Leaders in Cancer Drug Discovery
DONEHOWERSoon after the Johns Hopkins Kimmel Cancer Center opened its doors in 1977, it became one of the first comprehensive cancer centers to receive a grant to begin clinical trials of new drugs. Our experts quickly earned recognition as they aggressively tested the limits and power of existing drugs, and invented new agents when what we had failed to get the job done.
Today, the combination of drug therapy, radiation therapy and surgery is a mainstay of cancer therapy. However, in 1973, there was no such thing as combined therapies.
“There weren’t very many drugs, and the ones we had didn’t work well and were very toxic. There was no formal drug development program at that time. There wasn’t even much of a solid tumor program,” says Ross Donehower, one of the Cancer Center’s first medical oncologists and a drug discovery researcher. “The Center had three medical oncologists working on solid tumors. The solid tumor program began to grow in the 1980s, and drug development fostered the expansion.”
Launching Drug Discovery
COLVINThings started to change with Michael Colvin and his foundational work in deciphering the activity of the cancer drug cyclophosphamide and how to use it in bone marrow transplant.
Colvin recruited Donehower, who worked with another Center medical oncologist, David Ettinger, to win a grant from the National Cancer Institute to conduct clinical trials of new cancer drugs.
Many in the fledgling field of oncology scoffed at the idea of a drug discovery program, and took little notice when the Kimmel Cancer Center earned a grant from the National Cancer Institute for phase I trials of new drugs, Ettinger remembered. The prevailing thought at the time was that viruses were the likely cause of cancer, and antiviral drugs were the only thing worth studying. Although we had wonderful expertise in Paula Pitha Rowe, Nancy and Joel Shaper, and others, who were conducting pioneering research in the study of viruses and cancer, Kimmel Cancer Center researchers did not place artificial boundaries on improving the understanding and treatment of cancer.
ETTINGER“That was what was so special about our center. There was always support and encouragement to be innovative. We take it for granted, but this truly is an amazing place of healing and discovery,” said Ettinger.
The drug discovery grant Donehower and Ettinger submitted led to one of the most promising new anticancer drugs of the time, Taxol. It was the first drug Donehower studied.
Mold, Dirt and Bark
In the early days of cancer drug discovery, scientists looked everywhere for compounds and chemicals that contained the power to destroy the immortal cancer cell. They collected mold, dirt and plants, and even scraped organisms from the bottom of boats in search of new chemicals and compounds that could attack and kill cancer cells.
Taxol was no exception. It was made from the bark of the Pacific yew tree, and shown by researchers at other medical institutions to be effective against cancer cells.
In 1984, it was heralded as the most promising new drug in the battle against cancer in more than 15 years. However, it might not have made its way to patients if not for Donehower’s ingenuity and determination. The problem was that, although the drug was effective against cancer, it was too toxic to give to patients. It caused severe side effects in about one-third of patients, says Donehower.
Fixing Taxol
The promising drug was headed for abandonment when Donehower worked with Johns Hopkins allergists to develop premedications that allowed Taxol to be safely given to patients.
Donehower, who says he always enjoyed taking on tough problems, was driven by a desire to take care of people who really needed help and could benefit from research rooted in clear-headed thinking and compassion. Al Owens, the Center’s first director, called it science in human service, he says.
Eric Rowinsky, another recruit of Colvin’s, and ovarian cancer expert Bill McGuire drew national attention when they began to show in clinical studies that Taxol was effective against ovarian cancer, a cancer type that was in great need of new therapies.
Reporters descended upon the Kimmel Cancer Center when one clinical study showed that 30% of women taking the drug experienced a 50% decrease in tumor size.
McGuire became the national study chair of ongoing trials of Taxol, and Rowinsky worked to improve its effectiveness even further, launching a new clinical trial of the drug in combination with the anticancer drug cisplatin and a white blood cell stimulating growth factor called GCSF. Other clinical studies followed.
That was what was so special about our center. There was always support and encouragement to be innovative. We take for granted, but this is truly an amazing place of healing and discovery,"
Ettinger
Expanding the Benefit
Taxol remains a mainstay of cancer therapy, and is now used as a treatment for additional cancers, including breast and lung cancers.
Today, gynecologic cancer expert Stéphanie Gaillard, in collaboration with ovarian cancer and drug discovery experts Deborah Armstrong, Ie-Ming Shih and Tian-Li Wang, leads new studies of the drug.
“Taxol is critical in the treatment of gynecologic cancers, including ovarian, uterine and cervical cancers,” says Gaillard, director of gynecologic cancer trials and co-director of the developmental therapeutics/phase I clinical trials program.
The drug is typically given in combination with the anticancer drugs carboplatin or cisplatin, and she is working to figure out why some patients’ cancers grow resistant to the drug combination.
Gaillard, who studied mechanisms of treatment resistance in ovarian cancer during her fellowship training from 2009 to 2012, is focused on helping patients whose cancers come back after initial therapy.
Although Taxol continues to provide a good response in about 20% of patients, Gaillard wants to see if she and her colleagues can figure out how to expand the benefit to more patients.
She identified a protein called SYK that was present at high levels in in tumors that have recurred after prior exposure to Taxol. In laboratory studies, cells from recurrent tumors continued to grow, even in the presence of Taxol. However, when Taxol was combined with an SYK inhibitor — a drug that blocks the protein’s function — ovarian cancer tumor cell growth was blocked.
Although a SYK inhibitor has been FDA approved for the treatment of an auto-immune condition, it has never been used in combination with Taxol. In 2018, Gaillard launched a Phase 1 study to determine the appropriate dose of the SYK inhibitor, fostamatinib, to use in combination with Taxol for the treatment of platinum-resistant ovarian cancer.
The study team found that the combination of drugs was tolerable to patients and identified a dose to move forward in future studies. While this small study of 27 patients was not large enough to rigorously evaluate the efficacy of the combination, treatment results were promising with partial response (measured as at least 30% tumor reduction) seen in 39% of patients and stable disease in an additional 28% of patients.
“We are encouraged by these results and hope future studies will confirm that this combination is an improvement over what we’ve seen historically,” she says.
Gaillard says new research is aimed at understanding how levels of SYK correlate with response to treatment and how low levels may interfere with response. She is also looking at other cellular factors that might predict response to Taxol.
“It is a long process, but shows how continued work can make an already useful drug more successful,” she says.
The Best in the World
CARDUCCIIt is studies like these that have earned the Kimmel Cancer Center its reputation as a leader in drug development.
“Our clinical infrastructure grew around drug development,” says Donehower. “In the beginning, there was no recognition for drug development, and now we are known for it.”
Like Gaillard, a new generation of drug discovery researchers has taken on the charge, including Michael Carducci and Nilofer Azad, among many others.
Our experts continue to be among the best in the world at discovering cancer-promoting changes that can be targeted with therapy, finding or developing drugs that promise to go after the cancer target, and developing tests — known as assays — that show whether the drug is having its intended effect on the target.
“We are seeing things happening now we would have never expected in 1973,” says Donehower. “Melanoma patients, lung cancer patients, virtually no one back then lived five years. Now, because of targeted drug therapies, immunotherapy and other drug discoveries, these patients are living many years with advanced cancers.”
AZADStill, he is not content to rest on prior successes. The bold and adventurous spirit of inquiry remains strong. “We have to continue to look for better drugs and better targets,” says Donehower. We must look beyond to the next great discovery.”
Ross Donehower Honored for Training Leadership
In addition to his pioneering work in drug discovery, for the last three decades, Ross Donehower served as director of the Medical Oncology and Hematology Fellowship Training Program.
“Every year, I’m amazed by the incredibly talented group of people we have an opportunity to interview for positions in our hematology and oncology fellowship program. They come from a wide variety of backgrounds with varied interests. We provide a robust clinical training that prepares them to treat patients, but we also give them a strong research base. When they leave our program, they are prepared for anything,” says Donehower, reflecting on his tenure as fellowship program director.
A reception was held in his honor at the 2023 annual meeting of the American Society of Clinical Oncology.
Kristen Marrone, who was co-director of the fellowship training program, was appointed director.
Ross Donehower Honored for Training Leadership
In addition to his pioneering work in drug discovery, for the last three decades, Ross Donehower served as director of the Medical Oncology and Hematology Fellowship Training Program. “Every year, I’m amazed by the incredibly talented group of people we have an opportunity to interview for positions in our hematology and oncology fellowship program. They come from a wide variety of backgrounds with varied interests. We provide a robust clinical training that prepares them to treat patients, but we also give them a strong research base. When they leave our program, they are prepared for anything,” says Donehower, reflecting on his tenure as fellowship program director. A reception was held in his honor at the 2023 annual meeting of the American Society of Clinical Oncology. Kristen Marrone, who was co-director of the fellowship training program, was appointed director.