Potential New Drug Therapy for Breast Cancer

Institution: University of California, San Francisco
Investigator(s): Jack  Youngren , Ph.D. -
Award Cycle: 2002 (Cycle VIII) Grant #: 8WB-0099 Award: $199,740
Award Type: STEP Award
Research Priorities
Innovative Treatments>New drug design: creative science



Initial Award Abstract (2002)
New drugs are needed to treat breast cancer patients whose tumors do not respond to traditional therapy such as surgery, radiation, chemotherapy and sex hormone therapy. The aim of this research is to test a potential new class of anti-breast cancer agents. The insulin-like growth factor receptor (IGF-IR) a protein that is located on the surface of almost all cells, and plays a role in regulating cell growth. However, in breast cancer cells, evidence indicates that increased activity of this protein plays a key role in the initiation of growth of these cancers. Thus, if the activity of this receptor could be blocked, it is possible that cancers could be controlled. We have recently made the observation that certain synthetic chemical compounds block the activation of the IGF-IR in the test tube. Experiments using cancer cells and normal cells indicate that these chemicals inhibit the stimulating effects of IGF-IR on cell growth. Thus, these compounds are potential new agents for breast cancer.

This proposal is designed to provide evidence that small molecule inhibitors of the insulin-like growth factor-1 receptor will provide a novel treatment approach for breast cancer. These studies are designed to first identify the most effective of this class of compounds to inhibit growth of tumor cells, and then demonstrate the ability of these compounds to block the growth of breast cancer tumors in mice. We hypothesize that the compounds with a high ability to block the function of the IGF-IR will prove to be highly effective anti-cancer agents in animals.

We plan to perform more extensive studies in cell cultures to carefully identify the actions of these potential anti-tumor agents, and identify the compounds which are most potent at blocking the function of the IGF-IR without affecting other receptors or cellular functions. We will do this by adding compounds to breast cancer cells growing in culture and attempting to stimulate their growth with IGF and other hormones. We will determine the effectiveness of the compounds by measuring both IGF-IR activity and growth of the cells. We will also test whether the compounds kill off either normal or tumor cells. We will then test the most promising compounds by injecting them in mice with breast cancer tumors and measuring the tumor size over 3 to 6 weeks.

We believe, therefore, that these studies will provide new insights into the biology of breast cancer growth, and possibly lead to the development of a new class of drugs for the treatment of breast cancer.


Final Report (2004)
Breast cancer is a major cause of death in the US, and new drugs are needed to treat patients that do not respond to traditional therapy such as surgery, radiation, chemotherapy and sex hormone therapy. The aim of our research proposal was to test a potential new class of anti-breast cancer agents. The insulin-like growth factor receptor (IGF-IR) is a protein that is located on the surface of almost all cells, and plays a role in regulating cell growth. Activation of the IGF-1R contributes to the development of breast cancers cells, as well as stimulating the growth of these cells. Further activation of this receptor promotes the survival of breast cancer cells, limiting the effectiveness of several therapies. It is our goal to develop small molecules that inhibit the activity of this receptor so that breast cancer growth and survival can be controlled. Initially we observed that certain synthetic chemical compounds block the activation of the IGF-IR in cultured breast cancer cells and reduce cell growth. We then designed our proposal to further develop small molecule inhibitors of the insulin-like growth factor-1 receptor as a novel treatment approach for breast cancer. These studies were designed to first identify the most effective of this class of compounds to inhibit growth of tumor cells, and then demonstrate the ability of these compounds to block the growth of breast cancer tumors in mice. To accomplish these aims we screened a larger library of structurally related compounds to find the most potent chemical structures against the IGF-1R. In addition, we performed more extensive studies in cell cultures to carefully identify the specific cellular actions of these potential anti-tumor agents. Finally, we tested several compounds in mice bearing breast tumors to demonstrate that inhibition of the IGF-1R with these compounds could reduce the growth of breast tumors within the body.

To identify the most potent compound with which to inhibit the IGF-1R we synthesized and screened over 200 additional compounds for their effectiveness against cells containing the human IGF-1R protein. Two different compounds with slightly different structures, PQ401 and NDGA were then tested for their effects on breast cancer cells grown in culture and in tumor-bearing mice. Our studies in cells indicated that PQ401 was approximately 5 times more potent than NDGA at inhibiting the growth of cultured breast cancer cells. We demonstrated that some of this effectiveness could be attributed to the ability of PQ401 to block the signaling pathway whereby IGF-1R promotes cell survival. In fact, we observed that blocking the IGF-1R with PQ401 produced the programmed cell death response known as apoptosis in breast cancer cells. In contrast, a compound with a very similar structure that was ineffective against the IGF-1R did not have deleterious effects on cells, indicating the specificity of this response. Next, we demonstrated that both PQ401 and NDGA were able to significantly reduce the growth of breast tumors in mice.

Our studies have demonstrated the potential for small molecule inhibitors of the IGF-1R to impair the growth of breast cancer cells in culture and in vivo. In addition we have generated a large amount of information concerning the relationship between the chemical structure of diaryl urea compounds and their effectiveness against the IGF-1R. Our future studies will focus on the further development of diaryl ureas as potential agents against breast cancer.


Symposium Abstract (2003)
The goal of this project is to develop small molecule inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) will provide a novel treatment approach for breast cancer. IGF-1R is a transmembrane receptor tyrosine kinase regulating cellular proliferation, survival, and maturation. It is activated by its ligand IGF-1 (the IGF-1R undergoes autophosphorylation of the beta subunit, which activates its substrate tyrosine kinase activity). The tyrosine kinase activity of the IGF-1R activates several other proteins that are implicated in cell division and protection from cell death (apoptosis). High IGF-1 levels have been associated with an increased risk of developing cancer and a poorer prognosis. We hypothesize that the compounds with a high ability to block the function of the IGF-IR will prove to be highly effective anti-cancer agents.

We performed an initial screening in a cell based assay and selected the class of compounds diarylurea for further study due to the potent inhibitory effect of several of these compounds on the IGF-1R, and their minimal effect on the structurally related insulin receptor. DAU 21834 was the most potent compound tested of this class. In whole cell studies, DAU 21834 inhibited IGF-1R autophosphorylation in MCF7 cells with an IC50 of 1.7ug/ml. Furthermore, DAU 21834 inhibited autophosphorylation of purified IGF-1R kinase domain at concentrations as low as 0.1ug/ml. DAU 21834 inhibited cell proliferation in MCF7 cells by 93.3%, and the related compound DAU 17381 inhibited cell proliferation by 70%. Both compounds inhibited cell proliferation in MCF7 cells at an IC50 value of 5ug/ml. The structurally similar DAU 17402, which was inactive against IGF-1R activation, did not inhibit MCF7 proliferation. In contrast to results with MCF7 breast cancer cells, DAU 21834 was less effective at inhibiting growth of non-malignant MCF-10 breast epithelial cells. Preliminary toxicity studies in 20 mice suggest that both DAU 21834 and 17381 are tolerated at concentrations up to 100mg/kg injected ip. The diarylurea compounds appear to be promising new agents for the inhibition of the IGF1-R and for the treatment of breast cancer.


Symposium Abstract (2005)
The aim of our research is to test and develop a potential new class of anti-breast cancer agents. The insulin-like growth factor receptor (IGF-IR) is a protein that is located on the surface of almost all cells, and plays a role in regulating cell growth. However, in breast cancer cells, evidence indicates that increased activity of this protein plays a key role in stimulating growth and promoting survival of these cancers. By blocking the activity of this receptor, it is possible that cancers could be controlled. We have recently made the observation that certain chemical compounds sharing a similar basic structure, termed diaryl ureas (DAUs), block the activation of the IGF-IR in the test tube. Our previous experiments using cancer cells and normal cells indicate that these chemicals inhibit the stimulating effects of the IGF-IR on cell growth by stopping cells from progressing through their growth cycle. We have now increased our understanding of the mechanisms whereby DAU compounds reduce breast cancer cell growth, demonstrated the effectiveness of DAUs to inhibit breast cancer growth in animals, and screened several hundred variations of the basic DAU structure to better understand the important chemical structures of this class of compounds that are responsible for their effectiveness against the IGF-1R.

In studies of cultured breast cancer cells, we have shown that DAUs block IGF-1 stimulated growth, demonstrating the specificity of DAU effects for the IGF-1 signaling system, as opposed to the effects of other growth factors present under normal cell culture conditions. To further explain the reduction in cell growth and cell number in cultured breast cancer cells, we have now shown that DAUs activate a specific programmed cell death process termed apoptosis. Initiation of breast cancer cell death occurs due to a direct inhibition of the IGF-1 regulated anti-apoptosis signaling pathway, as demonstrated by the ability of DAUs to inhibit activation of the anti-apoptotic protein BAD. In mice with breast cancer cells implanted under their skin, treatment with DAU 3 times a week produced a significant reduction in tumor growth. This demonstrates the ability of DAUs to effectively block the growth of breast tumors within the body.

In order to further increase the potency of DAUs as anti-cancer agents, and to decrease any non-specific actions of these chemicals, it is our goal to better understand the structural aspects of DAU compounds that are responsible for the ability of these molecules to inhibit the IGF-1R. We have recently synthesized and tested a library of several hundred compounds consisting of various modifications to the basic structure of the initial DAU molecules. These studies have provided us with important information to produce more effective DAU compounds for development as anti-breast cancer agents.
Nordihydroguaiaretic Acid (NDGA) Inhibits the IGF-1 and c-erbB2/HER2/neu Receptors and Suppresses Growth in Breast Cancer Cells
Periodical:Breast Cancer Research and Treatment
Index Medicus: Breast Cancer Res Treat
Authors: Youngren JF, Gable K, Penaranda C, Maddux BA, Zavodovskaya M, Lobo M, Campbell M, Kerner J
Yr: 2005 Vol: 94 Nbr: 1 Abs: Pg:37-46