Long-term clinical benefit from adjuvant anti-cancer therapies is often determined by their ability to eliminate residual, clinically dormant disease that otherwise causes cancer recurrence. Clinically dormant cancer cells are undetectable by routine clinical methods, so the biology underlying their drug-resistant phenotype is practically unknown. Thus, understanding how such cells persist despite approved therapies will reveal new strategies to eliminate them. Estrogen receptor-positive (ER+) breast cancer patients are treated adjuvantly with anti-estrogen therapies that suppress, but do not eliminate, clinically dormant cancer cells. In our novel preclinical models of clinical dormancy in ER+ breast cancer, we have implicated the metabolic regulator AMP- activated protein kinase (AMPK) activity in the persistence of clinically dormant ER+ breast cancer cells. Conflicting reports have documented AMPK as both tumor-suppressive and oncogenic depending on cellular context. As such, the role(s) of AMPK in cancer is complex and unresolved. Nonetheless, the AMPK activator metformin, which is approved for the treatment of type II diabetes, is being tested clinically as an anti-cancer agent for breast and other cancers. Data from prospective clinical trials testing metformin have given conflicting results; Metformin treated neoadjuvantly has demonstrated anti-proliferative effects on breast tumors in some clinical studies, but not others. Precision oncology requires identification of the right drug for the right patient at the optimal time, but the optimal time during a disease course to implement an anti-cancer drug is often not tested preclinically; this gap creates a disconnect between drugs shown to prevent disease progression in the advanced setting, and their ability to prevent recurrence in the adjuvant setting. Based on preliminary findings, we propose that the timing of metformin treatment will be essential for efficacy as an anti-cancer agent. We hypothesize that the bipartite nature of AMPK as a tumor suppressor and promoter can be exploited therapeutically to eliminate clinically dormant ER+ BC cells, prevent cancer recurrence, and suppress tumor growth. We will test this hypothesis through the following Specific Aims: 1) Determine whether AMPK activity enables the survival of ER+ breast tumor cells during treatment with estrogen deprivation therapy; 2) Determine whether AMPK activation prevents recurrence of ER+ breast tumors. Results gleaned from these studies will offer therapeutic strategies to target clinically dormant breast cancer cells. Understanding the role of AMPK in the persistence of clinically dormant breast cancer cells despite anti-estrogen therapy, and in actively growing tumors, will reveal whether AMPK is a viable target for inhibition or activation clinically, and the optimal stage(s) of disease progression for targeting AMPK. Findings from these studies will also shape interpretation of the results on ongoing clinical trials testing metformin.

Public Health Relevance

Anti-estrogen therapies prevent cancer recurrence in patients with estrogen receptor-positive (ER+) breast cancer, but ~1/3 of patients ultimately develop advanced/metastatic disease that is rarely cured with approved therapies. Anti-estrogens likely elicit clinical benefit in part by suppressing the outgrowth of, but not eliminating, disseminated/micrometastatic breast cancer cells, keeping them in a ?clinically dormant? state. We will use our novel models of clinical dormancy in ER+ breast cancer to identify mechanisms underlying the persistence of dormant cancer cells, and therapeutic strategies to eradicate such cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA220936-01
Application #
9396844
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schmidt, Michael K
Project Start
2017-08-01
Project End
2021-01-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Social Sciences
Type
Schools of Arts and Sciences
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755