Common blood pressure drug could make cancer therapy far more powerful

"This study shows that a common, safe, tolerable, convenient, and inexpensive drug may significantly improve how well an important class of cancer therapies works," said Tyler J. Curiel, MD, MPH, FACP, the study's senior and lead author.

Making PARP Inhibitors Work for More Patients

Olaparib belongs to a group of targeted cancer drugs known as PARP inhibitors. These medicines work by taking advantage of defects in the way certain cancer cells repair damaged DNA. They are especially effective against tumors with problems in homologous recombination DNA damage repair, including cancers linked to BRCA gene mutations.

Many cancers, however, do not have those DNA repair defects, which means PARP inhibitors are not effective for a large number of patients. Even when the drugs initially work, tumors often become resistant over time.

The Dartmouth team found that telmisartan can make tumors more sensitive to PARP inhibitors, even if they do not have the DNA repair weaknesses that these drugs typically rely on.

Stronger Immune Response Against Tumors

In preclinical experiments, combining telmisartan with olaparib increased DNA damage inside cancer cells while also activating important immune defenses. The treatment combination boosted production of type I interferons, signaling molecules that help the immune system identify 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 Medications

Telmisartan is part of the angiotensin II receptor blocker (ARB) family of drugs, which are widely prescribed to treat hypertension. Researchers compared telmisartan with other ARBs and found that its cancer enhancing effects were unique within the class.

The drug also lowered levels of PD-L1 inside tumor cells. PD-L1 is a protein that many cancers use to avoid detection by the immune system, making this additional effect another potential advantage.

"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."

Early Clinical Trials Are Already Underway

Because telmisartan is taken by mouth, has an established safety record, and is well tolerated even by people without hypertension, researchers believe it is well suited for rapid testing in cancer patients. Curiel and colleagues at DCC have already launched two clinical trials to evaluate the combination.

One study is testing telmisartan with olaparib in men with metastatic, castration-resistant prostate cancer. According to Curiel, the first participant experienced an exceptional response to treatment. A second trial recently enrolled its first patient with platinum-resistant ovarian cancer.

"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 played a key role in completing the research and launching the clinical trials.