A “Crazy” Idea Leads to a Revolution in Prostate Cancer Care

Eric J. Small, MD

Eric J. Small, MD, developed an appreciation for all the various flavors of humanity during his childhood in Mexico City, Mexico, as the son of American parents transplanted there for work. There, he attended an American bilingual high school, taking classes in English and Spanish, before coming to the United States for college.

“From very early on, sort of a multicultural, multilingual environment was what I knew and what I grew up in. I didn’t know it then, but it’s what made me interested in and contributed to my being a people person and being interested in how people are different,” Small said.

Small credits his parents for having the greatest influence on his childhood. His father, in particular, instilled the belief in Small and his 2 brothers that people should contribute to humanity. He stressed to them that an individual’s role in life is to make the world a better place.

“[That’s true] whether it’s been very personal things or in broad career strokes, and that, in particular, has informed me all my life,” Small said. “I’ve always felt that making a difference is important. It has informed my career, certainly.”

After completing his undergraduate degree at Stanford, Small enrolled at Case Western University School of Medicine. He went to work for Oscar D. Ratnoff, MD, a famed researcher focusing on nonmalignant hematology who discovered one of the essential blood clotting elements.

“It was really my first introduction to what we now call translational science,” Small said. “That’s when it really clicked for me that what we do in the lab can have a very direct bearing on patients.”

Ratnoff, who died in 2008, once gave Small an important bit of advice: “Bad ideas die hard.” The phrase altered Small’s perception of what should and could advance medicine.

Small receives a warm welcome from the Sichuan Provincial People’s Hospital in Chengdu, China.

“Back then, it was certainly not the place of a young whippersnapper to question how things were done, but Dr Ratnoff gave me permission to do so, which was really important,” Small said. The “bad ideas” quote now sits on a plaque on his office desk as a reminder to challenge the status quo. The sentiment has served him well, particularly in the early 2000s when he crossed paths with James P. Allison, PhD, a Nobel laureate and the 2014 Giants of Cancer Care^® award winner in translational scientific advances.

Adhesion Molecules and Scientific Milestones

As a hematology/oncology fellow at the University of California, San Francisco (UCSF), Small sought out additional training in the lab. Under the mentorship of Marc Shuman, MD, another specialist in nonmalignant hematology who turned his interest to oncology, Small studied adhesion molecules, which are situated on the surface of cells and enable binding.

In an experiment, Small used a prostate cancer cell as the negative control because the disease was not supposed to have these molecules. “It kept coming up positive, but after a lot of work, it turned out that these adhesion molecules were on the prostate cancer cells, and up until that point, that [fact] had not been appreciated,” he said.

Small brought the finding to his advisor, questioning how these molecules might affect prostate cancer growth. Not long after, the sole urologic oncologist at UCSF left the institution, creating an opening for a full-time faculty position that would allow Small to continue his research in prostate cancer. He’s been at UCSF ever since.

In the early 2000s, Small began working on sipuleucel-T (Provenge), an immunotherapeutic vaccine, as part of the prostate cancer program. Allison, then at the University of California, Berkeley, was also a member of that program.

Small hypothesized that the vaccine-like product could allow the immune system to recognize and attack prostatic acid phosphatase, a differentiation antigen found only in the prostate epithelium that is highly active in patients with prostate cancer, which would in turn result in tumor regression. His hypothesis was correct in part, but the agent did not result in substantial clinical benefit despite showing immune activity.

“It was a solid base hit,” Small said. “Although it was not a home run, we established the principle that not just prostate cancer, but solid tumors [in general], could respond to immunotherapy.”

Nonetheless, the FDA approved sipuleucel-T for men with metastatic castration-resistant prostate cancer who had no or minimal symptoms in April 2010. It was the first therapeutic cancer vaccine to win agency approval.

Shortly thereafter, Small and Allison became friends, with Small taking an interest in Allison’s laboratory work, developing what would become the first checkpoint inhibitor approved in oncology. At the time, Allison had been working with the compound in a prostate cancer cell line, and together, Small and Allison conducted the first clinical investigation into what is now known as ipilimumab (Yervoy) in one of Small’s patients with hormone-refractory prostate cancer.

“This was the very first patient treated with ipilimumab, and even with 1 dose of this drug, we saw early activity,” Small said. Findings of the drug’s activity were published in Clinical Cancer Research in 2007, launching investigations of ipilimumab in other cancer types such as melanoma and skin cancer and breaking open the field of cancer immunotherapy.

However, Small noted that they didn’t strike gold immediately. Getting grants to fund research with immunotherapy proved to be incredibly difficult. “I can’t tell you how many times I was told I was nuts for thinking that immunotherapy could possibly work in any cancer, let alone prostate cancer,” he said.

Small with his daughters, from left, Rebecca and Sarah, at Rebecca’s graduation as a nurse practitioner from UCSF.

Their hard work finally paid off in March 2011 when Allison sent Small the note from the FDA announcing the approval of ipilimumab in metastatic melanoma, making it the first checkpoint inhibitor to win agency approval and the first agent shown to improve overall survival in advanced melanoma. Today, 10 checkpoint inhibitors are approved for use across a variety of solid tumors.

“It was just so exciting to see,” Small said. Outside of immunotherapy, Small played a critical role in the development and approvals of abiraterone acetate (Zytiga) and apalutamide (Erleada), agents that inhibit the androgen receptor; they are now used across prostate cancer settings to delay the time to metastasis and prolong survival.

“We knew we had hit a major drug early on in the phase 1 trial that we did,” Small said of abiraterone. He and his team noticed dramatic prostate-specific antigen (PSA) reductions from baseline, a discovery that might have gone unnoticed had Small not decided to make note of patients’ baseline PSA levels. “I knew immediately that we had a very active drug.

“The development of this drug was really exciting, and the process after that was great, because a number of other drugs were developed very rapidly that were similar including enzalutamide [Xtandi] and apalutamide, which I had a hand in, and darolutamide [Nubeqa],” he added. “These drugs have really exploited the androgen receptor pathway so that patients can benefit substantially before the cancers develop androgen receptor independence.”

A Scientist and a People Person

Small has long had a passion for helping patients disproportionately affected by prostate cancer. His love for research and desire for human connection informs his entire career. “That combination—of being able both to do science and to engage with people and what makes them special and unique—is what ultimately led me to medicine,” he said.

Small with his cats, from left, Emme and Micah, who appear to have mixed feelings about being photographed.

In his home state of California, for example, Spanish speakers from the Central Valley have less access to prostate cancer care. Small has worked programmatically with community partners to identify, understand, and ultimately remove barriers to clinical care.

In addition to bringing equipoise to medicine, Small has also worked to elevate patient perspective and advocacy. “It’s very easy for us, especially in academia, to go off on tangents. The immediacy and urgency that patient advocates bring to the table is really important,” Small said.

One of the first patient advocates Small met at UCSF was Andrew Grove, former chief executive officer of Intel. Small recalled, “He would always come to the table with: ‘Why are you dithering around? People are dying of prostate cancer.’ He would not mince words.”

From then on, Small made every effort to engage and educate the patients he served. One of those patients eventually put him in contact with the California Prostate Cancer Coalition, an organization for patient advocates and support groups across the state. The collaboration Small helped create between UCSF and the coalition led to the development of a curriculum coupled with daylong retreats for patients and their caregivers.

“It’s incredibly gratifying because there’s a real unmet need out there for information,” Small said. So much so, that the enduring materials from last year’s symposium have garnered approximately 350,000 views on YouTube.

Although Small is still heavily invested in research, mentoring now takes up approximately 25% to 30% of his time. “We all stand on the shoulders of the people before us, and paying it forward is really important,” he explained.

Personal Passions

Outside of the clinic, Small takes particular pride in his 2 now-adult daughters. One is a nurse practitioner who works with elderly disadvantaged patients in San Francisco. Small said that he often fields questions from her about issues in health care, which makes him smile knowing that the apple didn’t fall far from the tree. The other is now a third-year law student who, although similarly scientifically oriented, has directed her interest to environmental law.

Small said that a personal passion of his— baking—took off during the COVID-19 quarantine. The extra time at home allowed him to bake bread, pastries, and cookies. You can find him baking a loaf of bread most Sunday mornings.

“Both of my daughters tell me that, if oncology ever fails me, I should open a bakery,” Small said, adding that faculty at UCSF are no strangers to his baked treats, either. “I’m constantly looking for people to give them away to because I can’t possibly have it all [at home].”

He balances any indulgence in carbohydrates with running. Years ago, fellow oncologist and genitourinary specialist, Howard I. Scher, MD, convinced him to run the New York Marathon on behalf of Fred’s Team, a philanthropy group for pediatric oncology at Memorial Sloan Kettering Cancer Center. It remains the longest distance he’s ever run. He devoted approximately 5 months of training to the marathon, relying on his older daughter’s support and posttraining breakfasts for additional motivation.

His other great passion is doting on cats, a love he developed early in his career when it became clear that the travel and long hours required of his profession would be disruptive to a dog. It’s also an interest he shares with his daughters. “There’s an iPhone group chat of my daughters and me and assorted other people, and 85% to 90% of it is cat pictures from one person or another,” Small said.

His love for the furry pets is so great that he adopted several cats who had belonged to a friend who died during the pandemic. “I’ve gained so much from it because when you’re with them, as with any animal, you’re taking care of something else. It’s not about you, and there’s something very soothing about it,” Small said.