Treatment-Induced Autophagy Associated with Tumor Dormancy and Relapse
Abstract
Our finding can be broken down into three related components. I. Autophagy Dependent Tumor Dormancy. These studies indicate that use of pharmacologic agents such as chloroquine (now being tested in multiple clinical trials) could prolong chemotherapy induced cell arrest, which could contribute to a more durable disease remission. This type of transient blockade of autophagy does not affect breast tumor cell sensitivity to immunotherapy. In contrast, breast tumors that are intrinsically autophagy deficient may be more likely to contribute to recurrent disease; furthermore, a sustained knockdown of autophagy also renders the tumor cells resistant to immunotherapy. Consequently, transient inhibition of autophagy would be the preferred approach to enhance breast cancer sensitivity to chemotherapy. II. Senescence Dependent Breast Cancer Dormancy and Sensitivity to Senolytic Agents. These studies demonstrate that cells in a state of senescence are capable of proliferative recovery, which may reflect a form of tumor dormancy. Furthermore, senolytic agents have the potential to attenuate or suppress proliferative recovery, suggesting their utilization to prevent breast cancer recurrence. Ongoing studies are designed to determine the impact of the senolytic agents combined with chemotherapeutics on the recognition and elimination of breast tumor cells by the immune system. III, Epigenetic regulation of tumor cell sensitivity to chemotherapy. These studies indicate that pharmacologic inhibition of NURF (e.g. AU1) maybe effective in sensitizing breast tumor cells to chemotherapy, through both direct (cell autonomous) and indirect ( cell non-autonomous, immune mediated) pathways.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2018
- Accession Number
- AD1095698
Entities
People
- David A. Gewirtz
Organizations
- Virginia Commonwealth University