C. Kent Osborne, MD, FASCO, of the Baylor College of Medicine Dan L. Duncan Comprehensive Cancer Center, will be receiving the 2016 Gianni Bonadonna Breast Cancer Award and Lecture, in recognition of his 40-year research career dedicated to improving the effectiveness of endocrine and HER2-targeted therapies in patients with breast cancer. Dr. Osborne’s breakthrough research has led to the identification of fulvestrant as the most potent endocrine therapy in patients with breast cancer and has unraveled important insights into the mechanism of resistance to targeted endocrine and HER2 therapies.
Dr. C. Kent Osborne
“Gianni Bonadonna was a distant mentor and idol for many young oncologists, like me, in training in the early-and mid-1970s,” Dr. Osborne said in an interview with the ASCO Daily News. “Receiving this award bearing Gianni’s name is a true honor for me and represents recognition for many scientists and clinicians in our group who have worked so hard for decades with the hope that we have contributed a small piece to solving the breast cancer puzzle.”
Early Beginnings in Breast Cancer Research
After spending a year of clinical training at the National Cancer Institute (NCI), Dr. Osborne joined the research group of Marc Lippman, MD, at NCI, who worked on understanding how breast cancer progresses by combining his knowledge of endocrinology with his knowledge of cancer. Looking back, Dr. Osborne largely credits his former mentor for sparking his early interest in breast cancer research.
“The exciting emerging understanding of the biology of breast cancer that I was exposed to in the Lippman laboratory, combined with the practice-changing and exciting results of adjuvant chemotherapy coming from the studies of Drs. Bernard Fisher and Gianni Bonadonna, cemented my interest in clinical and translational research in breast cancer. I followed this path for the next 40 years,” he said.
Dr. Osborne’s initial research focused on the role of polypeptide growth factors, such as insulin, epidermal growth factor, and the insulin-like growth factors, on breast cancer development and progression. Dr. Osborne and his team demonstrated early on that breast cancer is a target for these hormones, as well as estrogen, and that targeting their pathways can inhibit breast cancer growth in experimental models.
“At the same time, we were studying how anti-estrogens work to suppress tumor growth, and we discovered that there is significant crosstalk between estrogen and growth factor signaling, such that blocking the estrogen receptors (ER) increased growth factor receptor activity, and blocking growth factor pathways upregulated ER activity, leading to ligand-independent growth,” he said.
These early findings turned the focus of his group to the “pure” anti-estrogen fulvestrant and its potential in breast cancer treatment; they subsequently found it to be the most potent endocrine therapy in xenograft models, which also worked in tumors resistant to tamoxifen. Similar effectiveness of fulvestrant was observed in human trials. “At last, fulvestrant is now being shown to be the most potent endocrine therapy in patients with breast cancer, confirming our laboratory observations of nearly 20 years ago,” Dr. Osborne said.
Preventing Resistance to Endocrine Therapy
More recently, his work has focused on understanding the mechanisms of resistance to targeted therapies in breast cancer, such as trastuzumab treatment. “We hypothesized that because the HER2 receptor was a member of a family of four receptors, all of which can activate the same downstream pathways, incomplete blockade of the receptor family by trastuzumab, which binds to and blocks HER2, might be a mechanism for resistance to that therapy by leaving other receptors in the family active to compensate,” Dr. Osborne said.
His group demonstrated that combining trastuzumab with other HER2 inhibitors, such as lapatinib, gefitinib, or pertuzumab, was capable of eradicating HER2-amplified tumors in mice.
In the clinical setting, combined therapy also proved to be much more effective than treatment with single agents. Dr. Osborne pointed out that the relatively high pathologic complete response rates seen in neoadjuvant trials with drug combinations indicate that there is a subset of patients who might not need chemotherapy at all, just targeted therapy.
Current projects in Dr. Osborne’s laboratory, which is codirected by his long-time academic partner Rachel Schiff, PhD, are focused on identifying the mechanisms of resistance to both endocrine therapy and HER2-targeted therapy. “If we can identify these escape pathways and biomarkers to predict resistance, then we can better develop new strategies to reverse or prevent resistance and improve the lives of patients with breast cancer,” Dr. Osborne said.
Dr. Osborne has authored or co-authored more than 400 research papers. He is currently director of the Dan L. Duncan Comprehensive Cancer Center and professor of medicine and molecular and cellular biology at Baylor College of Medicine. He serves on advisory committees for several cancer centers and continues to mentor students and early-career faculty.
This is the first year that the Gianni Bonadonna Breast Cancer Award and Lecture will be presented at the ASCO Annual Meeting. Attend the session on June 4.
– Jasenka Piljac Žegarac, PhD