Studies Reveal New Mechanisms of Drug Resistance in Cancer

In a study published in Cancer Research, researchers at the Bellvige Institute of Biology (IDIBELL) and the ProCure Program of the Institute of Oncology (ICO) in Catalonia, Spain, have revealed a new ...

In a study published in Cancer Research, researchers at the Bellvige Institute of Biology (IDIBELL) and the ProCure Program of the Institute of Oncology (ICO) in Catalonia, Spain, have revealed a new paradigm of drug resistance in cancer, in contrast to published studies of resistance that prevent the formation of blood vessels (antiangiogenesis). The study was led by Dr. Oriol Casanovas of the IDIBELL Tumor Angiogenesis Group, with Dr. Iratxe Zuazo as co-first author. 

Antibody development is an effective therapeutic approach in the search for alternatives to combat cancer. Antibodies have antitumor effects and can prevent normal tumor growth. In this study, scientists observed that one of the antibodies had effects similar to those of conventional anti-angiogenic drugs. However, long-term resistance and malignancy, ultimately through a previously unknown mechanism, render the initial therapeutic response ineffective. 

"It is believed that the hypoxic environment of tumor tissue causes tumor cells to become more malignant and migrate more easily." Zuazo said. "The tissue we studied did not experience hypoxia, but did experience this deterioration." 

The antibody used in this study was axon guidance factor 4-D (Sema4D). Sema4D is a family of proteins from the extracellular space, containing multiple proteins, involved in cell signaling and essential for the development and maintenance of many organs and tissues. Some of these have effects on angiogenesis and cancer progression. 

Sema4D is a protein predominantly expressed in the membranes of solid tumors, such as breast, prostate, and colon cancers. This protein is also present in tumor-associated macrophages (TAMs), which are immune cells that play important roles in tumor invasion, tumor formation, and metastasis. Sema4D has also been implicated in the formation of blood vessels. 

As this new situation emerged, the researchers looked for possible differential factors that are currently known, and they realized that there were large numbers of macrophages present. They found that in the presence of anti-Sema4D antibodies, macrophages secrete a molecule called SDF1, resulting in more migratory capacity of tumor cells: they show more motility and invasiveness. 

These tests were performed in a transgenic mouse model and improved survival of the animals was observed in the short term. In the long term, however, there is an unwanted effect (transfer) that significantly worsens the condition of the mice. 

"Now that we know the new mechanism, we can begin to find a way to suppress it—for example, to avoid secretion of SDF1—and provide an alternative to this approach, producing only the positive effects of antibodies," explained Dr. Oriol Casanovas. Depending on each case, both drugs can be used for treatment at the same time. Our recommendation is to also consider the immune system when doing some treatment, because now we know that there is a possibility of activating the immune system with some drugs, Dr. Iratxe Zuazo concluded.