Use of PARP Inhibitors in the Targeted Treatment of Cancer

Goodfellow

Paul Goodfellow

From the February 2010 issue of YWBCP magazine
By Paul Goodfellow, PhD
Professor of Surgery
Washington University School of Medicine

In July 2009, Dr. Peter Fong and his colleagues reported the results of their phase 1 clinical trial to evaluate a promising new approach to treating cancers (New England Journal of Medicine;2009;361:123-134). They evaluated a new drug, oalparib, a potent PARP inhibitor in people with metastatic cancer, with a focus on individuals who had an inherited BRCA1 or BRCA2 gene mutation. The knowledge gained from this study brings us closer to tailored cancer treatment for people with an underlying mutation in specific genes or individuals whose tumors have acquired specific gene defects.

First, a Little Background Information…
Our DNA, or genetic material, is subject to continuous disruption resulting in errors in the genetic code. These errors naturally occurs as cells divide or they may result from an outside stimulus, such as radiation. Fortunately, there are several highly effective repair mechanisms or systems which serve to correct DNA damage as it happens. Each of these mechanisms targets a specific type of error in the genetic code. Poly(adenosine disphosphate [ADP]-ribose) polymerases, or PARPs, are a group of enzymes that function to correct single-strand DNA breaks. Single strand DNA breaks are only one of the several classes of errors in our genetic make-up that contribute to tumor development.

Double-strand DNA errors represent a different type of abnormality and are corrected using a different DNA repair system. Although their names make reference to breast cancer, the BRCA1 and BRCA2 genes function to repair doublestrand DNA breaks/damage.

Every person has two copies of the BRCA1 gene and the BRCA2 gene, one inherited from her Mother and the other from her Father. For a person with an inherited BRCA1 or BRCA2 gene mutation, 1 of the 2 copies does not function properly in every cell. In order for a person with an inherited mutation to develop a cancer, it is believed the 2nd copy of the gene must acquire a mutation in a single cell, leaving the cell with no BRCA DNA repair activity. In essence, a person inherits a mutation in one copy of the gene but both copies of the gene must be rendered non-functioning in a given cell in order for a cancer to develop. Since normal cells have at least one functioning copy of the BRCA1 or 2 gene, it follows that drugs could be developed that would only target cancer cells in which both copies of the gene are nonfunctional.

Note
Most of the genes associated with breast cancer in young women have yet to be identified. As these genes are identified, new targeted therapies, like olaparib, may emerge. First these genetic factors need to be discovered. Click here to learn more about our study focused on the discovery of these unknown genetic factors and how to participate.
Dr. Fong and his colleagues hypothesized if the mechanism responsible for single-strand DNA repair was inhibited in a tumor in which the double-strand DNA repair mechanism was already lost, then the cancer cells would die. This is in part because a drug to increase single strand breaks would lead to more double strand breaks that the tumors cells are unable to repair. Stated another way, if we give a drug that hinders PARPs from functioning properly in a tumor in which BRCA1 or BRCA2 has already stopped working, then the cancer cells would stop growing. Furthermore, if this hypothesis were to be correct, normal tissue would not be damaged by a drug used to inhibit PARP functioning as the drug is specifically targeting BRCA1 or BRCA2-derived cancer cells.

The drug olaparib, also known as AZD2281, had previously been shown in laboratory studies to inhibit or stop PARPs from functioning properly. Olaparib was shown to reduce PARPs from correcting specific types of DNA errors. With these data, a phase 1 clinical trial was initiated. The primary goal of a phase 1 is to identify if the drug can be safely administered with minimal side effects or toxicities.

The Phase 1 Trial…
60 people, all of whom had advanced cancer and who had previously undergone standardized therapies for their cancers, were enrolled in the study.

There were three important findings from this phase 1 trial:

  1. There was minimal drug toxicity or side effects with the use of oral olaparib.
  2. There was a significant decrease in PARP activity. That is, the drug performed its intended function, inhibiting PARP functioning.
  3. The drug demonstrated antitumor properties only in people with an inherited BRCA1 or BRCA2 gene mutation. For the purpose of a clinical trial, antitumor refers to any agent that counteracts or prevents a cancer from developing or progressing.

The primary goal of a phase 1 trial is to examine drug safety, not to evaluate clinical response. However, critical preliminary data regarding the treatment response were found. 23 of the 60 people enrolled were known to have a gene mutation and among those 19 were followed throughout the study period. 12 of the 19 people (63%) showed a clinical benefit to the treatment. For example, one woman with a BRCA2 related breast cancer, who had previously been treated for pulmonary and lymph node metastases, showed a complete remission lasting for more than 60 weeks. Another woman showed regression of brain and skin metastases. One man with a BRCA2 advanced prostate cancer was found to have resolution of his bone metastases.

These results were so promising additional phase 2 and phase 3 clinical trials are now underway. This study provides exciting preliminary data regarding the use of drugs that inhibit PARP function in the treatment of people with cancer who have an inherited BRCA1 or BRCA2 gene mutation.

This study is an important step in developing therapies which target specific inherited gene mutations that led to the development of cancer. Importantly, some cancers arise in people who do not carry a BRCA1 or BRCA2 mutation but somehow these genes are completely shut off in the tumor. Like individuals with inherited BRCA mutations, people who have lost BRCA1 or BRCA2 function in their tumors could benefit from PARP inhibitor therapy.

Clinical trials with a much greater number of people are needed to demonstrate the treatment benefit of Olaparib therapy. Furthermore, scientists will continue to investigate the reasons why not every person with a gene mutation responded to the therapy.

To learn more about clinical trials and find specific clinical trials in your area, search the NIH sponsored website, www.clinicaltrials.gov.

Reference
Fong P, et al. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors frofm BRCA Mutation Carriers. New England Journal of Medicine;2009;361:123-124.