Blood pressure drug boosts effectiveness of cancer therapy

In a new Dartmouth Cancer Center (DCC) study led by clinical researcher Tyler J. Curiel, MD, MPH, FACP, investigators found that the FDA-approved blood pressure drug telmisartan can significantly enhance the cancer-killing activity of the targeted therapy olaparib, potentially expanding its use to many more patients. The findings are newly published in The Journal for ImmunoTherapy of Cancer.

This study shows that a common, safe, tolerable, convenient, and inexpensive drug may significantly improve how well an important class of cancer therapies works."

Tyler J. Curiel, MD, MPH, study's senior and lead author

Expanding the reach of PARP inhibitors

PARP inhibitors such as olaparib work by exploiting weaknesses in how some cancer cells repair damaged DNA. They are particularly effective in tumors with defective homologous recombination DNA damage repair, such as those with gene mutations in BRCA. However, many tumors lack these defects, limiting the number of patients who can benefit from PARP inhibitors. In addition, most cancers eventually develop resistance to PARP inhibitors.

Curiel's team discovered that telmisartan can make tumors more vulnerable to PARP inhibitors, even when they lack the specific DNA repair defects that usually make PARP inhibitors effective.

In preclinical studies, telmisartan increased DNA damage in tumor cells when used with olaparib and triggered powerful immune-stimulating signals. Specifically, the combination boosted production of type I interferons-molecules that help the immune system recognize and attack cancer.

"This immune activation appears to be a key reason the combination works so well," Curiel said.

A unique effect among blood pressure drugs

Telmisartan belongs to the angiotensin II receptor blocker (ARB) class of medications, commonly prescribed to treat hypertension. The DCC study found that the cancer-enhancing effects were unique to telmisartan among all the ARBs tested.

The drug also reduced levels of PD-L1 inside tumor cells-a protein that cancers use to evade immune attack-further increasing its therapeutic potential.

"Telmisartan has several distinct anticancer effects that, together with targeted therapy, could make tumors more responsive to distinct types of treatments," Curiel said. "We showed the improved efficacy with PARP inhibitors in this study, but we also have good data showing that telmisartan improves efficacy of distinct chemotherapy classes and immunotherapies in many other cancer types through related mechanisms."

Moving quickly to clinical trials

Telmisartan is orally bioavailable, safe, and well-tolerated, including by individuals without hypertension, making it an ideal candidate for clinical translation. Curiel and colleagues at DCC are already testing the strategy in patients through two ongoing clinical trials.

One trial is evaluating the combination in men with metastatic, castration-resistant prostate cancer. The first patient enrolled in the study experienced what Curiel described as an exceptional response to treatment. The second trial is in platinum-resistant ovarian cancer, which just enrolled its first patient.

"We are encouraged by what we are seeing so far," Curiel said. "Our goal is to determine whether this combination approach can help more patients benefit from greater effectiveness of PARP inhibitors and other cancer treatment classes and potentially overcome resistance to these drugs."

Support from the Guyre fund and Gmelich fund at DCC were instrumental in getting these studies completed and the clinical trials launched.