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The search for genes that cause diseases

Finding new targets for the treatment of adrenocortical cancer, multiple myeloma and resistant hypertension is the goal of studies presented during FAPESP Week Michigan-Ohio

Several studies aimed at finding genes related to the development or progression of diseases such as cancer and hypertension were presented March 28 in Ann Arbor, Michigan during FAPESP Week Michigan-Ohio.

The event, which runs through April 1 in the cities of Ann Arbor and Columbus, was organized by FAPESP together with the University of Michigan (UM) and the Ohio State University (OSU) for the purpose of promoting increased cooperation between scientists from São Paulo and the United States.

Among the speakers was endocrinologist Antônio Marcondes Lerario, of the University of Michigan Medical School, whose work is directed at identifying targets for the treatment of adrenal cortical carcinoma (ACC), a rare type of cancer characterized by abnormal growth of the outer layer (cortex) of the adrenal glands, which are located on top of the kidneys.

The adrenal cortex plays an important role in the endocrine system because it produces hormones that regulate metabolism and blood pressure. It also synthesizes cortisol and the male hormones known as androgens. ACC manages to unleash an overproduction of these hormones.

“From the clinical standpoint, the disease is quite heterogeneous. There are cases linked to inherited mutations, but most are sporadic. Some patients do well while others do not. We are identifying biomarkers that help distinguish these different cases,” Lerario said.

Besides surgery to remove the tumor, treatment of the disease includes chemotherapy, radiation and medications that block the production of cortisol when the levels of this hormone are very high.

According to Lerario, there are, however, no efficient options for treating advanced cases of the disease in which metastasis has occurred. “What we can do is begin aggressive chemotherapy, which improves symptoms a little, but does not affect overall survival. That’s why our research is geared towards the identification of specific molecular targets that can be blocked through the use of drugs and thus reduce disease progression without affecting healthy tissue. It’s what we call targeted therapy,” he explained.

Several candidate genes are being investigated at the University of Michigan Medical School. One of these therapeutic targets – IGF-2 (Insulin-like growth factor 2) – has been used in clinical trials, but did not demonstrate the expected effectiveness.

“IGF-2 is a gene that is hyper expressed in 90% of the carriers of adrenal cortical carcinoma and we know that it causes proliferation and growth of cells. We tried to use drugs that blocked the receptor of this particular protein. It worked in vitro and in animal models, but in humans, only 5% of patients responded,” the researcher said.

The 5% that responded presented significant improvement, however. The disease stopped progressing for a prolonged period of time, and in some cases even began to regress. According to Lerario, it is still impossible to know in advance which patients will respond to this therapy.

“It is a complex disease. In addition to the IGF-2, there are other active oncogenic pathways and what appears to be a synergy between them. Our goal now is to find ways to simultaneously engage several of the pathways or determine whether there is a central pathway,” Lerario said.

Resistant hypertension

The relationship between treatment-resistant hypertension and excess activation of cell receptors for the aldosterone hormone (known as a mineralocorticoid receptor) was the topic of the lecture presented by Professor Bryan Byrd of the Cardiovascular Medicine Division of the University of Michigan Medical School.

According to Byrd, patients considered to be treatment-resistant are those whose blood pressure remains above goal despite concurrent use of ideal doses of three medications of different classes, one of which should be a diuretic.

“The best statistics we have on these cases are Brazilian, provided by researchers at the Heart Institute (InCor) of the University of São Paulo School of Medicine (FMUSP), and they indicate that the problem affects approximately 10% of hypertensive patients,” Byrd said.

Among these cases of actual resistance to therapy, the researcher went on, 20% of the patients present excess activation of the system related to the aldosterone hormone, which causes the kidneys to retain larger quantities of water and sodium.

“During the process of evolution, the mineralocorticoid receptor emerged when mammals left the aquatic environment. Its mission was to prevent death due to dehydration. The activation of this receptor tells the kidney that it should retain water and sodium in situations in which finding water is difficult. But some people seem to produce high levels of the aldosterone hormone even when they drink sufficient amounts of water and ingest a lot of salt in their diets,” Byrd explains.

The researcher added that recent studies have shown that even some hypertensive patients with normal levels of aldosterone in the blood respond well to drugs that block the activation of the mineralocorticoid receptor.

“This suggests to us that there may be other ways to activate this receptor, perhaps through molecules with action similar to aldosterone that still need to be identified. Another possible explanation is that these patients have a superexpression of the mineralocorticoid receptor. Our studies are trying to identify the precise cause of this exaggerated activation of the system,” Byrd stated.

In the same session, Gisele Colleoni, a researcher at the Federal University of São Paulo (Unifesp), presented a line of research focused on finding therapeutic targets and predictive biomarkers for multiple myeloma, a type of cancer that affects cells of the immune system known as lymphocytes.

Nils Walter, a chemistry professor at the University of Michigan, talked about the use of fluorescence microscopy as a non-invasive tool for examining, in live cells, the role of RNA molecules that do not encode protein, but play a role in regulating gene expression and may be involved in the development of diseases.

USP researcher Alexandre da Costa Pereira presented initiatives aimed at mapping the genetic structure of the Brazilian population (highly heterogeneous as a result of the crossing between various ethnicities) and discussed how knowledge of genetic variants can help identify susceptibility in developing chronic diseases.

Karina Toledo, in Michigan | Agência FAPESP