Faculty Feature: Todd Miller, PhD

Todd Miller

Todd Miller, PhD, joined MCW in 2023 as a Professor of Pharmacology & Toxicology and Pathology, and as Co-Leader of the MCW Cancer Center’s Discovery and Developmental Therapeutics (DDT) Research Program. He was previously a Professor of Molecular & Systems Biology at the Dartmouth Cancer Center within the Geisel School of Medicine at Dartmouth College, and served as the Co-Director of the center’s Research Program in Cancer Signaling, Genomes & Networks, and as Scientific Director of the Comprehensive Breast Program.

For nearly two decades, Dr. Miller has dedicated his research to the identification of cancer signaling pathways and the development of targeted therapies for breast cancer—the most common and most lethal non-smoking-related type of cancer among women in the U.S. In the Miller Laboratory, investigators aim to understand the causes of drug resistance in the disease, and to develop improved treatment strategies to prevent and overcome it. Their work spans the spectrum of basic cancer biology, through translational studies in mouse models and human tissues, and engages with early-phase clinical trials.

Dr. Miller’s expertise as a translational researcher, professor, mentor, and MCW Cancer Center leader will help build important collaborations that are critical for turning scientific discoveries into real-life benefits for patients with cancer. Learn more about Dr. Miller and view his full list of research publications.

Q&A with Todd

What excites you about being part of the MCW Cancer Center and DDT program?
I’m excited to share in the vision of a renowned cancer center that (A) translates laboratory research findings into clinical studies, and (B) takes clinical observations back to the laboratory for mechanistic study, all with the goal of improving disease management for patients.

As Co-Leader of the DDT program alongside Dr. William Drobyski, I can help bring together scientists and physicians to create translational research collaborations across different cancer types, leveraging laboratory discoveries to inform clinical studies, and taking clinical observations back to the laboratory to understand mechanisms.

What challenges currently exist in breast cancer research and how are MCW cancer scientists working to address them?
Our research addresses two of the key phases in the breast cancer disease process: early-stage drug tolerance and late-stage endocrine resistance. To gain a better understanding of these phases, investigators in the Miller lab are working on projects that:

  1. Investigate how normal breast epithelial cells turn into cancer cells, and how cancer cell fate and sensitivity to chemotherapeutics can be directed.
  2. Identify metabolic changes that enable cancer cells to survive standard drug treatments, with the goal of developing metabolism-directed treatment strategies to target residual disease.
  3. Decipher the mechanism by which estrogens can elicit anti-cancer effects in late-stage endocrine-resistant disease to understand how to therapeutically apply estrogens in the clinic.

What role does precision medicine play in breast cancer treatment?
Precision medicine is important for improving therapeutic benefit in most cancer types. In breast cancer, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) have served as biomarkers for decades to inform drug selection. Genetic testing for inherited mutations in breast cancer susceptibility genes (e.g., BRCA1/2) has been important for understanding cancer risk, and now also informs the likelihood of response to select classes of drugs, such as PARP inhibitors. Most recently, genetic profiling of tumor tissue or tumor-derived “cell-free DNA” in blood has been developed to inform the selection of drugs targeting specific tumor mutations. With the introduction of immunotherapies for subtypes of breast cancer, biomarker assays to determine the types of immune cells within tumors have been developed.

What promising new breast cancer treatment is your lab working to develop?
While anti-estrogens are mainstay treatments for patients with ER+ breast cancer, estrogens have also been shown to elicit therapeutic effects. Our lab conducted preclinical research that showed the tumor size in mice would be controlled long-term through pulsatile administration of 17β-estradiol. Based on these findings, I co-developed the POLLY clinical trial to test the efficacy of alternating 17β-estradiol and anti-estrogen therapies in patients with metastatic ER+ breast cancer. During the study, we observed clinical benefit (a combined measure of tumor shrinkage or stabilization for at least 24 weeks) in 8 of 19 patients.

We genetically profiled tumor specimens to see if any mutations were predictive of benefit. Interestingly, the two patients who experienced tumor shrinkage within the first 8 weeks of 17β-estradiol treatment had tumor mutations in the ER gene. While such mutations are known to confer resistance to anti-estrogens, the reason they may cause sensitivity to 17β-estradiol remains unknown—the lab has now developed a new project to address this question. Based on the clinical observations from POLLY, we launched the ESTHER clinical trial to determine whether patients with ER-mutant tumors are more likely to benefit from 17β-estradiol therapy than patients with ER-normal tumors. We are hoping to open this phase 2 trial at MCW shortly.

View the lab’s full list of ongoing breast cancer clinical trials.

Can you share a patient story that has impacted your perspective of breast cancer?
Despite 70+ years of evidence to the contrary, estrogens are portrayed in popular culture as fertilizer for breast cancer. Even my scientific mentors said estrogens were not therapeutic. It was not until I observed toxic effects on breast cancer cells in a dish and in mice that I thought estrogen therapy could be beneficial given the right context.

The first patient in our POLLY trial had previously participated in several studies I was involved in, so I was familiar with her disease history and tumor genetics. She had lived with metastatic disease for many years and been treated with multiple lines of anti-estrogens and chemotherapies. Within 8 weeks on 17β-estradiol, her lung metastases shrank and I thought, “wow, it really worked!” Her tumor grew a little during subsequent anti-estrogen treatment, so she was switched back to 17β-estradiol and remained on treatment for several months. After a scalp metastasis developed, she had to go off the trial; however, I believe her lung metastases were being controlled by 17β-estradiol. She was treated with another drug and eventually her tumors grew through that drug. Her physician treated her again with 17β-estradiol and her tumors remained stable for several months, indicating that 17β-estradiol can be “recycled” as multiple lines of therapy.

Read more about the promising effects of 17β-estradiol and anti-estrogen therapies in Clinical Cancer Research.