Projects

Importance of endoxifen for the treatment of ERα+ breast cancer

In collaboration with Matthew P. Goetz, M.D., we were the first to demonstrate the clinical relevance, importance and unique mechanisms of action of endoxifen, a primary metabolite of tamoxifen, for the treatment of estrogen receptor alpha-positive (ERα+) breast cancer. Using laboratory models, we demonstrated that endoxifen is primarily responsible for the anti-breast cancer effects of tamoxifen. We have described multiple primary mechanisms by which endoxifen elicits its anticancer effects and have demonstrated how and why this metabolite behaves differently from the parent compound.

We have identified novel protein targets of endoxifen and have developed the first models of endoxifen-resistant breast cancer. We are devising approaches that could be implemented to overcome resistance to this drug. We also have generated and patented endoxifen-based PROTAC molecules that have shown very promising preclinical results, not only in ERα+ breast cancer, but also in triple-negative breast cancer and ovarian cancer, where the parent compound (endoxifen) has little to no activity.

Our studies have supported the development and completion of phase 1 and phase 2 clinical trials of endoxifen therapy for ERα+ metastatic breast cancer, as well as an ongoing phase 2 neoadjuvant trial of endoxifen in newly diagnosed patients with ERα+ breast cancer. These studies have been funded by the Mayo Clinic Breast Cancer SPORE, the Susan G. Komen Foundation and the George M. Eisenberg Foundation for Charities.

Functions of ERβ in breast cancer development and treatment

We are interested in elucidating the biological functions and mechanisms of action of estrogen receptor beta (ERβ) in normal breast tissue, in the development of breast cancer and in the treatment of breast cancer. We have developed novel animal and cell models and have used thousands of patient samples to address multiple complex questions pertaining to this form of the estrogen receptor. We have done this with support from the National Institutes of Health, the Mayo Clinic Breast Cancer SPORE, the Breast Cancer Research Foundation and the George M. Eisenberg Foundation for Charities.

Our findings have revealed that ERβ functions as a tumor suppressor in breast cancer and may prevent the development of breast cancer in some settings. Results from our studies have led to the development of an ongoing phase 2 clinical trial that is examining the utility of therapeutically targeting ERβ for the treatment of triple-negative breast cancer.

CDK4/6 inhibitors for the treatment of breast cancer

CDK4/6 inhibitors have revolutionized the outcomes for patients with ERα+ forms of primary and metastatic breast cancer. However, most patients eventually develop resistance to this class of drugs and experience rapid progression with little to no response to any form of treatment, ultimately leading to death. For this reason, there is a major need to understand the basis for CDK4/6 inhibitor resistance and identify effective alternative treatments.

Using cell line and patient-derived models, with genome-wide CRISPR screens and transcriptomic analyses, we have identified unreported genes, and their pathways, responsible for resistance. These genes can be therapeutically targeted. Multiple ongoing studies focus on prioritizing resistance mechanisms and devising novel strategies to target and eliminate resistant forms of the disease.

Roles of CTPS1 in breast and ovarian cancers

Through a bioinformatic approach, we identified CTPS1 as an essential gene in triple-negative breast cancer and ovarian cancer. Using a variety of laboratory models and assays, we have confirmed the importance of this gene in these forms of cancer and have demonstrated that down-regulation of CTPS1 expression leads to cell cycle arrest in cancer cells but not in normal breast and ovarian epithelial cells.

We have partnered with Step Pharma, a drug company that recently developed the first-in-class, CTPS1-specific small molecule inhibitor and have demonstrated in vitro and in vivo activity of this compound in treating advanced forms of triple-negative breast cancer and ovarian cancer. Additional preclinical studies are ongoing that are aimed at launching a clinical trial of this drug in solid tumors.

Importance of JAK/STAT signaling in ovarian cancer

Through the use of a small molecule drug library, we identified lestaurtinib as a potent inhibitor of both chemotherapy-sensitive and chemotherapy-refractory ovarian cancers. With support from the Department of Defense, the Mayo Clinic Ovarian Cancer SPORE and the Minnesota Ovarian Cancer Alliance, we have demonstrated that lestaurtinib primarily functions by suppressing JAK/STAT signaling. Lestaurtinib and other JAK/STAT inhibitors have been shown to synergize with standard-of-care chemotherapy and PARP inhibitor regimens in cell line models and inhibit the growth of patient-derived organoid models as a monotherapy.

Given that JAK/STAT signaling also is upregulated in cancer-associated fibroblasts and involved in the reprogramming of macrophages into an M2 cancer-promoting phenotype, we are performing complex co-culture, 3D bioprinting and single cell sequencing studies aimed precisely at determining the autocrine and paracrine roles of JAK/STAT signaling in driving disease progression. We also are investigating how specific components of JAK/STAT signaling could be targeted to effectively treat ovarian cancer.

Senescence and cancer

Many cancer drugs function by inhibiting cell cycle progression and inducing a pseudo-senescent phenotype characterized by prolonged cell cycle arrest. Arrested cells, also referred to as persister cells, can survive for years, even in the presence of highly toxic treatment regimens. They also are thought to ultimately be responsible for disease relapse. Theoretically, eliminating these persister cells would cure patients with cancer.

We are leveraging knowledge from the aging field in which selective elimination of senescent cells has been shown to improve health span and lifespan without increasing the risk of cancer. Work in this field has identified a class of compounds called senolytics that function by killing senescent cells. We are working to determine if combination treatments, or alternating regimens, of cancer-specific drugs with senolytics lead to better long-term outcomes.