Dataset Information

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

ABSTRACT: Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the ?V family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis. In addition, integrins promote events in the tumor microenvironment that are critical for tumor progression and metastasis, including tumor angiogenesis, matrix remodeling, and the recruitment of immune and inflammatory cells. In spite of compelling preclinical results demonstrating that the inhibition of integrin ?V?3/?V?5 and ?5?1 has therapeutic potential, clinical trials with integrin inhibitors targeting those integrins have repeatedly failed to demonstrate therapeutic benefits in cancer patients. Here, we review emerging integrin functions and their proposed contribution to tumor progression, discuss preclinical evidence of therapeutic significance, revisit clinical trial results, and consider alternative approaches for their therapeutic targeting in oncology, including targeting integrins in the other cells of the tumor microenvironment, e.g., cancer-associated fibroblasts and immune/inflammatory cells. We conclude that integrins remain a valid target for cancer therapy; however, agents with better pharmacological properties, alternative models for their preclinical evaluation, and innovative combination strategies for clinical testing (e.g., together with immuno-oncology agents) are needed.

SUBMITTER: Alday-Parejo B

PROVIDER: S-EPMC6678560 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

Alday-Parejo Begoña B Stupp Roger R Rüegg Curzio C

Cancers 20190712 7

Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the αV family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis. In addition, integrins promote events in the tumor microenvironment that are critical for tumor progression and metastasis, including tumor angiogenesis, matrix remodeling, and the recruitment of immune and inflammatory cells. In spite of compelling ...[more]

PMID: 31336983

Similar Datasets

Project description:As hematopoietic progenitors supply a large number of blood cells, therapeutic strategies targeting hematopoietic progenitors are potentially beneficial to eliminate unwanted blood cells, such as leukemic cells and immune cells causing diseases. However, due to their pluripotency, targeting those cells may impair the production of multiple cell lineages, leading to serious side effects such as anemia and increased susceptibility to infection. To minimize those side effects, it is important to identify monopotent progenitors that give rise to a particular cell lineage. Monocytes and monocyte-derived macrophages play important roles in the development of inflammatory diseases and tumors. Recently, we identified human monocyte-restricted progenitors, namely, common monocyte progenitors and pre-monocytes, both of which express high levels of CD64, a well-known monocyte marker. Here, we introduce a dimeric pyrrolobenzodiazepine (dPBD)-conjugated anti-CD64 antibody (anti-CD64-dPBD) that selectively induces the apoptosis of proliferating human monocyte-restricted progenitors but not non-proliferating mature monocytes. Treatment with anti-CD64-dPBD did not affect other types of hematopoietic cells including hematopoietic stem and progenitor cells, neutrophils, lymphocytes and platelets, suggesting that its off-target effects are negligible. In line with these findings, treatment with anti-CD64-dPBD directly killed proliferating monocytic leukemia cells and prevented monocytic leukemia cell generation from bone marrow progenitors of chronic myelomonocytic leukemia patients in a patient-derived xenograft model. Furthermore, by depleting the source of monocytes, treatment with anti-CD64-dPBD ultimately eliminated tumor-associated macrophages and significantly reduced tumor size in humanized mice bearing solid tumors. Given the selective action of anti-CD64-dPBD on proliferating monocyte progenitors and monocytic leukemia cells, it should be a promising tool to target cancers and other monocyte-related inflammatory disorders with minimal side effects on other cell lineages.

Dataset Information

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

Publications

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets