Novel Tools to Improve Responses to DNA-Damaging Therapeutics in Metastatic Breast Cancer
Abstract
DNA-damaging chemotherapies and radiation are commonly used in cancer management, including breast cancer. These include drugs and radiation that cause DNA double strand breaks (DSBs) in both cancer cells and normal cells, and unfortunately these agents can cause substantial side effects due to their effects in normal cells. The doses of DNA-damaging agents are already maximized in terms of what patients can tolerate. Another emerging class of treatment is called an antibody drug conjugate (ADC). These are antibodies that recognize antigens or proteins on the surface of cancer cells and in most cells these antigens are not present on the surface of non-cancer cells. After the ADC binds the cancer cell surface, it is internalized, and an attached (conjugated) drug is released into the cancer cell. These ADCs have demonstrated clinical efficacy in breast adenocarcinomas and non-small cell lung cancers. A total of 11 ADCs are now U.S. Food and Drug Administration-approved, including several in breast cancer. However, many conventionally used DNA-damaging agents in oncology are not suitable for use as ADC payloads because they lack the drug potency required. In this proposal, we seek to further develop novel ADC molecules with small molecule inhibitors of the DNA-damage response (DDRi). We propose that in this format, taking advantage of the tumor-targeting nature of an ADC, a broad range of systemically administered DNA-damaging therapies that induce DSBs can be rendered more effective if the DDR is selectively inhibited in antigen-expressing cancer cells. In preliminary data, we have synthetized ADCs containing small molecule inhibitors of the ATM kinase and DNA-PK, protein enzymes highly involved in cellular responses to DNA damage. The ATM kinase is a sensor of DSBs, activating downstream processes that help the cell survive DNA damage. The DNA-PK enzyme participates in non-homologous end joining, the most important pathway for DNA repair of two-ended DSBs and likewise enable the cell to survive DNA-damaging agents. Using complementary assays, we demonstrated high potency of these DDRi ADCs in a range consistent with clinically successful ADCs. In this proposal, we seek to create an additional category of ADC molecules with DDR inhibitor payloads and an antibody that recognizes the cell surface protein TROP2. The new therapeutics could help patients with both early and advanced breast cancer by improving the responses to these DNA-damaging agents. We believe this is a novel approach with potential to meet the overarching DOD challenge to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. In specific aim 1 (SA1), we will characterize the activity of the new ADCs in breast cancer cells with the TROP2 protein. In SA2, we will test combinations of the ADCs with DNA-damaging agents called doxorubicin, ionizing radiation, topoisomerase inhibitors, crosslinking agents, and PARP inhibitors. In SA3, we will test optimal combinations of the ADCs and DNA-damaging agents in mouse models of metastatic breast cancer. The overall goal of this proposal is to develop a novel means of improving the efficacy of DNA-damaging agents with the tumor-targeting nature of an ADC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310533
Entities
People
- Daniel Higginson
Organizations
- Sloan-Kettering Institute
- United States Army