Article Details - Overview

Upon completion of this educational activity, you should be able to:

• Examine the efficacy and safety of PARP inhibitors in the treatment of breast cancer
• Evaluate early-phase data on proapoptotic TRAIL-R agonists in anticancer therapy
• Define targets in the intrinsic and final apoptotic pathways that are being exploited in anticancer therapy

Authors

Medical writer: Aarati Ranganathan, PhD; Medical writer: Tristin Abair, PhD; Reviewed by: Alex Adjei, MD, PhD; Reviewed by: D. Ross Camidge, MD, PhD; Reviewed by: Joyce O’Shaughnessy, MD

Overview and Purpose

This activity features two animated figures illustrating PARP Inhibition and the Instrinsic and Extrinsic Apoptotic Pathway. See one of these animated figures now! Login below to see more!

Current approaches to targeted therapy consist predominantly of monoclonal antibodies and small-molecule receptor tyrosine kinase inhibitors. While effective, there remain many potential targets for cancer therapy, including molecules involved in the repair of DNA damage and the regulation of apoptosis.

Repair of DNA damage caused by radiation and cytotoxic agents used in the treatment of breast cancer requires the proper functioning of several proteins, including poly(ADP-ribose) polymerase (PARP), BRCA1, and BRCA2. PARP is important in the repair of single-stranded DNA breaks, while BRCA1 and BRCA2 play a role in the repair of double-stranded DNA breaks. Mutation of BRCA1 or BRCA2 leads to increased tumor formation and confers increased sensitivity to PARP inhibition, perhaps due to synthetic lethality. This has led to investigation of several PARP inhibitors in patients with BRCA-mutated cancers as well as those with triple-negative (estrogen receptor/progesterone receptor/HER2–negative) disease, which shares a similar molecular profile with BRCA1- mutated cancers. This novel therapeutic strategy has the potential to increase treatment options for this difficult-to-treat aggressive tumor type as well as other tumors harboring mutations in DNA repair pathways.

Apoptosis is initiated by 2 independent pathways, the extrinsic and the intrinsic, that converge in the final caspase cascade, leading to cell death. Signaling from these pathways provides several opportunities for the design of anticancer therapies, and several novel apoptosis-inducing agents that have the potential to specifically target tumor cell death are currently in clinical development. These include agonistic agents that induce apoptosis through the extrinsic pathway components tumor necrosis factor–related apoptosis-inducing ligand receptor (TRAIL-R)1 and TRAIL-R2 and antisense oligonucleotides or small-molecule inhibitors of antiapoptotic regulators in the intrinsic and common apoptotic pathways. Agents in this class are in early-phase trials and have shown promising results when combined with traditional chemotherapies.

The purpose of this activity is to update physicians on recent clinical data concerning the feasibility of PARP inhibitors and inducers of apoptosis in the treatment of cancer.

Target Audience

This publication is intended for medical oncologists involved in the care of patients with solid tumors. No specific skills or knowledge other than a basic training in oncology is required for successful participation in this activity.