ANTI-ADHESION Evolves To a Promising Therapeutic Concept in Oncology

Abstract

Adhesion is a hallmark of haematological and solid cancer cells. All five classes of cell adhesion molecules (CAM) - integrins, cadherins, immunoglobulin-like CAMs, selectins and CD44s - are characteristically dysregulated in human cancer. Adhesion enables and promotes cancer-defining biological processes like growth, survival, migration, extravasation, homing, and metastasis. Furthermore, cell adhesion mediates drug resistance (CAM-DR) in multiple myeloma, malignant lymphoma, acute and chronic leukaemias, as well as in pancreatic cancer, neuroblastoma, small cell and non-small cell lung cancer, mesothelioma, colorectal carcinoma, and breast cancer. Cell adhesion protects from death by radiation, genotoxic chemotherapy, or targeted pathway inhibitors. Adhesion molecules are overexpressed on drug resistant cells (e.g. multiple myeloma or prostate cancer). Very recently, several cell adhesion mediated survival pathways have been elucidated, with key mediators being LFA-1, VLA-4, FAK, ILK, Src, PI3K, Akt, Ras, MEK, Erk, HMG-CoA reductase, Rho, Rho kinase, PKC, and NFkB. Because the surface and the intracellular targets are now known and because specific compounds are becoming increasingly available, first clinical trials regarding ANTI-ADHESION therapies are ongoing. However, in comparison to the comprehensive preclinical and clinical knowledge about CAMs, the number of drugs developed thusfar is quite low. ANTI-ADHESION strategies include targeting of surface antigens, inhibition of cell adhesion associated pathways, inhibition of CAM-DR, and targeted drug delivery. As ANTI-ADHESION is based on general characteristics of cancer cells independent of specific disease entities or treatment modalities, it may become a successful, low-toxic and broadly applicable concept in cancer treatment.

Discovery of Very Late Antigen-4 (VLA-4, α4β1 Integrin) Allosteric Antagonists

“…This resulted in 20 M test compounds (6.7 M final in 15 l). Compounds were added to 320 wells (columns [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Column 2 was used for the negative control (no VLA-4 ligand added).…”

“…It participates in antigen presenting cell-lymphocyte interactions, retention and mobilization of immature progenitors in the bone marrow (1,2), cancer cell trafficking, metastasis, and other events (3,4). Integrins represent an attractive target for several existing drugs for treatment of inflammatory diseases, anti-angiogenic therapy, and anti-thrombotic therapy (5)(6)(7). Integrin ligands can also be used as imaging tools, as well as probes for studies of integrin functional activity and molecular conformation (8,9).…”

The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin

“…In addition, the enhanced expression of VLA-4 on melanomas correlates with poor clinical outcome [16][17][18]. A lot of efforts have been invested into inhibition of adhesion receptors of the selectin or integrin family and thereby intervention in metastasis [19].…”

The Novel, Proteasome-Independent NF-κB Inhibitor V1810 Induces Apoptosis and Cell Cycle Arrest in Multiple Myeloma and Overcomes NF-κB–Mediated Drug Resistance

“…NF-κB promotes growth, survival, and drug resistance in multiple myeloma cells (6). Moreover, NF-κB upregulates adhesion molecules and promotes cytokine secretion in both multiple myeloma cells and bone marrow stromal cells, thus contributing to cell adhesion-mediated drug resistance (7)(8)(9). Accordingly, inhibitors of IKKβ inhibit multiple myeloma cell growth (10)(11)(12) and first NF-κB inhibitors have been shown to induce apoptosis in multiple myeloma cells (6,13).…”