Researcher analyses how to improve the results of certain antitumor therapies

According to the estimates of the International Agency for Research on Cancer (IARC) published by the National Institute of Cancer (INC)-, based on available international data, for 2018, Argentina has an incidence rate of 212 cases of cancer per one thousand inhabitants (without considering skin tumor, not melanoma). Besides, according to the INC, in 2017 in Argentina, tumors were the second cause of death after cardiovascular diseases.

The importance of the problem motivates the creation of various research projects to seek for new oncology therapies to enhance the effectiveness of the treatments available or those under study and that, as far as possible, do not imply adverse effects.

Considering this need, the 2019 L’Oréal –UNESCO Scholarship “For women in science” is destined to recognize and support a research project whose ultimate goal is the optimization of cancer treatments with low side effects of different types of malignant tumors presented by Florencia Cayrol, CONICET assistant researcher at the Biomedical Research Institute (BIOMED, CONICET-UCA), under the direction of Graciela Cremaschi, principal researcher of the Council.

The work plan presented by Cayrol is called “Effect of membrane inhibition receptor for thyroid hormones on the antitumor action of rexinoids. Potential impact on cancer therapy.” The aim of the initiative is to make more effective antitumor therapies that are available or under evaluation for which a drug (rexinoid) known as bexatorene is used.

Cutaneous lymphoma, bexatorene and hyperthyroidism

“T-cell lymphoma (TCL) are a group of malignant diseases that originate from T lymphocytes (immune system cells) and despite having low incidente, they are very aggressive pathologies. One of the current available treatments for one of the TCL subtype, particularly for cutaneous lymphomas, is the administration of bexarotene, a drug with low toxicity for patients which is also being tested for other types of cancers (breast, thyroid, lung and melanoma). The problem is that bexarotene causes a decrease in the concentration of thyroid hormones (hypothyroidism), which must be compensated with the administration in high doses of levothyroxine (T4), the medicine supplied –although in lower amounts- to those who are hypothyroid” the scientist explains.

Thyroid hormones are a relevant factor, both for the proper functioning of the human metabolism and for the normal activation of the immune system. Nevertheless, some previous studies of the working group have proved that the normal amounts present in the blood of thyroid hormones –T3 and T4- can raise the proliferation and survival of different subtypes of tumor cells.

“During the development of my PhD thesis, I specifically analyzed different subtypes of TCL and what I found was that the normal physiological concentrations and of T4 and T3, which circulate in blood, promoted the growth and proliferation of tumor cells,” says the scientist.

Looking for a solution

This poses a question about whether the administration of T4 in high doses to counteract the impact of the hypothyroid state induced by bexatorene (whose supply to patients with cutaneous lymphomas does not always achieve good results) could not diminish its antitumor effects. The challenge is to find a way to guarantee the proper functioning of the metabolism and the immune system- for which it is necessary to restore normal amounts of thyroid hormones- without encouraging at the same time the survival and proliferation of tumor cells.

“We’ve found that the side effects of thyroid hormones (their contribution to the increase of the malignant features of tumor cells) were activated through a membrane receptor (integrirna AVB3), while their link with the good functioning of metabolism and the immune system depended on its intracellular receptor. We wonder if by inhibiting the integrina AVB3 -through different techniques- it is possible to moderate the effects of T3 and T4 on tumor cells,” Cayrol explains.

The in vivo and in vitro experiments allowed us to verify –in the case of certain subtypes of TCL- that the integrina AVB3 inhibition through molecular and pharmacological techniques helped to inhibit the effects that the normal concentrations in the bloodstream of T3 and T4 have on the proliferation and survival of tumor cells. Among the integrina AVB3 inhibitors, one of those tested is the cilengitide, which has already been tested for clinical use in other cancer diseases.

“In subsequent trials –in the specific case of cutaneous lymphomas- we tested in vitro and in vivo models that the administration of cilengetide, with the bexarotene and T4 enhanced the antitumor action in relation to when we only supplied the last two,” the scientist states.

Estos promotores resultados impulsan a Cayrol, y al equipo de trabajo del que participa en el BIOMED, a continuar con esta investigación y a expandirla hacia el estudio del tratamiento de otros tipos tumorales, como cáncer de mama o melanomas. El objetivo consiste en entender, por un lado, los efectos de las hormonas tiroideas sobre las células malignas de estos tumores, para luego ver cómo responden al bexaroteno –siempre en conjunto con la T4– con y sin el inhibidor de la integrina AVB3.

These results encourage Cayrol and her research team at the BIOMED to continue with this study and expand it towards the analyses of the treatment of other types of tumors like breast cancer or melanoma. The aim is to understand, on the one hand, the effects of the thyroid hormones on the malignant cells of these tumors to check how they respond to bexarotene –always in conjuction with T4– with and without integrina AVB3 inhibitor.