Optimizing the Delivery of Antineoplastic Therapies to the Central Nervous System.

Despite significant advances in the treatment of systemic cancers, progress in the treatment of primary brain tumors has been quite modest. In addition, an increasing proportion of patients with systemic cancers are presenting with brain-only metastases. These observations highlight the critical role that the blood-brain barrier plays in preventing antineoplastic therapies from reaching the central nervous system in therapeutic concentrations. This review describes the anatomy of the blood-brain barrier and currently available methods to quantify the entry of therapeutic compounds into the brain. It also summarizes data from a variety of approaches designed to improve drug delivery to the central nervous system. These include: 1) directly placing drugs inside the blood-brain barrier (polymeric implants, convection-enhanced delivery, and intraventricular administration), 2) modifying systemic chemotherapy (by using high-dose methotrexate and intra-arterial drug administration), 3) temporary disruption of the blood-brain barrier (via use of intra-arterial mannitol, focused ultrasound, or pharmacologic agents), and 4) designing drugs that can pass through the blood-brain barrier. Given that lymphocytes readily traverse the blood-brain barrier, immunotherapy represents a novel approach to cancer therapy that is of particular interest to practitioners in the field of neuro-oncology. The efficacy of vaccines and immune checkpoint inhibitors is currently being actively investigated in patients with primary and metastatic brain tumors, as well as leptomeningeal carcinomatosis. The challenge of delivering effective antineoplastic therapies to the central nervous system remains a primary obstacle to improving outcomes in patients with primary and metastatic brain tumors.

HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells.

Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor-negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB Overexpressed HOXC10 increases S-phase-specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443-56. ©2016 AACR.