New Therapeutic Targets for Breast Cancer Bone Metastasis
Abstract
Current cancer research often focuses on primary tumors alone. However, most cancer morbidity and mortality relate to metastasis, a complex process involving not only cancer cells but also their microenvironment in the host tissues such as bone. Bone metastases are frequent, debilitating, and essentially incurable consequences of breast cancer that affect approximately 70% of patients with advanced disease. This leads to severe bone pain, pathological fractures, anemia, life-threatening hypercalcemia, limited mobility, and eventually mortality. During breast cancer bone metastasis, cancer cells and the bone-degrading cells form a vicious cycle so that cancer cells promote bone cell differentiation and bone cells in turn facilitate cancer cell seeding and proliferation in the skeletal environment. Inhibition of the activity of bone-degrading cells by current anti-osteoporosis drugs can slow down bone metastasis, but these drugs are only at best palliative and do not improve overall patient survival. Moreover, some patients develop side effects such as osteonecrosis of the jaw and renal toxicity, thus better therapeutics are urgently needed. In December 2014, an inhibitor of Poly (ADP-ribose) polymerase (PARP), Olaparib, was approved by the Food and Drug Administration (FDA) for treating elapsed BRCA-defective ovarian cancer. Since then, two more PARP inhibitors also received FDA approval. Several PARP inhibitors are also currently in clinical trials as breast cancer therapy. Despite the clinical efforts on PARP inhibitors as cancer treatment, little is known about whether and how PARP impact cancer metastasis. Moreover, the functional distinctions among different PARP members are unclear. The overarching challenges that will be addressed in the proposed research are to (1) identify why some breast cancers become metastatic; (2) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; and (3) eliminate the mortality associated with metastatic breast cancer. To this end, we have identified a specific PARP member as a novel dual suppressor of breast cancer bone metastasis that inhibits both bone cells and cancer cells. In contrast, bone metastasis is not affected by another PARP member. We hypothesize that functional deficiency in certain PARP member may promote bone metastasis, and strategies to activate such PARP may more effectively block bone metastasis and reduce breast cancer mortality. In this research proposal, we will perform a series of studies to test these hypotheses by using integrated approaches and state-of-the-art technologies. This investigation is highly significant and clinically relevant because it will (1) identify a specific PARP as a powerful dual suppressor of breast cancer bone metastasis, (2) uncover potential deleterious effects of current non-specific PARP inhibitors to exacerbate bone metastasis, (3) reveal important functional distinctions between different PARPs, (4) suggest subtype-specific PARP inhibitors as better and safer options, and (5) highlight the therapeutic potential of subtype-specific PARP activation to effectively mitigate bone metastasis. The outcome of the proposed research will help all breast cancer patients, especially patients with advanced and metastatic diseases, and patients treated with PARP inhibitors. We envision that multiple benefits can be harnessed from the proposed research for the better prevention and treatment of metastatic complications, which will ultimately alleviate breast cancer mortality. Once our proposed preclinical studies are successful, this project can be immediately advanced to clinical development and application. The PARP-focused multi-investigator team at the University of Texas Southwestern Medical Center for both basic and clinical research, as well as the vast existing toolbox for PARP modulation, will facilitate the rapid translation of our discoveries to pa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810014
Entities
People
- Yihong Wan
Organizations
- United States Army
- University of Texas Southwestern Medical Center