What are Invasion and Metastasis in Cancer?

What are the targeted therapies for invasion and metastasis?

There are several proteins and cellular signals that tumor cells employ for promoting invasion and metastasis. Many therapies targeting invasion and metastasis are in development.

TGF-B inhibitors

Transforming growth factor beta (TGF-B) is a protein (cytokine) secreted by all types of white blood cells. TGF-B family has many proteins that play multiple roles in regulating cell growth, differentiation, migration, apoptosis and extracellular matrix production.

TGF-B proteins play a role in inhibiting growth in the initial stages of tumor, by releasing inflammatory cytokines. Genetic mutations in the cancer cells disrupt the TGF-B signaling pathways and negate the inhibitory effect. TGF-B also suppresses immune response to promote healing which helps the tumor evade immune surveillance and grow.

Other roles of TGF-B include promotion of epithelial-to-mesenchymal transition, formation of new blood vessels (neo-angiogenesis) and extracellular matrix, and migration, which enable the tumor cells to invade other tissue and metastasize. Many types of cancer have been found to secrete increased levels of TGF-B.

Both small molecule inhibitors and monoclonal antibody therapies targeting TGF-B inhibition are in clinical trials.

IGF-1R inhibitors

Insulin-like growth factor (IGF) is a signaling pathway that regulates fetal growth. IGF-1, IGF-2 and insulin are hormone molecules that attach to their respective protein receptors (IGF-1R, IGF-2R, IR) on cell surfaces and activate them. IGF-1R regulates the growth of skeleton and other organs in the fetus, while IR regulates the glucose metabolism in the cell.

Both IGF-1R and IR stimulate cell division and have been found to promote metastasis in many types of cancers. Several IGF-1R inhibitors and IR inhibitors are in various stages of clinical trials.

SRC SMI

The proto-oncogene c-SRC encodes SRC protein, a type of intracellular protein known as non-receptor tyrosine kinase (NRTK). A proto-oncogene is a gene that has a high potential for causing cancer if it mutates into an oncogene.

SRC kinases play an important role in cell division, adhesion, migration, invasion and metastasis. High levels of SRC proteins have been found in many types of cancers.

Following are the FDA-approved small molecule inhibitor therapies targeting the SRC protein:

• Dasatinib: Approved for two types of invasive/metastatic cancers:
• Bosutinib: approved for chronic, accelerated or blast-phase Philadelphia positive chronic myeloid leukemia

The above two therapies are also being evaluated for treating other metastatic cancers. Many other small molecule inhibitors are in clinical trials.

FAK inhibitors

The focal adhesion kinase (FAK) is a type of non-receptor protein kinase that regulates signaling pathways essential for cell adhesion, migration, proliferation and death. FAK also acts as a scaffold for connecting the cells to the extracellular matrix.

When stimulated by growth factors, FAK activates many other proteins including the SRC protein, promoting metastasis. Excessive levels of FAK are found in many types of cancer. Currently, small molecule inhibitors of FAK are in early-phase of trials.