Targeting Pol-Theta as a Novel Breast Cancer Target
Abstract
DNA often breaks in actively growing (replicating) cells due to normal cellular processes such as the complex mechanism of genome duplication. The accurate repair of DNA in replicating cells is essential for cell growth and survival and for preventing chromosome rearrangements and mutations that are known to cause cancer. Homologous recombination (HR) is a major cellular pathway that promotes the accurate repair of DNA in replicating cells. Thus, the proper function of this important pathway in growing cells is necessary for suppressing chromosome instability and cancer. For example, DNA mutations in central HR genes such as BRCA1 or BRCA2, which cause defects in HR repair of DNA, strongly predispose women to breast cancer. New studies indicate that precision medicines that are able to target BRCA-deficient breast cancer cells for killing can be developed with sufficient research funding. For example, biochemical and cellular research on the molecular mechanisms of HR has revealed particular defects in BRCA-deficient breast cancer cells that inform strategies how to specifically target these cells for killing, while sparing normal cells. Specifically, new studies show that cells defective in HR, such as due to mutations in BRCA1/2, rely upon DNA polymerase theta (Polq) — a backup DNA repair factor — for their growth and survival. In contrast, normal cells do not require Polq at all. In fact, normal human cells and mice that are deficient in Polq do not exhibit any major problems. Together, these new studies demonstrate that suppression of Polq activity specifically kills HR-deficient cancer cells, but has no effect on normal cells. Thus, drugs that specifically inhibit Polq activity are likely to target HR-deficient breast cancer cells for killing, while sparing normal cells. Since such drugs would have no effect on normal cells, they would enable a non-toxic form of breast cancer treatment. Because defects in HR are frequently observed in breast cancers, drugs that target HR-deficient cells for killing will significantly increase the survival rate of breast cancer patients. Recent studies demonstrate that Polq DNA synthesis activity is essential for the survival of HR-deficient breast cancer cells. Our objective is therefore to develop drugs that inhibit Polq DNA synthesis activity and specifically kill HR-deficient cells, such as breast cancer cells mutated in BRCA1/2 tumor suppressor genes. Successful identification and development of drugs that specifically inhibit Polq activity will undoubtedly lead to new improved treatments for patients with breast cancer. For example, such treatments are likely to specifically kill breast cancer cells that are deficient in BRCA1/2 and therefore be non-toxic to patients. Because there are currently no highly effective non-toxic treatments that specifically kill breast cancer cells, the proposed research addresses a central problem in breast cancer research. The development of Polq inhibitors is likely to lead to new and effective non-toxic treatments for breast cancer patients that can potentially replace current therapies that are highly toxic to patients and can cause permanent side effects. Thus, the proposed research is highly relevant to the vision and mission of the Breast Cancer Research Program. In summary, the successful development of Polq inhibitors represents an important and necessary step towards personalized and non-toxic breast cancer treatment and will likely yield benefits for patients within a 3- to 5-year time frame.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010031
Entities
People
- Richard Pomerantz
Organizations
- Temple University
- United States Army