Carey K. Anders, MD
American Association for Cancer Research
2011-2012 BCRF Project:
Assistant Professor, Breast Cancer
Lineberger Cancer Center
University of North Carolina
Chapel Hill, North Carolina
Triple negative breast cancer is an aggressive subset of breast cancer with a high rate of brain metastases and poor survival. Studies indicate progressive intra- and extra-cranial disease is diagnosed concurrently 80% of the time, underscoring the need for a systemic approach. No effective systemic chemotherapeutic is currently approved to treat patients with triple negative breast cancer brain metastases.
The primary aim of Dr. Anders's research is to improve survival, through the development and application of novel agents, for patients diagnosed with triple negative breast cancer brain metastases. To accomplish these goals, Dr. Anders plans to use a preclinical approach to test novel therapies, namely Poly (ADP-Ribose) polymerase (PARP) inhibitors and nanoparticle anti-cancer agents, in laboratory models of triple negative breast cancer.
PARP inhibitors, a class of drugs which inhibit DNA repair, have emerged as an exciting class of agents to augment the effect of chemotherapy in treating triple negative breast cancer. The physical properties of many of the clinically available PARP inhibitors allow blood brain barrier (BBB) penetration and preclinical models are confirmatory. A challenge faced in studying PARP inhibitors to treat intracranial triple negative breast cancer is the inability of most standard chemotherapeutic partners to cross the BBB. Nanoparticle formulations of anti-cancer agents have been shown in preclinical and clinical studies to enhance central nervous system delivery.
Dr. Anders hypothesizes that nanoparticle formulations of chemotherapeutics may augment the expected intracranial efficacy of PARP inhibition plus chemotherapy to treat intracranial triple negative breast cancer. To test this hypothesis, this team proposes to compare plasma, brain, and intracranial tumor disposition of the PARP inhibitor, ABT-888 (Abbott), combined with nanoparticle and non-nanoparticle chemotherapeutics in an intracranial triple negative breast cancer laboratory model. In the same model, Dr. Anders's team proposes to determine the efficacy of ABT-888 combined with nanoparticle and non-nanoparticle chemotherapeutics as measured by overall survival and reduction in intracranial tumor via luciferase-based imaging. The preclinical studies will inform the optimal study design for clinical trials testing the novel combination of PARP inhibitors with nanoparticle chemotherapeutics to treat triple negative breast cancer brain metastases.
This research team is conducting an ongoing phase II clinical trial assessing the efficacy of PARP inhibition with a non-nanoparticle chemotherapeutic known to cross the BBB to treat intracranial breast cancer. Thus, they are well-positioned to efficiently and effectively translate their preclinical findings from bench-to-bedside. This approach accelerates the development and application of novel therapies for a group of patients who, at present, has poor prognosis and meager therapeutic options.
Mid-year Progress: Triple negative breast cancer is an aggressive type of breast cancer that lacks expression of the estrogen and progesterone receptors and the HER2 protein and is over-represented among women with advanced breast cancer. Recent studies illustrate half of women with advanced triple negative breast cancer experience brain metastases. Systemic therapies capable of treating triple negative breast cancer brain metastases are limited by the paucity of anti-cancer agents capable of crossing the blood-brain barrier. Presently, there is no effective systemic therapy approved to treat patients with triple negative breast cancer brain metastases.
PARP inhibitors, a class of drugs which inhibit DNA repair, have emerged as an exciting class of agents to combine with chemotherapy to treat advanced extracranial triple negative breast cancer Dr. Anders and colleagues are comparing (1) pharmacokinetics (i.e. the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body) and (2) efficacy of nanoparticle versus non-nanoparticle formulations of doxorubicin and docetaxel, respectively, in combination with ABT-888 (a new PARP inhibitor). To date, they have tested both the pharmacologic disposition of Doxil® (doxorubicin encapsulated in a closed lipid sphere) versus doxorubicin and the efficacy of both drugs both in combination with ABT-888. Their results indicate higher brain exposure to doxorubicin when administered as Doxil® as compared to delivery as free doxorubicin. Initial efficacy studies show improvement in survival for models treated with Doxil® plus ABT-888 versus doxorubicin plus ABT-888 and to control. Their current efforts are focused on replicating our results and applying these methods to study nanoparticle docetaxel plus ABT-888.
Dr. Anders and colleagues' initial results illustrate both enhanced exposure and efficacy for Doxil® plus ABT-888 versus doxorubicin plus ABT-888 in intracranial triple negative breast cancer models. They are optimistic that their results will be translated to the clinic such that early phase clinical trials can be designed based on their preclinical findings. If successfully translated to the clinic, nanoparticle drug delivery plus PARP inhibition could represent a new treatment paradigm for women with triple negative breast cancer brain metastases.
Dr. Anders is a clinician-scientist and an Assistant Professor of Medicine at the University of North Carolina (UNC) School of Medicine, a member of both the UNC Lineberger Comprehensive Cancer Center and the UNC Breast Center. Dr. Anders's research focuses on the biology of breast cancer; during fellowship she did research examining age-specific genomic differences in human breast carcinoma. Her productivity included first author in Journal of Clinical Oncology and ten other research articles. She is currently serving as a voting member on the LIVESTRONG Young Adult Alliance Cancer Centers Working Group Steering Committee.
As a junior faculty member, she has addressed brain metastases arising from breast cancer. She has served as the Principal Investigator of a Cancer and Leukemia Group B (CALGB) Young Investigator Award examining the activation status of important oncogenic signaling pathways in human breast carcinoma brain metastases. She conceived, designed and serves as the principal investigator of a phase II, pilot study testing PARP inhibition in the setting of triple negative breast cancer brain metastases (first patient on study July, 2010). In parallel and supported by the UNC Chapel Hill Hematology Oncology K12, she has developed an intracranial triple negative breast cancer tumor model to test novel therapies, namely PARP inhibitors in combination with nanoparticle chemotherapeutics. Her BCRF-AACR Grant for Translational Breast Cancer Research award will foster the development of novel, therapeutic strategies to treat intracranial triple negative breast cancer to be tested pre-clinically at the bench and, if promising, allow for the design and conduct early phase clinical trials - a truly translational approach.