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Development of new targets for immunotherapy in cancer metastasis

18th national competition for scientific and technical research

Immunotherapy and cancer

Senior Researcher : José Ignacio Casal Álvarez

Research Centre or Institution : Centro de Investigaciones Biológicas (CSIC)

Abstract

Metastasis is responsible for 90% of deaths associated with cancer. The objectives of this project aimed to the development and validation of new and effective strategies in the treatment of cancer metastasis. The investigated targets included RGD-containing cadherins 17 and 5, the interleukin 13 receptor α2 (IL13Rα2) and the PAUF protein All these proteins participate in various cellular functions essential for the establishment of metastasis. The main goal was the development of specific monoclonal antibodies (mAbs) for immunotherapy. The final conclusions of this project were the following:

- A panel of RGD-specific mAbs was developed. These antibodies provoked a significant reduction in cell adhesion and proliferation of metastatic cancer cells.

- Treatment with RGD-specific mAbs impaired the integrin signaling pathway activation of FAK, JNK, ERK, Src and AKT in different cancers.

- In vivo, RGD-specific mAbs increased mouse survival to lung and liver metastasis, after inoculation of melanoma and colorectal cancer cell lines, respectively.

- Mab 6.6.1 variable sequences have been sequenced. Twenty five combinations of humanized variants have been tested in different in vitro assays. At least, three humanized variants showed higher efficiency for blocking invasion of metastatic cells. The humanized version is being tested.

- In addition, we developed two mAbs against an IL13Rα2 peptide in the IL-13 binding site. They caused a strong inhibition of cell invasion in metastatic cancer cells.

- Mab 5.5.4 anti-IL13Rα2 peptide inhibited mouse liver colorectal cancer metastasis.

- In summary, blocking the interaction between RGD cadherins and α2β1 integrin with highly selective mAbs or between IL-13 and IL-13Rα2 with mAbs or peptides has shown a tremendous efficacy to prevent cancer metastasis in different tumors. These results pave the way for their potential clinical application.

- Finally, PAUF loss caused very relevant phenotypic and genotypic alterations in colorectal cancer cells that deserve further investigation.