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November 20, 2017

Using Cancer Drugs to Control Blood Pressure

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  • In the fast-paced world of drug discovery, repurposing existing FDA-approved drugs is a logical strategy, as it not only can save time and money but can ultimately save lives since drugs can get to patients much quicker. It is incumbent upon researchers to explore all potential treatment possibilities for various compounds, even when they seem unlikely—as investigators from Georgetown University Medical Center have just discovered. The research team found that drugs designed to halt cancer growth may offer a new way to control hypertension. Findings from the new study—published today in Hypertension in an article entitled “Blood Pressure Control by a Secreted FGFBP1 (Fibroblast Growth Factor–Binding Protein)”—could offer a real advance in hypertension treatment because although a number of high blood pressure drugs are now available, they work by different mechanisms that are not suited for all patients.

    The Georgetown team uncovered that fibroblast growth factors, or FGFs, involved in increasing blood vessel growth so that cancer can grow, also have a systemic effect on blood pressure. Moreover, results from the new study suggest that just as oncologists use FGF inhibitors to control cancer, clinicians may be able to use FGF inhibitors to regulate blood pressure and control disease associated with hypertension.

    "It's rare that a single class of drugs can be used for such different conditions, but that is what our study strongly suggests," noted senior study investigator Anton Wellstein, M.D., Ph.D., professor of oncology and pharmacology at Georgetown University School of Medicine and a researcher at Georgetown Lombardi Comprehensive Cancer Center.

    In previous studies, the researchers found that the FGF pathway, when switched on, drives the growth of blood vessels that feed a growing tumor (angiogenesis). The development of FGF inhibitors is based in part on their ability to inhibit angiogenesis. The current analysis went further into the pathway and found that a protein, FGF binding protein 1 (FGFBP1, or BP1), modulates FGF. Other research teams have uncovered that a population in Eastern Europe that had hypertension also had a variation of the FGFBP1 gene. Due to this gene variation in these individuals, FGFBP1 was overexpressed in kidney tissue, the major control hubs for blood pressure.

    With this knowledge in mind, the researchers decided to test the link between FGFBP1 and hypertension in a mouse model where the link between FGF and cancer was initially found. In these mice, FGFBP1 expression can be switched on or off.

    “We report on the effects of inducible BP1 expression in a transgenic mouse model. Induction of BP1 expression in adult animals leads to a sustained rise in mean arterial pressure by >30 mm Hg,” the authors wrote. “The hypertensive effect of BP1 expression is prevented by candesartan, an angiotensin II (AngII) receptor antagonist, or by tempol, an inhibitor of reactive oxygen species. In vivo, BP1 expression sensitizes peripheral resistance vessels to AngII constriction by 20-fold but does not alter adrenergic vasoconstriction. FGF receptor kinase inhibition reverses the sensitization to AngII. Also, constriction of isolated renal afferent arterioles by AngII is enhanced after BP1 expression and blocked by FGF receptor kinase inhibition. Furthermore, AngII-mediated constriction of renal afferent arterioles is abolished in FGF2−/− mice but can be restored by add-back of FGF2 plus BP1 proteins. In contrast to AngII, adrenergic constriction is not affected in the FGF2−/− model.”

    Commenting on the results that their blood pressure shot up after investigator switched on FGFBP1 in mice, Dr. Wellstein remarked "It was amazing. It actually went up [30 mm Hg] from a normal blood pressure to pretty bad hypertension."  

    Dr. Wellstein added that he turned the gene on "just to a level you see in people in the Eastern European group who have hypertension." Dr. Wellstein also clarified that when a cancer switches on overproduction of the FGF pathway, in order to stimulate blood vessel production, that has only a local tumor effect, not a systemic one. Most patients using cancer treatment have normal blood pressure, he explained.

    Further research revealed that hypertension regulation by FGFBP1 occurred in the resistance vessels—the end portion of vessels in different tissues that control the flow to that tissue. The aberrant FGFBP1 gene increased the vessel response to a hormone (AngII) that constricts the blood vessels, making blood pressure rise.

    “FGF can control how sensitive the blood pressure regulation by AngII is," Dr. Wellstein said. "That tells us that if a person has hypertension, it is possible to target FGF signaling because it contributes to the maintenance of high blood pressure by altering sensitivity to a major vasoconstrictive hormone, AngII."

    Investigators then used an FGF inhibitor in mice with a switched on FGFBP1 gene and found the drug effectively lowered the sensitivity to AngII in several vascular beds.

    “Of course, we can't say that this tactic will work in humans with hypertension, but it will be straightforward to test this rather surprising possibility to target a new mechanism of blood pressure control," Dr. Wellstein concluded.

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