A triple weapon against melanoma

One strategy to hinder tumor growth is to control neoangiogenesis, that is, the ability of cancer to induce the proliferation of a network of blood vessels in the vascular system that promotes its own growth and self-defense.

The process, mediated by the protein VEGF, is triggered by oxygen starvation due to the tumor's hypermetabolism. This condition, hypoxia, stimulates tumor cells to produce VEGF, enabling them to establish a dedicated vascular network and thus receive more oxygen. Compared to a physiological network, however, this network is chaotic. For example, in its vessels, the outward pressure exceeds the inward pressure.

This "reversed permeability" benefits cancer by blocking the entry of chemotherapy into tumor cells and promoting metastasis. Indeed, this is precisely where research is attempting to target cancer. The mechanism, however, is complex, and initial partial successes are only now being achieved with a therapy that combines three drugs, each of which enhances the action of the others and brings with it different experiences and approaches to the problem.

After discovering, a quarter of a century ago, that tumor angiogenesis is triggered by VEGF , efforts were made to inhibit this factor to block the cancer's ability to progress "at the source." "The results, however, were not as positive as hoped," explains Federico Bussolino , an oncologist at the University of Turin and the IRCCS Candiolo Institute, "because the reduced oxygenation caused by anti-VEGF therapies is a double-edged sword: after a while, it ends up stimulating the selection of resistant cells, carrying mutations that make them aggressive again. Furthermore, antiangiogenic drugs are not very specific, that is, they are quite toxic even for healthy cells."

The researchers then attempted to modulate angiosuppression based on the stage of the tumor. "Even in this case," Bussolino specifies, "the results were lower than expected, because it's not easy to calibrate the dosages." The Turin team, however, is now experimenting with other approaches, capable of reducing the relapse rates of melanoma, a tumor that, due to its characteristics, is ideally suited to this type of research.

"In more than 50 percent of cases," Bussolino continues, "cutaneous melanoma is caused by a mutation in the BRAF oncogene, which controls cell proliferation. Research has developed specific inhibitors of this enzyme-oncogene, which have increased patient survival and quality of life, although they cannot prevent resistance."

Having put this partial resource to use, a significant step forward is now finally looming. "A preclinical study by my colleague Valentina Comunanza at the Candiolo Institute has led to some observations that suggest reconsidering anti-angiogenic agents." This is the monoclonal antibody bevacizumab, the very same one that 25 years ago helped shed light on the role of VEGF and angiogenesis in the evolution of solid tumors.

The first observation concerns the broad-spectrum effect between bevacizumab and BRAF oncogene inhibitors. We knew that the latter controlled tumor proliferation, while the monoclonal antibody 'normalized' tumor blood vessels, reoxygenating them and preventing the selection of more aggressive tumor clones. The novelty lies in another effect, already hypothesized and now verified, of VEGF: it is not only a powerful modulator of angiogenesis, but also has immunosuppressive activity. Therefore, bevacizumab helps 'defend the immune system' from the action of VEGF, stimulating the appearance of anti-tumor macrophages. At the same time, together with the anti-BRAF, it activates innate and adaptive immunity and 'prepares' the tumor to receive immunotherapy.

Making antimelanoma therapy even more effective is the addition of a third ingredient to the "anti-BRAF + bevacizumab" combination: anti-PD1 monoclonal antibodies, which moderate the activity of so-called "checkpoint" proteins, which slow the immune response to tumor cells. Bussolino confirms that the BRAF inhibitor, bevacizumab, and the anti-checkpoint inhibitor also enhance each other. "Their combination provides a stronger and more prolonged anti-tumor effect, leads to eradication in 50% of cases, and establishes an immunological memory that helps prevent relapse."

This new therapeutic approach, currently in the preclinical phase, could be useful for melanomas characterized by high VEGF production, which represents about 8% of this type of tumor. This won't be a final victory, but wars are won like this, battle after battle.