Verified by 
Carol Basbaum’s cancer story began before she had an inherited BRCA1 mutant cancer and continued after her death. It began the 1960s with the fundamental discovery of an enzyme activity called PARP and subsequent decades of basic and clinical science that built a strong base of knowledge. The long and rough terrain to travel when seeking “cures” for different cancers is unpredictable but with continued efforts are reachable. Basbaum traveled on some of these unpaved roads and this post (Part I: A Patient Becomes a Cancer Biologist and a PARP Becomes a Cancer Target) is the first part of her quest. The immediate next post (Part II: The Trials of Iniparib: Opening the door for Olaparib) is the second part of her story. Basbaum’s efforts inspire and the twists in her story instruct. Her “moonshot” story illustrates the grit it takes to deliver a cancer drug to patients and the side effects drug trial results can have on cancer drug development.
Part I: Patient Becomes a Cancer Biologist and PARP Becomes a Cancer Target
She was known as the “Queen of Mucus” but Dr. Carol Basbaum’s medical legacy was far more profound. With President Obama’s revival of “moonshots” for cancer cures, her story reminds us of what the effort to “cure” cancer can look like.
Dr. Basbaum, a well-regarded basic scientist at the University of California/San Francisco (UCSF), investigated and obsessed over the biology of how cells secrete mucus into the trachea. After she was diagnosed with ovarian cancer, she extended her studies into the biology of cancer; studies that included a cancer drug called Inipirib.
Basbaum lived and researched for over five years with her ovarian cancer. It finally took her life on April 2nd, 2005. How she was able to keep producing great research for so long while tolerating surgery and chemotherapy is a mystery. Did her love for science and mucus keep her immune system revved up? We’ll never know. What we do know is a promising “targeted” drug for ovarian cancer wasn’t available to her -- but not for the lack of trying.
Her early efforts preceded the conditional approval of Olaparib (a distant relative of Iniparib) by the Food and Drug Administration (FDA) in 2014 – almost 10 years after Basbaum’s death. The approval of Olaparib came on the heels of a promising phase II trial for patients with BRCA gene mutations. Olaparib is the first in the family of drugs to be approved that inhibit poly(ADP)-ribose polymerase (abbreviated as PARP). The drug is for treatment of advanced ovarian cancer in patients who are also carriers of BRCA mutations. Olaparib was approved as “fast track,” which means it’s conditional. If phase III data refute the phase II trial, Olaparib may be pulled -- a speedbump in the road to curing ovarian cancer.
Shortly after Basbaum’s diagnosis of ovarian cancer, her lab began investigating tobacco’s role in cancer. Down the hall was an elderly Hungarian scientist, Dr. Ernest Kun. For years he’d worked on a chemical compound that under special conditions, like Olaparib, blocked the PARP enzyme. One day Kun walked into Basbaum’s lab and said, “I can cure your cancer. I have the drug for you.” To humor him, she threw his “drug” (ultimately called Iniparib) onto cancer cells already growing in her laboratory. The cancer cells died while normal cells thrived.
The PARP enzyme activity was discovered in the 1960s and in the 1980s, the idea that inhibition of PARP activity could help cancer therapies work was born. This idea arose because scientists discovered that the PARP enzyme mended broken DNA, like an electric company called out to repair downed wires after a storm. Many types of chemotherapy and radiation are like such storms that damage DNA. Cells unable to repair enough of these DNA breaks die. Without PARP to repair the DNA, cancer therapies kill cancer cells more effectively.
Normal cells die less than cancer cells because they have backup repair systems many cancer cells lack. For example, tumors with BRCA mutations are unable to fix certain kinds of complex breaks in both DNA strands. When repairs are needed on only one strand, they are relatively easy to fix because the information on the normal DNA strand can be copied. When the PARP enzyme activity is blocked with a PARP inhibitor, single-strand DNA damage can develop into more serious double-stranded damages. The job of BRCA proteins is to fix these double-strand breaks. However, in tumors that have no BRCA function, the cancer cells can’t fix the double-strand breaks and die. Thus, when treated with a PARP inhibitor, a BRCA mutant tumor cell is defenseless to repair itself after DNA damaging chemotherapy and dies while the surrounding normal cells put up a defense, repair their DNA, and survive.
According to Basbaum’s husband, Dr. Allan Basbaum (another UCSF scientist), the topic of PARP inhibitors came up one evening at dinner with friends shortly after Basbaum had witnessed the cancer cells’ demise in her lab. One of the friends suggested “Carol and Allan need to start a company” to get the drug from Kun’s hands into patients. So, by 2002 the Basbaums, Kun and several others became the co-founders of a company ultimately called BiPar.
