New Therapy To Beat Chemotherapy Resistance

In a study that was just published in the Journal of Medicinal Chemistry, a multidisciplinary team of medical professionals and researchers from the Hospital del Mar Medical Research Institute (IMIM-Hospital del Mar) and the Institute for Research in Biomedicine (IRB Barcelona) put forth a therapeutic strategy for preventing the emergence of resistance to chemotherapy with oxaliplatin, one of the go-to treatments for colon and rectal cancer. The project, which also included academics from the University of Oviedo and the CIBER on Cancer (CIBERONC), pathologists from the Hospital del Mar’s Pathological Anatomy and Medical Oncology departments, and others, is a step closer to individualizing cancer treatment.

This team had previously demonstrated how this kind of chemotherapy accumulates in the healthy fibroblasts that surround the tumor in a research that was published in Nature Communications. This stimulates the tumor environment and aids in the proliferation of tumor cells that have survived chemotherapy by activating a number of genes related to poor treatment response and tumor progression. The authors of the new research suggest supplementing oxaliplatin with a cell-penetrating peptide to avoid this.

“Converting a systemic treatment, which affects healthy organs and the tumor microenvironment, by adding this peptide, allows us to transform it into something more specific, a targeted therapy, taking us closer to personalized medicine,” points out Dr. Alexandre Calon, a researcher at the IMIM-Hospital del Mar and co-leader of the study.

The findings are founded on the examination of tumor samples from close to 200 patients with colon and rectal cancer. Additionally, ex vivo tumor samples from patients and mice were examined to demonstrate that adding a particular peptide to the chemotherapy drug oxaliplatin reduced its negative impacts on normal tumor cells and may therefore reduce chemotherapy resistance.

The results indicate that platinum accumulation in the tumor microenvironment in mice treated with this new approach drops dramatically and is up to 3.5 times lower. “We have seen that the chemotherapy load is reduced in fibroblasts treated with the new compound compared to those treated with oxaliplatin. This reduces the possibility of inducing tumor cell treatment resistance,” explains Dr. Calon. It is therefore important to bear in mind that “Cancer does not just involve tumor cells, but there is also a microenvironment made up of blood vessels, fibroblasts, and immune system cells, which are there to structure the tumor.”

The researchers also determined that the new drug not only accumulates less around the tumor in mice, but also in the organs that are normally most heavily affected by chemotherapy, such as the colon itself, the kidneys, and the liver. In this sense, as Dr. Jenniffer Linares, a researcher in the same group and first author of the study, explains “The classic treatment has a series of side effects on the patient, which we think could be reduced with the new drug, as less platinum accumulates in healthy tissues.”

This study is a crucial first step for the future clinical development of treatments that cause fewer side effects and are more effective in patients with colon and rectal cancer, taking into consideration the fact that the normal cells involved in tumors play a key role in treatment efficacy,” explains Dr. Clara Montagut, head of the gastrointestinal tumor unit at the Hospital del Mar and a CIBERONC researcher.

These findings prompted Dr. Daniele Lo Re, who co-led the study, to observe that “By chemically modifying the structure of oxaliplatin, we can modulate its activity in the tumor microenvironment without any loss of efficacy. From this point on, we can think about integrating this approach into drug discovery processes, using appropriate cellular models that allow us to validate a greater number of potential new drugs both in the tumor and in its microenvironment.”

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