A new targeted therapy for breast cancer

Institution: Scripps Research Institute
Investigator(s): Xiaohua Wu, Ph.D. -
Award Cycle: 2017 (Cycle 23) Grant #: 23IB-0020 Award: $290,250
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2017)

Non-technical overview of the research topic and relevance to breast cancer: Breast cancer patients urgently need effective new therapies with minimal side effects or toxicity. In the new era of Precision Medicine, our new knowledge about breast cancer offers a great hope for tumor-specific targeted therapy. For example, the synthetic lethality strategy is a tumor-specific targeted therapy that kills cancer cells with minimal toxicity to normal breast cells. This strategy takes advantage of a vulnerability in breast cancer cells and uses inhibitors or drugs to inactivate another related biological pathway, thereby efficiently killing the breast cancer cells. Since normal cells do not have this vulnerability, they are not affected by the inhibitors or drugs. This strategy has shown promise in the treatment of BRCA1 or BRCA2-deficient breast tumors using PARP inhibitors, but is limited to only a small fraction of breast cancer patients with BRCA1 and BRCA2 defects. We strive to develop a new tumor-specific therapy broadly effective for majority of the breast cancer patients.

The question(s) or central hypotheses of the research: We propose a new “broad spectrum” synthetic lethality strategy based on the DNA repair pathways preferably utilized in breast cancer cells. DNA polymerase Q (PolQ) is a “backup” DNA repair enzyme which is dispensable in normal cells. However, PolQ is overexpressed in a large percentage of breast cancers (~70%) especially those with poor prognosis, suggesting its important role in tumor cells. What is unique in cancer cells is they are under “oncogene-induced replication stress”, which is caused by expression of tumor specific genes, and thus requires special care from a checkpoint protein called ATR to protect their genome to avoid generating too many DNA breaks. Meanwhile cancer cells also need Pol Q to fix DNA breaks generated by replication stress. When there are too many DNA broken ends to be fixed in time, tumor cells die. Generating many DNA breaks when ATR activity is inhibited is a vulnerability of breast cancer, because tumor cells rely on PolQ to survive. In normal cells, however, withdrawing ATR function would not cause too many breaks and PolQ is not essential for the cells to live. We thus hypothesize that combination of inhibiting PolQ and ATR will have lethal effect on breast cancer cells while sparing the normal cells. Since PolQ overexpression is associated with a large percentage of breast cancer, this strategy would be effective for a wide range of patients.

The general methodology: We will use a number of PolQ-overexpressing breast cancer cell lines which represent different types of breast cancer as model systems for our study. We will inhibit PolQ by a technology called RNA interference and simultaneously inhibit ATR with ATR inhibitors to test our synthetic lethality strategy, which is designed to effectively eradicate breast cancer cells with minimal toxicity to normal breast cells. We will also use mouse tumor models to verify our work. Furthermore, we will find out which part of PolQ is most important for its ability to rescue tumor cells from ATR inhibition. This knowledge will help to design small molecule inhibitors for PolQ to use as treatment drugs.

Innovative elements of the project and potential impact: Our proposal is innovative and significant as it provides a novel strategy to treat a broad spectrum of breast cancers with minimal toxicity to normal breast cells. First, we take advantage of a vulnerability of breast cancer cells by targeting specific DNA repair pathways that breast cancer cells, but not normal breast cells, prefer to use. Second, PolQ is at abnormally high levels in 70% of breast cancers, and such high levels correlates with poor prognosis. Therefore, our proposed treatment strategy can potentially benefit majority of breast cancer patients. Third, PolQ contains enzymatic activities and is an ideal target for developing effective inhibitor drugs and our study will provide scientific basis for drug development. Finally, ATR inhibitors are already in clinical trials to treat other types of cancer. This will help speed up the translation of our findings to clinic use.