Under the Microscope: Building on the Promise of PARP Inhibitors

Cancer drugs known as PARP inhibitors target an enzyme that repairs damaged DNA. Blocking this repair mechanism can keep cancer cells from repairing themselves and cause them to die. However, not all cancers respond well to PARP inhibitors. In particular, about half of cancers with mutations to the BRCA 1 and BRCA 2 genes (mutations found in about 10 percent of breast cancers and 15 percent of ovarian cancers) are resistant to PARP inhibitors. Many develop resistance to the therapy even after an initial positive response.

As part of its efforts to combat BRCA-related cancers, the V Foundation, in collaboration with the BRCA Foundation, supports research aimed at understanding PARP inhibitor resistance and developing new therapies to overcome it.  

Taking the brakes off immune responses

Roger Greenberg, MD, PhD, together with Kate Nathanson, MD, of the University of Pennsylvania’s Abramson Cancer Center, analyzes BRCA related cancers in order to understand the role different types of tumor cells play in resistance to PARP inhibitors.

“We are looking to identify the prevalence of PARP inhibitor resistant cells within tumors and to determine whether the body’s immune responses can be used to overcome this resistance,” said Greenberg, who received $2.1 million from the V Foundation to support the project.

Different cells within a given tumor can have different levels of sensitivity to targeted therapies. For example, cells with intact DNA repair capacity may be harder to kill with PARP inhibitors. Sometimes, these resistant cells are within the tumor before treatment begins and sometimes they result from DNA replication in the tumor, so resistance to PARP inhibitors can be acquired even after successful treatments.

Greenberg and colleagues hypothesize that immune responses triggered by DNA damage can be harnessed as a method to activate anti-tumor responses that would kill the resistant cancer cells. Based on data from their own work and other clinical studies, the team plans to use the DNA repair deficiency found in cells sensitive to PARP inhibitors to activate inflammatory and immune responses against resistant cells within tumors.

“Homologous Hope,” suspended from the glass atrium in the Perelman Center for Advanced Medicine at the University of Pennsylvania, is a sculpture that illustrates how a healthy cell repairs DNA that causes breast, ovarian and pancreatic cancers. It depicts the part of the BRCA 2 gene that is responsible for DNA repair.

“Essentially we are exploiting the communication between DNA damage and anti-tumor immune responses,” said Greenberg. “Signals from the cells sensitive to DNA-damaging agents illicit an immune response to eliminate all cancer cells within a tumor, regardless of whether or not those cells have an intrinsic DNA repair capacity.”

This process, referred to as an immune checkpoint blockade, takes the brakes off the immune system by stopping the proteins that normally keep immune responses in check, thereby releasing the body’s T cells to attack cancer cells. Although Greenberg’s work focuses on breast and ovarian cancer, this kind of immunotherapy has great potential for treating all types of BRCA related cancers, and could mean better outcomes for patients and a promising path to finding cures.

New drug combinations for better treatments

Another project aimed at overcoming PARP inhibitor resistance is led by Fiona Simpkins, MD, along with colleagues Payal Shah, MD, and Eric Brown, PhD, at the Hospital of the University of Pennsylvania. The work, supported by a $600,000 V Foundation grant, focuses on inhibiting an enzyme known as ATR kinase.

“ATR kinase is basically a shock absorber during DNA replication,” said Brown. “It stabilizes replication and gives cells time to repair. By inhibiting ATR, we are essentially taking away that signal.”

Inhibiting PARP and ATR kinase at the same time shuts down both an important DNA repair pathway and a stress response pathway, a double-whammy that’s very hard for cancer cells to recover from. When applied to BRCA related tumors, that means more cancer cells die.

In pre-clinical studies, the therapy resulted in complete tumor regression of BRCA2-associated ovarian cancer. To further evaluate the new treatment combination, Simpkins’ team is conducting a clinical study of its effectiveness in treating ovarian cancer.

Fiona Simpkins, front row center, with the research team at the Simpkins Lab, University of Pennsylvania School of Medicine. The lab works to identify novel targets and strategies to overcome drug resistance in ovarian cancer and bring these new findings to the clinic.

“Evaluation of tumor biopsies from patients on this trial will allow us to define gene and protein biomarkers associated with response to this combination treatment,” says Simpkins. “These results will help us identify patients who will respond to therapy and therefore guide future clinical trial design.”

The researchers plan to expand their approach by testing ATR inhibitors in combination with other PARP inhibitors in mice to uncover the best drug combinations for treating BRCA associated ovarian cancers. “Our ultimate goal is to develop the most effective and well-tolerated treatment for BRCA-mutated ovarian cancers for which standard therapies such as PARP inhibitors have failed,” Simpkins said. “PARP inhibitors have been a major advance in treatment, and now we want to build on that and develop something even better.”