Novel Agents that Simultaneously Downregulate Her2, EGFR, and Her3
Abstract
Approximately 20%-25% of human breast cancers overproduce the HER2 protein. HER2 drives the growth of these cancers, and high levels of the HER2 protein correlate with poor prognosis. Patients with HER2-positive cancers benefit from the drug Trastuzumab (Herceptin), which is an antibody that inactivates the HER2 protein. There are two major problems with the current standard of care for HER2-positive breast cancer. First, Trastuzumab is only marginally effective unless combined with cytotoxic drugs such as taxanes or anthracyclines, and these combination therapies are associated with significant toxicities. Second, many patients ultimately fail standard therapies due to primary or acquired drug resistance and progress to metastatic disease. Clearly, new drugs are needed for the treatment of HER2-positive breast cancer to combat drug-resistant cancers and to replace cytotoxic drugs with safer, more effective agents. A major source of drug resistance derives from the fact that HER2 does not function alone to drive tumor growth and metastasis, but cooperates with family members HER3 and EGFR (HER1), and EGFR and HER3 can maintain tumor growth even if HER2 activity is blocked. Stopping the growth of HER2-positive cancers, therefore, may require simultaneously inactivating HER2, EGFR, and HER3. Our analysis of how these three HER-family proteins fold into the shape that is required for their biological activities revealed patterns of chemical repeats that are common among the family members. We hypothesized that drugs that target the common chemical patterns among the HER-family members would selectively kill the cancer cells that are dependent on these proteins without harming normal tissues. Consistent with this expectation, a compound that was selected based on its ability to decrease the levels of HER2, EGFR, and HER3 in parallel strongly blocked the growth of human breast tumor xenografts with no indication of any toxic effects. Similarly, cell culture experiments indicated that this class of compounds does not affect the proliferation of normal breast cells, but strongly suppresses the replication of breast cancer cells that overproduce the HER2 or EGFR proteins. Overall, our preliminary results indicate that this new class of anti-cancer drugs may have several advantages over currently used agents. These drugs can be produced cheaply and in large quantity. This class of drugs was initially investigated for its ability to protect experimental animals from radiation toxicity and was used at very high dosages without toxicity. Further, because of the unique mechanism of actions of these agents, they may be useful in combination with existing drugs such as Trastuzumab, and this combination therapy may be sufficiently effective so that cytotoxic drugs such as taxanes and anthracyclines are not needed. The two major goals of this project are directed toward collecting the critical information needed to advance these new drugs targeting HER2/EGFR/HER3 into clinical trials to benefit patients with HER2-positive breast cancer. The first goal is to produce different versions of these drugs to ensure that the drug that we advance for clinical studies has maximal effectiveness and lacks toxicity. These efforts will also include studies to more precisely define how these agents produce their anti-cancer effects and to use this information in the optimization efforts. The second major goal of this project is to examine the ability of these drugs to block the growth of human breast tumors transplanted directly from cancer patients into experimental animals and to determine whether these drugs are effective against breast tumors that have become resistant to Trastuzumab-based therapies. These studies will be carried out by a complementary team of investigators. Dr. Law has expertise in the areas of cancer biology, experimental therapeutics, and the study of the biochemical pathways involved in breast cancer initi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510199
Entities
People
- Brian K Law
Organizations
- United States Army
- University of Florida