Metformins in Triple-Negative Breast Cancer Immunotherapy

Institution: University of California, Los Angeles
Investigator(s): Richard Pietras, M.D., Ph.D. -
Award Cycle: 2018 (Cycle 24) Grant #: 24IB-0058 Award: $187,358
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2018)

Non-technical overview of the research topic and relevance to breast cancer: Breast cancer (BC) survival has improved in recent years due to use of modern targeted therapies, but there remain subsets of patients that do very poorly. One of these is termed the triple-negative breast cancer (TNBC) subtype because these tumors lack expression of estrogen, progesterone and HER2 receptors on routine clinical testing. Consequently, patients with TNBC cannot be treated with targeted therapies such as antiestrogens (tamoxifen) or Herceptin (trastuzumab). Although initially responsive to some cytotoxic chemotherapies (such as taxanes), most TNBCs tend to relapse and metastasize early, leading to poor survival. TNBC occurs in only about 15% of all BCs, yet it accounts for a disproportionately large number of all BC deaths. These patients tend to be younger and are often African American. The prevalence of TNBC among premenopausal African American women is about 39% as compared to 16% among non-African American women. The poorest survival is reported in non-Hispanic African American women with advanced disease with a 5-year survival of only 14%. Work is urgently needed to develop targeted therapies for highly aggressive TNBC subtypes. An important set of findings from recent epidemiologic, preclinical and clinical studies suggest that a drug widely used to treat type 2 diabetes mellitus – metformin (Glucophage®) - exerts significant anticancer activity in BC. Diabetic patients treated with metformin have a reduced incidence and better outcome from BC. In particular, TNBC cells are especially sensitive to metformin with profound biologic and molecular effects likely to have translational relevance. The high growth rate of TNBCs requires enormous energy supplies to maintain tumor progression, and metformin appears to cut critical energy supply lines. In neoadjuvant clinical trials, metformin slows breast tumor cell proliferation based on pathologic studies after surgical resection, but clinical benefit of metformin appears to be dose-dependent. As in preclinical laboratory studies, the dose of metformin needed for optimal killing of TNBC cells appears to exceed the drug levels that can be safely achieved in clinic. To remedy this problem, we have made small changes in the structure of metformin to markedly amplify its anticancer activity at lower doses while maintaining its safety profile. Moreover, we find that the new metformin derivatives also work indirectly to ‘unmask’ TNBCs and allow tumor recognition and elimination by the immune system. These novel metformins may thereby improve and enhance the clinical benefit of immune checkpoint inhibitors that currently show antitumor activity in only a fraction of TNBC patients in the clinic.

The question(s) or central hypotheses of the research: We hypothesize that drug-like structural analogues of the antidiabetes drug metformin can be developed with more potent anticancer activity and safety than parental metformin. A few promising metformin analogues never made before that exhibit superior anti-TNBC effects will be assessed in order to advance the best antitumor candidates to clinical trials if found safe and potent in eradicating TNBC. Further, we will test the additional hypothesis that these metformin analogues have beneficial interactions with the immune system to promote TNBC cell killing and elimination.

The general methodology: Beginning in the chemistry laboratory, we will prepare metformin analogues expected to yield potent new anticancer agents. Using a structure-TNBC activity study design, biologic effects of these analogues will be tested in the oncology laboratory to find if analogues block critical tumor cell signal transduction pathways, suppress TNBC growth and increase killing (apoptosis) of TNBC cells in vitro. Feedback from biologic studies will be used to modify drug structures or formulations as needed to achieve optimal antitumor efficacy and minimal toxicity to normal tissue. Based on results of in vitro work, final drug candidates will be selected to assess optimal antitumor efficacy in preclinical TNBC models in vivo. A major aim is to validate preliminary findings showing that metformin analogues promote antitumor actions indirectly by interactions with specific immune cells such as immune suppressor cells and tumor-infiltrating lymphocytes that ‘unmask’ TNBCs to allow tumor recognition and attack by the immune system or immune checkpoint inhibitors.

Innovative elements of the project and potential impact: Early metastasis, resistance to most current therapies and strong dependence on glucose metabolism for progression is common in TNBC, and the need for new therapeutic approaches is urgent. Our preliminary work provides evidence that a metabolism-based approach using novel metformin analogues never made before yields potent anticancer activity in TNBC. Further, interactions of these analogues with the natural immune system and with immune checkpoint inhibitors may well allow a significant breakthrough in TNBC management leading to increased patient survival.