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Targeted Therapies for Breast Cancer Tutorial

Inhibition of Insulin-Like Growth Factor Signaling

In This Section:

IGF Signaling in Normal Cells

The insulin-like growth factor—or IGF—signaling pathway plays an important role in normal breast development and during pregnancy and lactation. The IGF signaling pathway can be activated by two growth factors, IGF1 and IGF2. When one of these binds to an IGF1 receptor, the receptor activates downstream signaling pathways inside the cell. These signaling pathways regulate cell growth, proliferation, and differentiation.

A cross-section of a cell is shown, including the cell membrane, cytoplasm, and nucleus. There are many blue growth factors outside the cells, some labeled 'IGF1' and 'IGF2.' There are several membrane-spanning proteins.

IGF Signaling in Cancer Cells

There is strong evidence that alteration of IGF signaling plays a role in breast cancer. Preclinical studies in cell culture and animal models suggest that dysregulation of the IGF signaling pathway promotes the transformation, survival, growth, and metastasis of breast cancer cells. Epidemiologic studies have found that premenopausal women with breast cancer have high levels of circulating IGF1. And immunohistochemical staining has revealed that the IGF1 receptor is overexpressed in nearly half of all breast cancers.

A green cancer cell is shown. There are many growth factors circulating outside the cell and several membrane-spanning receptors visible. The frame is labeled, 'Premenopausal women with breast cancer have high levels of circulating IGF1.'

Furthermore, there is evidence that the IGF signaling pathway participates in crosstalk with other signaling pathways, such as those activated by EGF receptor, HER2, VEGF receptor, and mTOR.

Inhibiting IGF Signaling

There are several potential strategies for targeting the IGF pathway. One approach is to use hormone inhibitors to reduce circulating levels of IGF1 and IGF2.

A green cancer cell is shown. There are several membrane-spanning receptors visible. The number of circulating growth factors is decreased compared to the previous image. Some of the growth factors are labeled, 'Target IGF1.'

Other agents are being developed to directly target either IGF1 or the IGF1 receptor.

A green cancer cell is shown. There are several membrane-spanning receptors visible, some labeled, 'Target IGF1R.'

Several monoclonal antibodies are being developed to target the IGF1 receptor. These antibodies may prevent IGF1 or IGF2 from binding to the receptor and, thus, prevent activation of the pathway. They also appear to reduce levels of IGF1 receptor.

This image shows a cross-section of a green cancer cell in the background. An inset circle in the foreground shows a close-up view of the cancer cell with two receptors spanning the cell membrane. A purple antibody is bound to the receptors and preventing the receptors from interacting with a growth factor. An intracellular signaling pathway visible in the cell in the background is colored gray to indicate that it is inactive.

Several monoclonal antibodies directed against IGF1 receptor and small-molecule inhibitors of this receptor are currently being tested in breast cancer patients in Phase I and Phase II clinical trials. Many of these trials are testing these agents in combination with standard chemotherapy drugs, antihormone therapies, or drugs that target HER2 or mTOR.

More Information

IGF1R

The IGF signaling pathway is very complex, with a number of receptor types as well as IGF-binding proteins that modulate the interaction of IGFs with their receptors. One complicating aspect of inhibiting the IGF1 receptor (IGF1R) is its similarity to the insulin receptor. This similarity makes it particularly challenging to develop small molecules that inhibit the kinase activity of IGF1R but not the insulin receptor. However, because insulin signaling is critical for maintaining normal physiological processes, it is very important that anti-IGF1R therapies do not interfere with the insulin receptor.

The following table lists several monoclonal antibodies that target insulin-like growth factor receptor that are being studied in clinical trials.

 Research NameGeneric NameTrade NameDrug Type
IGF1R inhibitorsIMC-A12Cixutumumabn/aMonoclonal antibody
 CP-751,871Figitumumabn/aMonoclonal antibody
 AVE1642n/an/aMonoclonal antibody
 AMG-479n/an/aMonoclonal antibody
 R1507n/an/aMonoclonal antibody

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

Self Test

Questions

  1. The IGF1R is commonly mutated in breast cancer.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      There is no evidence that IGF1R mutations contribute to breast cancer. However, breast tumors may express high levels of normal IGF1R.
    2. False - Correct.
      There is no evidence that IGF1R mutations contribute to breast cancer. However, breast tumors may express high levels of normal IGF1R, leading to increased activity of the pathway.