Elucidating the Role of Glycolysis in the Growth and Metastasis of HER2+ Breast Cancer
Abstract
Breast cancer cells need a sugar called glucose to grow more rapidly than normal healthy cells. Many breast cancers have high levels of a protein called HER2, which markedly increases the dependence of these tumors on glucose for energy and growth. The increased use of glucose in these tumors is facilitated by a group of enzymes named PFKFB1-4. We have found that members of this family of enzymes, called PFKFB3 and PFKFB4, are overproduced by HER2 positive (HER2+) breast cancers and play an important role in helping these breast cancer cells use more glucose to support their growth and spread. We have developed inhibitors of the PFKFB3 and PFKFB4 enzymes that significantly decrease glucose use and growth in these tumors without toxic side effects. We have recently found that inhibiting PFKFB3 and PFKFB4 also markedly decreases suppressive immune cells in tumors (which function to decrease good immune cells and increase tumor growth and metastasis) and increases the numbers of good immune cells in these tumors. With this project, we plan to examine the mechanisms by which PFKFB3 and PFKFB4 affect both HER2+ breast cancer cells and immune cells to fully understand the effects of PFKFB3 and 4 in HER2+ breast cancer growth and metastasis. We will also examine effects of PFKFB3 and 4 inhibitors on tumor growth and metastasis and immune cell populations. We anticipate that our experiments will prove the importance of PFKFB3 and 4 in HER2+ breast cancer cells and immune cells and also demonstrate that co-targeting PFKFB4 and PFKFB3 is highly effective in decreasing HER2+ breast cancer growth and metastasis without harmful side effects. Our proposal aims to address the program challenges by examining the roles of PFKFB3 and 4 in driving the growth of HER2+ breast cancer and by evaluating the effectiveness of inhibiting PFKFB3 and PFKFB4 with inhibitors to successfully treat and cure HER2+ breast cancer and thus ultimately revolutionize treatment for HER2+ breast cancer by replacing current treatment options by a strategy that is highly effective, less toxic and improves survival and will eliminate the mortality associated with metastatic breast cancer. Although HER2+ breast tumors are highly dependent on glucose, no drugs that target the regulation of their glucose utilization are currently available for use in patients. Our studies will examine the effectiveness of a novel treatment strategy that, importantly, has no toxic side effects, to treat these tumors. Our results will provide strong justification to develop our novel PFKFB4 inhibitor first towards evaluation in a phase 1 trial with the ultimate goal of evaluation in combination with the PFKFB3 inhibitor (already examined in a phase 1 trial) in HER2+ breast cancer patients. Based on the noted increase in tumor effector CD8+ cells caused by PFKFB inhibition, we anticipate that these agents will also be effective in combination with immune checkpoint inhibitors to produce significantly greater anti-tumor effects. We therefore anticipate that our therapy will lead to a significant improvement in outcomes and survival in HER2+ breast cancer patients within the next 5 to 10 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210767
Entities
People
- Sucheta Telang
Organizations
- United States Army
- University of Louisville