones may modulate this disease course, she added. For example, in Italy, COVID-19 incidence and severity was lower in men with prostate cancer who were on androgen deprivation therapy (ADT), compared with those not receiving ADT.

As such, Marshall and her colleagues are preparing to launch a trial, RECOVER, to test the hypothesis that androgen blockade may improve COVID-19 outcomes. The study will randomly assign 60 patients, both men and women, to receive bicalutamide alongside best supportive care for COVID-19, or standard care alone.

“Bicalutamide has been used off-label for women with hirsutism, polycystic ovarian disease, and breast cancer,” Marshall said. “We chose this drug because it has mild side effects and generic availability makes it widely accessible.” Bicalutamide also elevates estradiol levels, “which we think may be important for an improved immune response,” she added. Preliminary findings suggest that in mice with pneumonia, estradiol alleviates lung injury through a concomitant increase in regulatory T cells.

RECOVER will enroll patients who are hospitalized, albeit with minimal respiratory symptoms. “We think bicalutamide might have the greatest impact at this phase, when it can both target SARS-CoV-2 replication and augment the mounting host immune response,” Marshall explained. “Once patients have progressed to acute respiratory distress syndrome [ARDS] and shock, bicalutamide is unlikely to be effective.”

Additional studies of androgen blockade's utility in COVID-19 are ongoing, including trials evaluating enzalutamide (Xtandi; Pfizer) and degarelix. Based on the preclinical estradiol data, “it may also be worth looking at tamoxifen,” Marshall suggested, “to investigate estrogen/progesterone modulation in this context.”

A flash point with COVID-19 occurs if the disease course turns hyperinflammatory: Patients experience dangerously high cytokine levels that can provoke ARDS and cardiac as well as renal failure. Cytokine release syndrome, though, is not uncommon with cancer immunotherapy, “so our extensive experience with understanding the pathophysiology of overly exuberant immune responses to CAR-T, for example, has really created an opportunity” for drug repurposing, Flaherty observed.

At the AACR meeting, Louis Staudt, MD, PhD, of the NCI, highlighted a potential COVID-19 therapeutic role for Bruton tyrosine kinase (BTK) inhibitors, which suppress B-cell receptor signaling and are part of the treatment arsenal for blood cancers. BTK itself is also activated when SARS-CoV-2 binds to and stimulates Toll-like receptors, chiefly TLR7/8; this “leads to downstream activation of NFκB and the NLRP3 inflammasome, forming the cytokine storm that characterizes this phase of COVID-19,” he explained.

Staudt and several NCI colleagues initiated an observational study of the BTK inhibitor acalabrutinib (Calquence; AstraZeneca) in 19 patients with severe COVID-19, of whom 11 were on supplemental oxygen and eight on mechanical ventilation. Their clinical improvement—increased oxygen uptake efficiency and normalization of inflammation markers—was rapid, often within 1 to 3 days of receiving acalabrutinib. At the end of treatment, 10 patients were discharged, able to breathe without help; another two had been extubated. No serious toxicities were seen.

Laboratory analyses of blood monocytes from these patients and healthy donors revealed significantly elevated BTK activity and IL6 production in the former, Staudt said, “supporting our hypothesis that BTK inhibitors block hyperinflammation in COVID-19 and could be an effective therapeutic strategy.”

Steven Treon, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, hailed Staudt's report as “important and confirmatory.” The benefit of BTK inhibition appears to extend to those facing the double whammy of cancer and COVID-19, he added: According to an analysis from Icahn School of Medicine at Mount Sinai in New York, NY, patients being treated with ibrutinib (Imbruvica; Janssen) or acalabrutinib for chronic lymphocytic leukemia largely experienced mild to moderate viral disease. Treon and his group, meanwhile, have suggested that ibrutinib protects against lung injury and improves COVID-19 symptoms among patients receiving the drug for Waldenström macroglobulinemia, a rare lymphoma.

“Interestingly, one patient had been on a reduced dose of ibrutinib because of side effects; he did end up hospitalized for COVID-19–related dyspnea and hypoxia,” Treon said. “When we gave him the full dose that the others were getting, though, he was discharged within a few days.”

Patients with severe COVID-19 often have underlying conditions—hypertension, obesity, diabetes—“associated with systemic low-level inflammation that's manifested in macrophages,” Staudt observed. Whereas cytokine storms are much less of a risk for otherwise healthy patients, “this is not so for those with such comorbidities and ‘preactivated’ macrophages ready to switch on the inflammasome” upon SARS-CoV-2 infection.

“We'd like to submit that perhaps BTK is at the trunk of this [cytokine storm] tree,” Staudt added, “and by felling it with the ax of acalabrutinib, patients may do much better. This drug class is really interesting and hasn't been fully investigated against diseases where we could reasonably expect macrophage-driven inflammation to play a role—not just COVID-19, but also atherosclerosis, type II diabetes, even Alzheimer's.”

In all, “these are provocative data from early, uncontrolled analyses” that warrant further investigation, Flaherty concluded. An international trial of acalabrutinib, randomizing the drug with best supportive care, is under way, as are controlled evaluations of ibrutinib and zanubrutinib (Brukinsa; BeiGene). Together with studies of endocrine therapy, “the hope is that we can aggregate enough knowledge from this first wave of drug repurposing trials,” he said, to better navigate a pandemic that shows little sign of abating. –Alissa Poh