Cancer Projects
Targeting the Estrogen Receptor for Metastatic Breast Cancer Therapy
As part of the Bolton/Thatcher collaboration, we established significant literature in design, synthesis, mechanism, and metabolism of ER modulators, notably benzothiophene ligands related to raloxifene. This unique and holistic understanding is now permitting us to design novel ligands for estrogen receptors (ER), which are capable of tissue selective partial agonism, antagonism, and degradation (SERDs and PROTACs). We pursued these ligands as breast cancer therapeutics. Although ER+ breast cancer is well treated with endocrine therapy and increasing classes of targeted therapeutic agents, resistance to therapy occurs in more than half of patients, leading to metastatic disease: the majority of breast cancer victims have ER+ disease. Two distinct therapeutic approaches, have led to drugs from our labs completing clinical trials, a ShERPA and a selective ER degrader (SERD). A brain-SERD (BSERD) is poised for IND studies to treat breast cancer patients with brain metastases who have very poor prognosis and no targeted therapies.
See Publications 3, 4, 72-86.
Epigenetic modulators in cancer therapy
See Publications 2, 68, 81, 87-89.
The development of SERDs, B-SERDs, and ShERPAs was driven by breast cancer cell lines resistant to endocrine therapy and resistant to the newer targeted therapeutics, fulvestrant and Cdk4/6 inhibitors (e.g. Palbociclib). All our work uses drug-resistant cell lines with the intent to discover new treatments for metastatic breast cancer, since adjuvant endocrine therapy is one the successes of targeted therapeutics for cancer, resulting in up to 50% of women never progressing to metastatic disease. Indeed, the SERM tamoxifen, standard-of-care for premenopausal women with ER+ breast cancer, is considered the first targeted therapy for any cancer. Since BET bromodomain proteins enhance the transcriptional effects of ER signaling, we developed BET inhibitors to treat these resistant tumors. BET proteins are epigenetic readers binding to acetylated histones to stabilize transcriptional complexes at DNA. Although effective in Palbociclib-resistant breast cancer, our BET inhibitors have proven most impressive in combination with checkpoint inhibitors in pancreatic cancer and in non-cancer indications, such as fibrosis (unpublished). Both the effects in pancreatic cancer and fibrosis derive from regulation of the immune response. Other immuno-oncology projects are approaching the role of MLK3 and other kinases in T-cell activation and sensitization to checkpoint inhibitors in collaboration with Ajay Rana at UIC; aiming for a dual kinase inhibitor for therapy of solid tumors. In a project recently initiated at UA, we are collaborating with Tim Marlowe (UA, Phoenix) to discover small molecules that inhibit the scaffolding function of the FAT domainof focal adhesion kinase (FAK). Evidence suggest that such compounds will induce apoptosis in some cancer cells and may share the phenotype of BET inhibitors in inhibiting fibrosis and activating the host immune system to immunotherapies, such as checkpoint inhibitors. In earlier work, we studied the chimera of a SERM with HDAC inhibition as an alternative epigenetic modulator.