Dr. Robert A. Nagourney, MD
NOTHING NEW UNDER THE SUN: PERSPECTIVES ON OVARIAN CANCER
Updated: Oct 18, 2021
I gave a Ted Talk entitled "The Future of Cancer Research Lies Behind Us." I was commenting on the fact that many new things are actually old, that many new ideas come from previous concepts, and that many of the most advanced scientists need to look back to the origins of their research to more clearly grasp the truths that lie within.
I am reminded of the dictum that there is nothing new under the sun when I look at modern ovarian cancer therapy. Patients who present with ovarian cancer, after surgery and chemotherapy are offered a new class of drugs known as PARP inhibitors. PARP is an acronym for an enzyme known as poly ADP ribose polymerase. It is part of the cellular processes that recognize and respond to DNA damage. This class of genes is known as the genomic fidelity genes as they maintain the true structure and function of the DNA despite the wear and tear associated with lifelong exposures.
The first recognition that this collection of enzymes existed came in 1976. The next landmark was the development of an inhibitor. Finally, investigators working at New Castle and Agouron Pharmaceutics developed the first clinical trial for this class of drugs.
The most striking observation came when two separate groups realized that patients who carry specific DNA damage repair deficiencies known as the BRCA1 and BRCA2 genes, were 250 times more sensitive to this class of drugs. This launched an entire era of therapy based on the inhibition of DNA repair and today there are 4 commercially available PARP inhibitors.
What is the origin of this class of drugs and why were they discovered? That is the story of old science becoming new again.
The earliest recognition that DNA damage would lead to clinical response came from the accidental release of a drug known as nitrogen mustard in December of 1943. When the Germans bombed the port of Bari, Italy, it released a chemical from one of the US ships in the harbor that caused serious injury to the people exposed. A specialist in chemical warfare examined the findings and recognized mustard gas exposure.
That launched an investigation into how the mustards worked and why individuals exposed showed very low white blood counts. Soon, it became evident that damaging DNA could lead to clinical response; the presumption being that damaged DNA inhibited cellular proliferation.
An intensive effort to develop derivatives of these classes drugs ensued and a dozen different compounds with related activities came to clinical use. Shortly thereafter, working in a laboratory at the Michigan State University, a doctor by the name of Barnett Rosenberg realized that a drug called cisplatin had a similar DNA damaging effect. Once again, the premise was that damage to DNA would stop cells from growing.
The mustards and then platinums became entrenched in the therapy of advanced ovarian and uterine cancers and the modern era of ovarian cancer management was born.
But what were these drugs really doing? It turns out that these drugs were damaging DNA in a way that made it very difficult for the cells to repair. It was not inhibition of growth or proliferation that resulted in the clinical benefit, but instead the induction of cell death.
In 1972, the publication of a paper in the British Journal of Cancer confirmed that chemotherapy does not stop cells from growing - it kills them outright in the process known as programmed cell death.
Now we return to the modern PARP inhibitors, the new class of drugs designed to inhibit DNA repair. But what are they actually doing to the cells that are exposed? Well, not surprisingly, these drugs cause damage that the cells cannot repair. The cells take inventory and come to the conclusion that they cannot carry on life and function normally.
It is at this point that a decision is made by the cells to sacrifice themselves in service of the organism as a whole. Cancer cells are not murdered by these drugs, they commit suicide.
We began our PARP research with a compound known 3-aminobenzamide and then years later moved to AZD 2281, the modern Olaparib. What we saw from the very start was that PARP inhibitors were not growth inhibitors: Not at all. When they worked, they killed cells outright. In fact, they acted quite a lot like the mustard and platinum drugs.
So now we see that the first chemotherapy drug ever developed is the great-great-grandfather to the most modern of therapies. We see that the cellular processes that we are preying upon today are every bit the same as those that investigators were preying upon 70 years ago.
More importantly, we see that the fundamentals of human biology supersede our scientific premises. Investigators of the 1940s were every bit as clever and insightful as our most modern researchers.
Human biology and human cancer share features that held true long before the modern era of molecular biology. Scientists require humility and context when they examine their discoveries, for it was William Shakespeare who said, "The wheel has come full circle."